greenmedinfo--2020-12-04--Melatonin can compensate for the adverse effects of dexamethasone on sperm parameters.

Dexamethasone is a common medicine that is capable of causing malformation in the male reproductive system .
The aim of @ @ @ @ @ the effect of melatonin on testis histological changes and Spermatogenesis indexes in adult mice following @ @ @ @ @ male NMRI mice were divided randomly into four groups : control , dexamethasone ( i.p @ @ @ @ @ , dexamethasone + melatonin and melatonin ( i.p injections , 20 mg/kg/day ) .
After @ @ @ @ @ the right testes were studied stereologically and the left testes were used to measure the @ @ @ @ @ ) .
The serum levels of malondialdehyde ( MDA ) , testosterone and total antioxidant @ @ @ @ @ also measured .
The left caudal epididymis was used to analyze sperm parameters .
Data @ @ @ @ @ ANOVA and means were considered significantly different at

Dexamethasone is a common medicine that is capable of causing malformation in the male reproductive system. The aim of this study was to investigate the effect of melatonin on testis histological changes and Spermatogenesis indexes in adult mice following treatment with dexamethasone. Adult male NMRI mice were divided randomly into four groups: control, dexamethasone (i.p injections, 7 mg/kg/day), dexamethasone + melatonin and melatonin (i.p injections, 20 mg/kg/day). After 7 days of treatment, the right testes were studied stereologically and the left testes were used to measure the daily sperm production (DSP). The serum levels of malondialdehyde (MDA), testosterone and total antioxidant capacity (TAC) were also measured. The left caudal epididymis was used to analyze sperm parameters. Data were analyzed using one way ANOVA and means were considered significantly different at < 0.05. A significant decrease in the testis volume, seminiferous tubules volume, the number of spermatocytes, round and long spermatids, Spermatogenesis indexes, sperm parameters such as motility, count, viability, tail length and DSP, serum testosterone level, TAC and the body weight was found inthe dexamethasone group compared to the control. Meanwhile a significant swelling of the interstitial tissue and a significant increase in the MDA level was found in the dexamethasone group compared to the control. The above parameters reached the control level in the dexamethasone + melatoningroup. Melatonin can compensate for the adverse effects of dexamethasone on sperm parameters and the histology of the seminiferous tubules in mice.


greenmedinfo--2020-12-04--Melatonin ameliorated CUMS-induced depression-like behavior via restoring endoplasmic reticulum stre

Melatonin ameliorated CUMS-induced depression-like behavior via restoring endoplasmic reticulum stress in rat hippocampus.

Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm .
Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression .
Recently , the melatonergic system has been implicated in the pathophysiology and treatment of depression .
In this study , we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress ( CUMS ) in rats , and its molecular mechanism was explored .
Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks .
Melatonin or saline was injected @ @ @ @ @ @ @ were detected by the open field test , sugar preference test , elevated O maze test and forced swimming test .
In addition , the plasma corticosterone level and the expression of endoplasmic reticulumstress-related protein in the hippocampus of rats were measured .
Compared with the control group , the CUMS-exposed Sprague-Dawley rats showed depression-like behavior , which was significantly improved by melatonin treatment .
Moreover , CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus .
Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by @ @ @ @ @ @ @ improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS .
This study demonstrates that melatonin can improve depression-like behavior induced by CUMS , which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus .

Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm. Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. Recently, the melatonergic system has been implicated in the pathophysiology and treatment of depression. In this study, we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in rats, and its molecular mechanism was explored. Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks. Melatonin or saline was injected intraperitoneally. Behavioral changes of Sprague-Dawley rats were detected by the open field test, sugar preference test, elevated O maze test and forced swimming test. In addition, the plasma corticosterone level and the expression of endoplasmic reticulumstress-related protein in the hippocampus of rats were measured. Compared with the control group, the CUMS-exposed Sprague-Dawley rats showed depression-like behavior, which was significantly improved by melatonin treatment. Moreover, CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus. Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by CUMS. These results suggest that melatonin improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS. This study demonstrates that melatonin can improve depression-like behavior induced by CUMS, which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus.


greenmedinfo--2020-12-04--Effects of melatonin supplementation on oxidative stress.

Objectives Previous studies showed that melatonin supplementation may suppress oxidative stress , however , the results have not been consistent .
So , we conducted this meta-analysis to assess the precise relationship between melatonin supplementation and oxidative stress .
Methods PubMed and Scopus were searched for randomized controlled trials that investigated the effect of melatonin supplementation on oxidative stress up to March 2020 .
Heterogeneity was assessed by Cochran 's Q test and I-square ( I2 ) statistic .
Data were pooled using the random effect model and standardized mean difference ( SMD ) was considered as the summary effect @ @ @ @ @ @ @ used for assessment of sensitivity analysis and publication bias .
Results We included 15 related articles and our findings indicated that melatonin supplementation significantly increased total antioxidant capacity ( TAC ) level ( SMD : 1.03 , 95 % CI : 0.24 , 1.81 , p=0.011 ) and reduced protein carbonyl ( PCO ) ( SMD : -1.78 , 95 % CI : -2.97 , -0.58 , p=0.004 ) and malondialdehyde ( MDA ) levels ( SMD : -0.94 , 95 % CI : -1.48 , -0.40 , p=0.001 ) .
Additionally , @ @ @ @ @ @ @ by using ≥20 mg/d melatonin and in people under 35 years old .
MDA level also decreased using dosage of below 20 mg/d and in people ≥35 years old .
Conclusions The present study showed a promising effect of melatonin administration for reducing MDA , PCO , and increasing TAC levels .
However , further studies especially with more attention to PCO level assessment are needed to confirm the findings of the present study in larger samples on different populations .

Objectives Previous studies showed that melatonin supplementation may suppress oxidative stress, however, the results have not been consistent. So, we conducted this meta-analysis to assess the precise relationship between melatonin supplementation and oxidative stress. Methods PubMed and Scopus were searched for randomized controlled trials that investigated the effect of melatonin supplementation on oxidative stress up to March 2020. Heterogeneity was assessed by Cochran's Q test and I-square (I2) statistic. Data were pooled using the random effect model and standardized mean difference (SMD) was considered as the summary effect size. Also, standard methods were used for assessment of sensitivity analysis and publication bias. Results We included 15 related articles and our findings indicated that melatonin supplementation significantly increased total antioxidant capacity (TAC) level (SMD: 1.03, 95% CI: 0.24, 1.81, p=0.011) and reduced protein carbonyl (PCO) (SMD: -1.78, 95% CI: -2.97, -0.58, p=0.004) and malondialdehyde (MDA) levels (SMD: -0.94, 95% CI: -1.48, -0.40, p=0.001). Additionally, there was considerable effect on TAC level by using ≥20 mg/d melatonin and in people under 35 years old. MDA level also decreased using dosage of below 20 mg/d and in people ≥35 years old. Conclusions The present study showed a promising effect of melatonin administration for reducing MDA, PCO, and increasing TAC levels. However, further studies especially with more attention to PCO level assessment are needed to confirm the findings of the present study in larger samples on different populations.


greenmedinfo--2020-12-04--First evidence of the protective role of melatonin in counteracting cadmium toxicity in the rat ovar

First evidence of the protective role of melatonin in counteracting cadmium toxicity in the rat ovary.

Herein , the first evidence of the ability of melatonin ( MLT ) to counteract cadmium ( Cd ) toxic effects on the rat ovary is reported .
Cd treatment , enhancing oxidative stress , provoked clear morphological , histological and biomolecular alterations , i.e .
in the estrous cycle duration , in the ovarian and serum Econcentration other than in the steroidogenic and folliculogenic genes expression .
Results demonstrated that the use of MLT , in combination with Cd , avoided the changes , strongly suggesting that it is an efficient antioxidant for preventing oxidative stress in the rat @ @ @ @ @ @ @ underlying mechanism involved , at molecular level , in the effects of Cd-MLT interaction , the study focused on the mTOR and ERK1/2 pathways .
Interestingly , data showed that Cd influenced the phosphorylation status of mTOR , of its downstream effectors and of ERK1/2 , inducing autophagy and apoptosis , while cotreatment with MLT nullified these changes .
This work highlights the beneficial role exerted by MLT in preventing Cd-induced toxicity in the rat ovary , encouraging further studies to confirm its action on human ovarian health with the aim to use @ @ @ @ @ @ @ women with fertility disorders .

Herein, the first evidence of the ability of melatonin (MLT) to counteract cadmium (Cd) toxic effects on the rat ovary is reported. Cd treatment, enhancing oxidative stress, provoked clear morphological, histological and biomolecular alterations, i.e. in the estrous cycle duration, in the ovarian and serum Econcentration other than in the steroidogenic and folliculogenic genes expression. Results demonstrated that the use of MLT, in combination with Cd, avoided the changes, strongly suggesting that it is an efficient antioxidant for preventing oxidative stress in the rat ovary. Moreover, to explore the underlying mechanism involved, at molecular level, in the effects of Cd-MLT interaction, the study focused on the mTOR and ERK1/2 pathways. Interestingly, data showed that Cd influenced the phosphorylation status of mTOR, of its downstream effectors and of ERK1/2, inducing autophagy and apoptosis, while cotreatment with MLT nullified these changes. This work highlights the beneficial role exerted by MLT in preventing Cd-induced toxicity in the rat ovary, encouraging further studies to confirm its action on human ovarian health with the aim to use this indolamine to ameliorate oocyte quality in women with fertility disorders.


greenmedinfo--2020-12-04--Chronobiotic effect of melatonin in experimental optic neuritis.

Optic neuritis ( ON ) is an inflammatory condition of the optic nerve , which leads to retinal ganglion cell ( RGC ) loss .
A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system ( NIFVS ) functions such as pupillary light reflex ( PLR ) and circadian rhythms .
Melatonin is a chronobiotic agent able to regulate the circadian system .
We analyzed the effect of ON on the NIFVS , and the effect of melatonin on the NIFVS alterations induced by ON .
For this purpose , optic nerves from male Wistar rats received vehicle @ @ @ @ @ @ @ and one group of animals received a subcutaneous pellet of melatonin or a sham procedure .
The NIFVS was analyzed in terms of : i ) blue light-evoked PLR , ii ) the communication between the retina and the suprachiasmatic nuclei ( by anterograde transport , and ex vivo magnetic resonance images ) , iii ) locomotor activity rhythm , and iv ) Brn3a ( + ) and melanopsin ( + ) RGC number ( by immunohistochemistry ) .
Experimental ON significantly decreased the blue light-evoked PLR , induced a misconnection between the @ @ @ @ @ @ @ Brn3a ( + ) RGCs , but not melanopsin ( + ) RGC number .
A bilateral injection of LPS significantly increased the light ( but not dark ) phase locomotor activity , rhythm periodicity , and time of offset activity .
Melatonin prevented the decrease in blue light-evoked PLR , and locomotor activity rhythm alterations induced by ON .
These results support that ON provoked alterations of the circadian physiology , and that melatonin could restore the circadian system misalignment .

Optic neuritis (ON) is an inflammatory condition of the optic nerve, which leads to retinal ganglion cell (RGC) loss. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system (NIFVS) functions such as pupillary light reflex (PLR) and circadian rhythms. Melatonin is a chronobiotic agent able to regulate the circadian system. We analyzed the effect of ON on the NIFVS, and the effect of melatonin on the NIFVS alterations induced by ON. For this purpose, optic nerves from male Wistar rats received vehicle or bacterial lipopolysaccharide (LPS), and one group of animals received a subcutaneous pellet of melatonin or a sham procedure. The NIFVS was analyzed in terms of: i) blue light-evoked PLR, ii) the communication between the retina and the suprachiasmatic nuclei (by anterograde transport, and ex vivo magnetic resonance images), iii) locomotor activity rhythm, and iv) Brn3a(+) and melanopsin(+) RGC number (by immunohistochemistry). Experimental ON significantly decreased the blue light-evoked PLR, induced a misconnection between the retina and the suprachiasmatic nuclei, decreased Brn3a(+) RGCs, but not melanopsin(+) RGC number. A bilateral injection of LPS significantly increased the light (but not dark) phase locomotor activity, rhythm periodicity, and time of offset activity. Melatonin prevented the decrease in blue light-evoked PLR, and locomotor activity rhythm alterations induced by ON. These results support that ON provoked alterations of the circadian physiology, and that melatonin could restore the circadian system misalignment.


greenmedinfo--2020-12-04--Melatonin attenuates branch chain fatty acid induced apoptosis mediated neurodegeneration.

Valproic acid ( VPA ) -a short branched chain fatty acid ( BCFA ) , is widely recognized as an @ @ @ @ @ , but various adverse effects of VPA have also been investigated .
However , the @ @ @ @ @ brain cells , in the pathogenesis of neurodegeneration remains elusive .
The objective of this @ @ @ @ @ cellular mechanisms underlying VPA-induced neuronal cell death mediated by oxidative stress , and the neuroprotective @ @ @ @ @ on VPA-induced cell death .
Neurotoxicity of VPA and protective role exerted by melatonin were @ @ @ @ @ cells and in vivo in the cerebral cortex and cerebellum regions of Wistar rat brain @ @ @ @ @ melatonin pre-treatment protects the cells from VPA-induced toxicity by exerting an anti-apoptotic and anti-inflammatory effect @ @ @ @ @ pro-inflammatory cytokines .
The findings of the present study emphasize novel insights of melatonin as @ @ @ @ @ and treatment of neuronal dysfunction induced by VPA .

Valproic acid (VPA)-a short branched chain fatty acid (BCFA), is widely recognized as an anticonvulsant and a mood-stabilizing drug, but various adverse effects of VPA have also been investigated. However, the impact of BCFAs aggregation on brain cells, in the pathogenesis of neurodegeneration remains elusive. The objective of this study is to understand the cellular mechanisms underlying VPA-induced neuronal cell death mediated by oxidative stress, and the neuroprotective role of exogenous melatonin treatment on VPA-induced cell death. Neurotoxicity of VPA and protective role exerted by melatonin were assessed in vitro in SH-SY5Y cells and in vivo in the cerebral cortex and cerebellum regions of Wistar rat brain. The results show that melatonin pre-treatment protects the cells from VPA-induced toxicity by exerting an anti-apoptotic and anti-inflammatory effect by regulating apoptotic proteins and pro-inflammatory cytokines. The findings of the present study emphasize novel insights of melatonin as a supplement for the prevention and treatment of neuronal dysfunction induced by VPA.


greenmedinfo--2020-12-04--Melatonin supplementation is useful in treating H. pylori-associated dyspepsia.

BACKGROUND : Dyspeptic syndrome is particularly common in postmenopausal women in the form of epigastric pain .
The aim of the study was to assess the role of melatonin in chronic dyspepsia in this group of women , and examine the role of Helicobacter infection .
METHODS : The study comprised 152 subjects including 30 healthy women ( Group I ) , 60 women with asymptomatic H.pylori infection ( Group II ) , and 64 women with H. pylori infection with chronic dyspepsia ( Group III ) .
Endoscopic examination was performed , as well as histological assessment of gastric @ @ @ @ @ @ @ ( UBT-13C ) , and immunoenzymatic assessment of serum 17-β-estradiol , follicle stimulating hormone and melatonin , and urinary 6-sulfatoxymelatonin .
In Group III , 14-day antibacterial treatment was introduced with pantoprazole , amoxicillin and levofloxacin followed a six-month treatment with placebo in 32 women ( Group IIIa ) , and melatonin 1 mg/morning and 3 mg/at bedtime in the other 32 women ( Group IIIb ) .
RESULTS : No significant differences were found between serum level of female hormone .
Serum melatonin levels were similar between Group I ( 12.5 ± @ @ @ @ @ @ @ 10.5 ± 3.73 pg/ml ; p > 0,05 ) .
The level was significantly lower in Group III ( 5.72 ± 1.42 pg/ml ; p 0.05 ) .
After six months , dyspeptic symptoms resolved in 43.7 % patients in Group IIIa and 84.3 % in Group IIIb ( p CONCLUSION : Melatonin supplementation is useful in treating H. pylori-associated dyspepsia , particularly in postmenopausal women with lower levels of this hormone .

BACKGROUND: Dyspeptic syndrome is particularly common in postmenopausal women in the form of epigastric pain. The aim of the study was to assess the role of melatonin in chronic dyspepsia in this group of women, and examine the role of Helicobacter infection.
METHODS: The study comprised 152 subjects including 30 healthy women (Group I), 60 women with asymptomatic H.pylori infection (Group II), and 64 women with H. pylori infection with chronic dyspepsia (Group III). Endoscopic examination was performed, as well as histological assessment of gastric end duodenal mucosa, urease breath test (UBT-13C), and immunoenzymatic assessment of serum 17-β-estradiol, follicle stimulating hormone and melatonin, and urinary 6-sulfatoxymelatonin. In Group III, 14-day antibacterial treatment was introduced with pantoprazole, amoxicillin and levofloxacin followed a six-month treatment with placebo in 32 women (Group IIIa), and melatonin 1 mg/morning and 3 mg/at bedtime in the other 32 women (Group IIIb).
RESULTS: No significant differences were found between serum level of female hormone. Serum melatonin levels were similar between Group I (12.5 ± 2.72 pg/ml) and Group II (10.5 ± 3.73 pg/ml; p > 0,05). The level was significantly lower in Group III (5.72 ± 1.42 pg/ml; p < 0.001). Eradication of H.pylori was obtained in 75.0% women in Group IIIa, and in 84.3% in Group IIIb (p > 0.05). After six months, dyspeptic symptoms resolved in 43.7% patients in Group IIIa and 84.3% in Group IIIb (p < 0.001).
CONCLUSION: Melatonin supplementation is useful in treating H. pylori-associated dyspepsia, particularly in postmenopausal women with lower levels of this hormone.
TRIAL REGISTRATION: NCT04352062, date of registration: 15.04.2020.


greenmedinfo--2020-12-04--Melatonin is promising in the management of prostate cancer metastasis.

Prostate cancer has high metastatic potential .
Men with higher urinary levels of the sleep hormone melatonin are much less @ @ @ @ @ cancer compared with men with lower levels of melatonin .
Melatonin has shown anticancer activity @ @ @ @ @ , the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery @ @ @ @ @ Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 ( MMP-13 @ @ @ @ @ prostate cancer patients than in healthy cancer-free individuals .
Mechanistic investigations revealed that melatonin inhibits @ @ @ @ @ and invasive capacities of prostate cancer cells via the MTreceptor and the phospholipase C , @ @ @ @ @ cascades .
Importantly , tumor growth rate and metastasis to distant organs were suppressed by @ @ @ @ @ cancer model .
This is the first demonstration showing that melatonin impedes metastasis of prostate @ @ @ @ @ in both in vitro and in vivo models .
Thus , melatonin is promising in @ @ @ @ @ metastasis and deserves to undergo clinical investigations .

Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP-13) expression are higher in prostate cancer patients than in healthy cancer-free individuals. Mechanistic investigations revealed that melatonin inhibits MMP-13 expression and the migratory and invasive capacities of prostate cancer cells via the MTreceptor and the phospholipase C, p38, and c-Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP-13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.


greenmedinfo--2020-12-04--Melatonin restricts the periodontitis-induced inflammatory stress, apoptosis, and structural but not

BACKGROUND : Two main aims of this animal study were to inspect the possible effects of periodontitis on the structure and functions of the kidneys and the therapeutic effectiveness of melatonin .
METHODS : Twenty-four male Sprague-Dawley rats were randomly divided into three groups : control , experimental periodontitis ( Ep ) , and Ep-melatonin ( Ep-Mel ) .
Periodontitis was induced by placing 3.0-silk sutures sub-paramarginally around the cervix of right-left mandibular first molars and maintaining the sutures for 5 weeks .
Then melatonin ( 10 mg/kg body weight/day , 14 days ) , and the vehicle was administered @ @ @ @ @ @ @ were obtained following the euthanasia .
Periodontal bone loss was measured via histological and microcomputed tomographic slices .
On right kidney histopathological and immunohistochemical , and on the left kidney biochemical ( malonyl-aldehyde [ MDA ] , glutathione , oxidative stress [ OSI ] , tumor necrosis factor [ TNF ] -α , interleukin [ IL ] -1β , matrix metalloproteinase [ MMP ] -8 , MMP-9 , and cathepsin D levels ) evaluations were performed .
Renal functionalstatus was analyzed by levels of serum creatinine , urea , cystatin-C , and urea @ @ @ @ @ @ @ ligature-induced periodontal bone loss ( P < 0 .01 ) and suppressed the levels of proinflammatory cytokines ( TNF-α and IL-1β ) , oxidative stress ( MDA and OSI ) , and proteases ( MMP-8 , MMP-9 , and CtD ) that was significantly higher in the kidneys of the rats with periodontitis ( P < 0.05 ) .
In addition , periodontitis-related histological damages and apoptotic activity were also significantly lower in the Ep-Mel group ( P < 0.05 ) .
However , the markers of renal function of the Ep group @ @ @ @ @ @ @ the control group ( P > 0.05 ) ; and the therapeutic activity of melatonin was limited ( P > 0.05 ) .
CONCLUSION : Melatonin restricts the periodontitis-induced inflammatory stress , apoptosis , and structural but not functional impairments .

BACKGROUND: Two main aims of this animal study were to inspect the possible effects of periodontitis on the structure and functions of the kidneys and the therapeutic effectiveness of melatonin.
METHODS: Twenty-four male Sprague-Dawley rats were randomly divided into three groups: control, experimental periodontitis (Ep), and Ep-melatonin (Ep-Mel). Periodontitis was induced by placing 3.0-silk sutures sub-paramarginally around the cervix of right-left mandibular first molars and maintaining the sutures for 5 weeks. Then melatonin (10 mg/kg body weight/day, 14 days), and the vehicle was administered intraperitonally. Mandibular and kidney tissue samples were obtained following the euthanasia. Periodontal bone loss was measured via histological and microcomputed tomographic slices. On right kidney histopathological and immunohistochemical, and on the left kidney biochemical (malonyl-aldehyde [MDA], glutathione, oxidative stress [OSI], tumor necrosis factor [TNF]-α, interleukin [IL]-1β, matrix metalloproteinase [MMP]-8, MMP-9, and cathepsin D levels) evaluations were performed. Renal functionalstatus was analyzed by levels of serum creatinine, urea, cystatin-C, and urea creatinine.
RESULTS: Melatonin significantly restricted ligature-induced periodontal bone loss (P <0 .01) and suppressed the levels of proinflammatory cytokines (TNF-α and IL-1β), oxidative stress (MDA and OSI), and proteases (MMP-8, MMP-9, and CtD) that was significantly higher in the kidneys of the rats with periodontitis (P <0.05). In addition, periodontitis-related histological damages and apoptotic activity were also significantly lower in the Ep-Mel group (P <0.05). However, the markers of renal function of the Ep group were detected slightly impaired in comparison with the control group (P >0.05); and the therapeutic activity of melatonin was limited (P >0.05).
CONCLUSION: Melatonin restricts the periodontitis-induced inflammatory stress, apoptosis, and structural but not functional impairments.


greenmedinfo--2020-12-04--Melatonin alleviates benzo(a)pyrene-induced ovarian corpus luteum dysfunction by suppressing excessi

Melatonin alleviates benzo(a)pyrene-induced ovarian corpus luteum dysfunction by suppressing excessive oxidative stress and apoptosis.

Benzo ( a ) pyrene ( B ( a ) P ) is a widespread persistent organic pollutant ( POP ) and a well-known endocrine disruptor .
Exposure to BaP is known to disrupt the steroid balance and impair embryo implantation , but the mechanism under it remains unclear .
The corpus luteum ( CL ) , the primary source of progesterone during early pregnancy , plays a pivotal role in embryo implantation and pregnancy maintenance .
The inappropriate luteal function may result in implantation failure and spontaneous abortions .
Therefore , this study was conducted to assess the effects @ @ @ @ @ @ @ ) P on the CL function .
Our results showed that pregnant mice received B ( a ) P displayed impaired embryo implantation and dysfunction of ovarian CL .
The estrogen and progesterone levels decreased by B ( a ) P. In vitro , exposure to BPDE , which is the metabolite of B ( a ) P , affected the luteinization of granular cell KK-1 .
Additionally , melatonin and its receptors , which are important for ovarian function and anti-oxidative damage , were affected by B ( a ) P or @ @ @ @ @ @ @ or BPDE-treated alone impaired antioxidant capacity of ovarian granulosa cells , caused an increasing of ROS and cell apoptosis , and disrupted the PI3K/AKT/GSK3β signaling pathway in vivo and in vitro .
Co-treatment with melatonin alleviated B ( a ) P or BPDE-induced CL dysfunction by ameliorating oxidative stress , counteracting phosphorylation of PI3K/AKT/GSK3β signaling pathway , decreasing the apoptosis of the ovarian cells .
Moreover , activation of the melatonin receptor by ramelteon in KK-1 cells exhibits an analogous protective effect as melatonin .
In conclusion , our findings not only firstly @ @ @ @ @ @ @ dysfunction , but also extend the understanding about the ovarian protection of melatonin and its receptors against B ( a ) P exposure .

Benzo(a)pyrene (B(a)P) is a widespread persistent organic pollutant (POP) and a well-known endocrine disruptor. Exposure to BaP is known to disrupt the steroid balance and impair embryo implantation, but the mechanism under it remains unclear. The corpus luteum (CL), the primary source of progesterone during early pregnancy, plays a pivotal role in embryo implantation and pregnancy maintenance. The inappropriate luteal function may result in implantation failure and spontaneous abortions. Therefore, this study was conducted to assess the effects and potential mechanisms of B(a)P on the CL function. Our results showed that pregnant mice received B(a)P displayed impaired embryo implantation and dysfunction of ovarian CL. The estrogen and progesterone levels decreased by B(a)P. In vitro, exposure to BPDE, which is the metabolite of B(a)P, affected the luteinization of granular cell KK-1. Additionally, melatonin and its receptors, which are important for ovarian function and anti-oxidative damage, were affected by B(a)P or BPDE. B(a)P or BPDE-treated alone impaired antioxidant capacity of ovarian granulosa cells, caused an increasing of ROS and cell apoptosis, and disrupted the PI3K/AKT/GSK3β signaling pathway in vivo and in vitro. Co-treatment with melatonin alleviated B(a)P or BPDE-induced CL dysfunction by ameliorating oxidative stress, counteracting phosphorylation of PI3K/AKT/GSK3β signaling pathway, decreasing the apoptosis of the ovarian cells. Moreover, activation of the melatonin receptor by ramelteon in KK-1 cells exhibits an analogous protective effect as melatonin. In conclusion, our findings not only firstly clarify the potential mechanisms of BaP-induced CL dysfunction, but also extend the understanding about the ovarian protection of melatonin and its receptors against B(a)P exposure.


greenmedinfo--2020-12-04--Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic mo

Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer's disease.

Alzheimer 's disease ( AD ) is an age-related neurodegenerative disease with multiple predisposing factors and complicated pathogenesis .
Aβ peptide is one of the most important pathogenic factors in the etiology of AD .
Accumulating evidence indicates that the imbalance of Aβ production and Aβ clearance in the brain of AD patients leads to Aβ deposition and neurotoxic Aβ oligomer formation .
Melatonin shows a potent neuroprotectiveeffect and can prevent or slow down the progression of AD , supporting the view that melatonin is a potential therapeutic molecule for AD .
Melatonin modulates the regulatory network of secretase expression @ @ @ @ @ @ @ thereby inhibiting amyloidogenic APP processing and Aβproduction .
Additionally , melatonin ameliorates Aβ-induced neurotoxicity and probably promotes Aβ clearance through glymphatic-lymphatic drainage , BBB transportation and degradation pathways .
In this review , we summarize and discuss the role of melatonin against Aβ-dependent AD pathogenesis .
Weexplore the potential cellular and molecular mechanisms of melatonin on Aβ production and assembly , Aβ clearance , Aβ neurotoxicity and circadian cycle disruption .
We summarize multiple clinical trials of melatonin treatment in AD patients , showing that melatonin has a promising effect on improving sleep @ @ @ @ @ @ @ aims to stimulate further research on melatonin as a potential therapeutic agent for AD .

Alzheimer's disease (AD) is an age-related neurodegenerative disease with multiple predisposing factors and complicated pathogenesis. Aβ peptide is one of the most important pathogenic factors in the etiology of AD. Accumulating evidence indicates that the imbalance of Aβ production and Aβ clearance in the brain of AD patients leads to Aβ deposition and neurotoxic Aβ oligomer formation. Melatonin shows a potent neuroprotectiveeffect and can prevent or slow down the progression of AD, supporting the view that melatonin is a potential therapeutic molecule for AD. Melatonin modulates the regulatory network of secretase expression and affects the function of secretase, thereby inhibiting amyloidogenic APP processing and Aβproduction. Additionally, melatonin ameliorates Aβ-induced neurotoxicity and probably promotes Aβ clearance through glymphatic-lymphatic drainage, BBB transportation and degradation pathways. In this review, we summarize and discuss the role of melatonin against Aβ-dependent AD pathogenesis. Weexplore the potential cellular and molecular mechanisms of melatonin on Aβ production and assembly, Aβ clearance, Aβ neurotoxicity and circadian cycle disruption. We summarize multiple clinical trials of melatonin treatment in AD patients, showing that melatonin has a promising effect on improving sleep quality and cognitive function. This review aims to stimulate further research on melatonin as a potential therapeutic agent for AD.


greenmedinfo--2020-12-04--Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway.

Mitochondrial calcium uptake 1 ( MICU1 ) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions .
However , it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II ( Ang-II ) -induced cardiac hypertrophy or if it has a role in the function of melatonin .
Here , small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes ( NMVMs ) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophyand .
In contrast , MICU1 @ @ @ @ @ @ @ .
Ang-II administration , particularly in NMVMs with MICU1 knockdown , led to significantly increased reactive oxygen species ( ROS ) overload , altered mitochondrial morphology , and suppressed mitochondrial function , all of which were reversed by MICU1 supplementation .
Moreover , peroxisome proliferator-activated receptor gamma coactivator 1-α ( PGC-1α ) /MICU1 expression in hypertrophic myocardia increased with melatonin .
Melatonin ameliorated excessive ROS generation , promoted mitochondrial function , and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice .
Collectively , our results demonstrate that MICU1 attenuates @ @ @ @ @ @ @ stress .
MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy .

Mitochondrial calcium uptake 1 (MICU1) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions. However, it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II (Ang-II)-induced cardiac hypertrophy or if it has a role in the function of melatonin. Here, small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophyand. In contrast, MICU1 upregulation decreased cardiomyocyte susceptibility to hypertrophic stress. Ang-II administration, particularly in NMVMs with MICU1 knockdown, led to significantly increased reactive oxygen species (ROS) overload, altered mitochondrial morphology, and suppressed mitochondrial function, all of which were reversed by MICU1 supplementation. Moreover, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)/MICU1 expression in hypertrophic myocardia increased with melatonin. Melatonin ameliorated excessive ROS generation, promoted mitochondrial function, and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice. Collectively, our results demonstrate that MICU1 attenuates Ang-II-induced cardiac hypertrophy by inhibiting mitochondria-derived oxidative stress. MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy.


greenmedinfo--2020-12-04--Melatonin/Nrf2/NLRP3 connection in mouse heart mitochondria during aging.

Aging is a major risk for cardiovascular diseases ( CVD ) .
Age-related disorders include oxidative stress , mitochondria dysfunction , and exacerbation of the NF-κB/NLRP3 innate immune response pathways .
Some of the molecular mechanisms underlying these processes , however , remain unclear .
This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects .
With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium , we analyzed the expression of proteins implied in mitochondria dynamics , @ @ @ @ @ @ @ and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of3 , 12 , and 24 months-old , with and without melatonin treatment .
Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging .
The deficiency of the inflammasome affected Bax/Bcl2 ratio , but not p53 or caspase 9 .
The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3 .
Furthermore , NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type @ @ @ @ @ @ @ mitochondrial dynamics altered by aging and had few effects on cardiac autophagy .
Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging .

Aging is a major risk for cardiovascular diseases (CVD). Age-related disorders include oxidative stress, mitochondria dysfunction, and exacerbation of the NF-κB/NLRP3 innate immune response pathways. Some of the molecular mechanisms underlying these processes, however, remain unclear. This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects. With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium, we analyzed the expression of proteins implied in mitochondria dynamics, autophagy, apoptosis, Nrf2-dependent antioxidant response and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of3, 12, and 24 months-old, with and without melatonin treatment. Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging. The deficiency of the inflammasome affected Bax/Bcl2 ratio, but not p53 or caspase 9. The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3. Furthermore, NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type animals. Interestingly, melatonin treatment recovered mitochondrial dynamics altered by aging and had few effects on cardiac autophagy. Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging.


greenmedinfo--2020-12-04--Protective effects of melatonin against severe burn-induced distant organ injury.

Extensive burns result in a local wound response and distant-organ injury ( DOI ) caused by oxidative-stress and inflammation .
Melatonin ( MT ) shows promise in alleviating oxidative-stress and inflammation , but its role in thermal injury is largely unexplored .
The present systematic review and meta-analysis were designed to assess the effects of MT on oxidative-stress and inflammatory markers against severe burn-induced DOI .
Mean difference ( MD ) /standard mean difference ( SMD ) with 95 % confidence interval ( CI ) were estimated using fixed-effect/random-effects models .
Eighteen experimental studies met the inclusion criteria .
Compared @ @ @ @ @ @ @ decreased the levels of malondialdehyde ( SMD , -1.03 ; 95 % CI , -1.30 , -0.76 , < 0.00001 ) and 4-hydroxynonenal ( MD , -1.06 ; 95 % CI , -1.57 , -0.56 , < 0.0001 ) .
Additionally , MT increased the levels of glutathione ( SMD , 1.94 ; 95 % CI , 1.27 , 2.61 , < 0.00001 ) and superoxide-dismutase ( SMD , 0.76 ; 95 % CI , 0.08 , 1.45 , = 0.03 ) .
Finally , MT significantly decreased the levels of tumor necrosis @ @ @ @ @ @ @ % CI , -1.92 to -0.77 ; < 0.00001 ) and C-reactive protein ( MD , -12.67 ; 95 % CI , -16.72 to -8.62 ; < 0.00001 ) .
Meta-analysis indicates that severe burn followed by immediate MT ( 10 mg/kg ) intervention shows significant beneficial effects after 24-h against DOI by regulating oxidative-stress and the inflammatory response .

Extensive burns result in a local wound response and distant-organ injury (DOI) caused by oxidative-stress and inflammation. Melatonin (MT) shows promise in alleviating oxidative-stress and inflammation, but its role in thermal injury is largely unexplored. The present systematic review and meta-analysis were designed to assess the effects of MT on oxidative-stress and inflammatory markers against severe burn-induced DOI. Mean difference (MD)/standard mean difference (SMD) with 95% confidence interval (CI) were estimated using fixed-effect/random-effects models. Eighteen experimental studies met the inclusion criteria. Compared with the control group, MT significantly decreased the levels of malondialdehyde (SMD, -1.03; 95% CI, -1.30, -0.76,<0.00001) and 4-hydroxynonenal (MD, -1.06; 95% CI, -1.57, -0.56,<0.0001). Additionally, MT increased the levels of glutathione (SMD, 1.94; 95% CI, 1.27, 2.61,<0.00001) and superoxide-dismutase (SMD, 0.76; 95% CI, 0.08, 1.45,= 0.03). Finally, MT significantly decreased the levels of tumor necrosis factor-α (SMD, -1.34; 95% CI, -1.92 to -0.77;<0.00001) and C-reactive protein (MD, -12.67; 95% CI, -16.72 to -8.62;<0.00001). Meta-analysis indicates that severe burn followed by immediate MT (10 mg/kg) intervention shows significant beneficial effects after 24-h against DOI by regulating oxidative-stress and the inflammatory response.


greenmedinfo--2020-12-04--Effect of shikonin on function of rheumatoid arthritis fibroblast like synoviocytes.

To observe the effect of shikonin on the proliferation , migration , adhesion and invasion of rheumatoid arthritis ( RA ) fibroblast like synoviocytes induced by tumor necrosis factor-α ( TNF-α ) , and to explore its mechanism of action from aspects of protein kinase B ( Akt ) and mitogen activated protein kinase ( MAPK ) signaling pathways .
TNF-α ( 20 ng·mL~ ( -1 ) ) was used in this experiment to induce human RA fibroblast like synovial cell line ( MH7 A ) .
After addition of different concentrations of shikonin ( 0.025 , 0.05 , 0.1 @ @ @ @ @ @ @ proliferation , migration , adhesion and invasion ability of MH7 A cells were detected by MTT test , scratch test , adhesion test , Transwell invasion test , respectively .
Protein expression of Akt and MAPK signaling pathway molecules in MH7 A cellswas detected by Western blot .
The results showed that as compared with the control group , TNF-α could significantly induce the proliferation , migration , adhesion and invasion of MH7 A cells , and increase the phosphorylation level of Akt , JNK , p38 and extracellular regulatory protein kinase ( @ @ @ @ @ @ @ group , shikonin had no significant effect on TNF-α-induced proliferation of MH7 A cells after 24 h treatment , and it could reduce the TNF-α-induced proliferation of MH7 A cells in a concentration dependent manner after 48 h treatment .
Shikonin also significantly reduced the TNF-α-induced migration , adhesion , invasion and phosphorylation levels of Akt , JNK , p38 , ERK in MH7 A cells within 24 h. These results suggested that shikonin could reduce the proliferation , migration , adhesion and invasion ability of MH7 A cells induced by TNF-α , @ @ @ @ @ @ @ the down-regulation of Akt and MAPK signaling pathway activation .

To observe the effect of shikonin on the proliferation, migration, adhesion and invasion of rheumatoid arthritis(RA) fibroblast like synoviocytes induced by tumor necrosis factor-α(TNF-α), and to explore its mechanism of action from aspects of protein kinase B(Akt) and mitogen activated protein kinase(MAPK) signaling pathways. TNF-α(20 ng·mL~(-1)) was used in this experiment to induce human RA fibroblast like synovial cell line(MH7 A). After addition of different concentrations of shikonin(0.025, 0.05, 0.1 pmol·L~(-1)), the proliferation, migration, adhesion and invasion ability of MH7 A cells were detected by MTT test, scratch test, adhesion test, Transwell invasion test, respectively. Protein expression of Akt and MAPK signaling pathway molecules in MH7 A cellswas detected by Western blot. The results showed that as compared with the control group, TNF-α could significantly induce the proliferation, migration, adhesion and invasion of MH7 A cells, and increase the phosphorylation level of Akt, JNK, p38 and extracellular regulatory protein kinase(ERK). Ascompared with the TNF-α group, shikonin had no significant effect on TNF-α-induced proliferation of MH7 A cells after 24 h treatment, and it could reduce the TNF-α-induced proliferation of MH7 A cells in a concentration dependent manner after 48 h treatment. Shikonin also significantly reduced the TNF-α-induced migration, adhesion, invasion and phosphorylation levels of Akt, JNK, p38, ERK in MH7 A cells within 24 h. These results suggested that shikonin could reduce the proliferation, migration, adhesion and invasion ability of MH7 A cells induced by TNF-α, and its mechanism may be related to the down-regulation of Akt and MAPK signaling pathway activation.


greenmedinfo--2020-12-04--Shikonin ameliorates lipopolysaccharide-induced cardiac dysfunction.

Shikonin ( SHI ) is an anti-inflammatory agent extracted from natural herbs .
It is still unknown whether SHI ameliorates lipopolysaccharide ( LPS ) -induced cardiac dysfunction .
This study aims to explore the protective effects of SHI on LPS-induced myocardial injury and its mechanism .
The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of SHI .
In the present study , we found that SHI treatment improved the survival rate and cardiac function and remarkably ameliorated the release of inflammatory cytokines and macrophage infiltration in heart tissue of LPS-treated mice .
SHI also reduced @ @ @ @ @ @ @ troponin ( cTn ) release , cell inflammation , and apoptosis in LPS plus adenosine triphosphate ( ATP ) -treated H9c2 cells .
In addition , SHI significantly upregulated silent information regulator 1 ( SIRT1 ) expression and suppressed the upregulation of NOD-like receptor protein 3 ( NLRP3 ) , cleaved caspase-1 , and caspase-1 activity in heart tissues induced by LPS .
Meanwhile , we got the same results in LPS plus ATP-treated H9c2 cells .
Further , SIRT1 inhibitor or siRNA partially blocked SHI-mediated upregulation of SIRT1 expression and downregulation of @ @ @ @ @ @ @ activity in heart tissues induced by LPS .
Therefore , we conclude that SHI ameliorates LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes and might be a promising therapeutic strategy for the treatment of LPS-induced cardiac dysfunction .

Shikonin (SHI) is an anti-inflammatory agent extracted from natural herbs. It is still unknown whether SHI ameliorates lipopolysaccharide (LPS)-induced cardiac dysfunction. This study aims to explore the protective effects of SHI on LPS-induced myocardial injury and its mechanism. The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of SHI. In the present study, we found that SHI treatment improved the survival rate and cardiac function and remarkably ameliorated the release of inflammatory cytokines and macrophage infiltration in heart tissue of LPS-treated mice. SHI also reduced lactate dehydrogenase (LDH) and cardiac troponin (cTn) release, cell inflammation, and apoptosis in LPS plus adenosine triphosphate (ATP)-treated H9c2 cells. In addition, SHI significantly upregulated silent information regulator 1 (SIRT1) expression and suppressed the upregulation of NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Meanwhile, we got the same results in LPS plus ATP-treated H9c2 cells. Further, SIRT1 inhibitor or siRNA partially blocked SHI-mediated upregulation of SIRT1 expression and downregulation of NLRP3, cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Therefore, we conclude that SHI ameliorates LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes and might be a promising therapeutic strategy for the treatment of LPS-induced cardiac dysfunction.


greenmedinfo--2020-12-04--Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a r

Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a refractory HCC cell line.

AIMS : In tumor cells , shikonin treatment has been reported to inhibit glycolysis by suppressing the activity of pyruvate kinase M2 ( PKM2 ) and to induce apoptosis by increasing reactive oxygen species ( ROS ) production .
However , hepatocellular carcinoma ( HCC ) shows variable sensitivity to shikonin treatment , and the mechanism for these differences remains unclear .
We evaluated the effects of shikonin on metabolic and oxidative pathways in sensitive and refractory HCC cell lines to identify mechanisms of differential sensitivity .
MAIN METHODS : Cell viability and apoptosis were evaluated by MTT assay , @ @ @ @ @ @ @ function was further evaluated by measurements of ROS and mitochondrial mass .
Oxygen consumption rates , NAD/NADH , ATP and lactate were measured as indicators of energy metabolism and glycolysis .
Protein expression associated with glycolysis and apoptosis was evaluated by western blotting , RT-qPCR and immunofluorescence staining .
KEY FINDINGS : The sensitivity to shikonin treatment was significantly higher for HepG2 cells than for HCCLM3 cells , with less dramatic effects in HCCLM3 cells on apoptosis , ROS , and oxidative phosphorylation .
Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation @ @ @ @ @ @ @ opposite trend in HCCLM3 cells .
Mechanistically , shikonin promoted nuclear expression of PKM2 and HIF1α in HCCLM3 cells , with upregulation of glycolysis-related gene transcription and glycolysis .
SIGNIFICANCE : These results suggest that PKM2 rewires glucose metabolism , which explains the differential sensitivity to shikonin-induced apoptosis in HCC cells .
Our findings elucidate mechanisms for differential responses to shikonin , provide potential biomarkers , and indicate a theoretical basis for targeting glycolytic enzymes in refractory HCC .

AIMS: In tumor cells, shikonin treatment has been reported to inhibit glycolysis by suppressing the activity of pyruvate kinase M2 (PKM2) and to induce apoptosis by increasing reactive oxygen species (ROS) production. However, hepatocellular carcinoma (HCC) shows variable sensitivity to shikonin treatment, and the mechanism for these differences remains unclear. We evaluated the effects of shikonin on metabolic and oxidative pathways in sensitive and refractory HCC cell lines to identify mechanisms of differential sensitivity.
MAIN METHODS: Cell viability and apoptosis were evaluated by MTT assay, PI/Annexin V and JC-1 staining. Mitochondrial function was further evaluated by measurements of ROS and mitochondrial mass. Oxygen consumption rates, NAD/NADH, ATP and lactate were measured as indicators of energy metabolism and glycolysis. Protein expression associated with glycolysis and apoptosis was evaluated by western blotting, RT-qPCR and immunofluorescence staining.
KEY FINDINGS: The sensitivity to shikonin treatment was significantly higher for HepG2 cells than for HCCLM3 cells, with less dramatic effects in HCCLM3 cells on apoptosis, ROS, and oxidative phosphorylation. Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation in HepG2 cells, but displayed the opposite trend in HCCLM3 cells. Mechanistically, shikonin promoted nuclear expression of PKM2 and HIF1α in HCCLM3 cells, with upregulation of glycolysis-related gene transcription and glycolysis.
SIGNIFICANCE: These results suggest that PKM2 rewires glucose metabolism, which explains the differential sensitivity to shikonin-induced apoptosis in HCC cells. Our findings elucidate mechanisms for differential responses to shikonin, provide potential biomarkers, and indicate a theoretical basis for targeting glycolytic enzymes in refractory HCC.


greenmedinfo--2020-12-04--The results of the present study may provide a potential therapeutic strategy for liver fibrosis.

Liver fibrosis is a tissue repair process that occurs following various types of chronic liver injury and can develop into liver cirrhosis , portal hypertension or liver cancer without effective treatment .
Shikonin has anti-inflammatory , antiviral and antitumor properties .
Furthermore , shikonin has an additional effect of antagonizing tissue and organ fibrosis .
The aim of the present study was to evaluate the mechanisms of action underlying shikonin against liver fibrosis .
Cell viability was assessed using the Cell Counting Kit-8 and EdU incorporation assays .
Protein and mRNA expression levels were measured via western blotting and immunofluorescence @ @ @ @ @ @ @ via flow cytometry and autophagy via transmission electron microscopy .
Compared with the control group , shikonin did not significantly alter LX-2 cell viability at 0.2µmol/ml , which was used as the intervention concentration .
However , shikonin significantly inhibited fibrosis , as indicated by a decrease in the expression of α-smooth muscle actin and collagen-I in the TGF-β + shikonin group compared with the TGF-β group .
The results indicated that shikonin potentially inhibited fibrosis via promoting cell apoptosis and inhibiting autophagy .
Additionally , the results of the present study indicated @ @ @ @ @ @ @ platelet-activating factor ( PAF ) in TGF-β-treated cells , which subsequently activated the MAPK signaling pathway , leading to enhanced cell apoptosis and reduced autophagy .
Collectively , the present study indicated that shikonin promoted cell apoptosis and suppressed autophagy via the PAF-MAPK axis in LX-2 cells , thus blocking the development of fibrosis .
The results of the present study may provide a potential therapeutic strategy for liver fibrosis .

Liver fibrosis is a tissue repair process that occurs following various types of chronic liver injury and can develop into liver cirrhosis, portal hypertension or liver cancer without effective treatment. Shikonin has anti-inflammatory, antiviral and antitumor properties. Furthermore, shikonin has an additional effect of antagonizing tissue and organ fibrosis. The aim of the present study was to evaluate the mechanisms of action underlying shikonin against liver fibrosis. Cell viability was assessed using the Cell Counting Kit-8 and EdU incorporation assays. Protein and mRNA expression levels were measured via western blotting and immunofluorescence assays, respectively. Apoptosis was examined via flow cytometry and autophagy via transmission electron microscopy. Compared with the control group, shikonin did not significantly alter LX-2 cell viability at 0.2µmol/ml, which was used as the intervention concentration. However, shikonin significantly inhibited fibrosis, as indicated by a decrease in the expression of α-smooth muscle actin and collagen-I in the TGF-β + shikonin group compared with the TGF-β group. The results indicated that shikonin potentially inhibited fibrosis via promoting cell apoptosis and inhibiting autophagy. Additionally, the results of the present study indicated that shikonin downregulated the expression levels of platelet-activating factor (PAF) in TGF-β-treated cells, which subsequently activated the MAPK signaling pathway, leading to enhanced cell apoptosis and reduced autophagy. Collectively, the present study indicated that shikonin promoted cell apoptosis and suppressed autophagy via the PAF-MAPK axis in LX-2 cells, thus blocking the development of fibrosis. The results of the present study may provide a potential therapeutic strategy for liver fibrosis.


greenmedinfo--2020-12-04--MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis.

Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death .
Mixed-lineage kinase domain-like protein ( MLKL ) has been identified as a key executor of necroptosis , but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis .
In this study , we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo , which are accompanied with nuclear translocation of AIF andγ-H2AX formation .
In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or @ @ @ @ @ @ @ glioma cell necroptosis , as well as chromatinolysis .
Mechanistically , activated MLKL targets mitochondria and triggers excessive generation ofmitochondrial superoxide , which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS .
Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation bysuppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis .
Then , we found that RIP3 accounts for shikonin-induced activation of MLKL , and activated MLKL reversely up-regulates the protein level of CYLD @ @ @ @ @ @ @ RIP3 .
Taken together , ourdata suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis , and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3 .

Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death. Mixed-lineage kinase domain-like protein (MLKL) has been identified as a key executor of necroptosis, but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis. In this study, we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo, which are accompanied with nuclear translocation of AIF andγ-H2AX formation. In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or knockdown of MLKL with siRNA abrogates shikonin-induced glioma cell necroptosis, as well as chromatinolysis. Mechanistically, activated MLKL targets mitochondria and triggers excessive generation ofmitochondrial superoxide, which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS. Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation bysuppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis. Then, we found that RIP3 accounts for shikonin-induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3. Taken together, ourdata suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis, and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3.


greenmedinfo--2020-12-04--Humulone modulation of GABA A receptors and its role in hops sleep-promoting activity.

L. ( hops ) is a major constituent of beer .
It exhibits neuroactive properties that make it useful as a sleeping aid .
These effects are hypothesized to be mediated by an increase in GABAreceptor function .
In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops , recent evidence revealed that humulone , a prenylated phloroglucinol derivative comprising 35-70 % of hops alpha acids , may act as a positive modulator of GABAreceptors at low micromolar concentrations .
This raises the question whether humulone plays a key role in hops pharmacological activity @ @ @ @ @ @ @ as ethanol , bringing further enhancement in GABAreceptor-mediated effects of beer .
Here we assessed electrophysiologically the positive modulatory activity of humulone on recombinant GABAreceptors expressed in HEK293 cells .
We then examined humulone interactions with other active hops compounds and ethanol on GABA-induced displacement of [ H ] EBOB binding to native GABAreceptors in rat brain membranes .
Using BALB/c mice , we assessed humulone 's hypnotic behavior with pentobarbital- and ethanol-induced sleep as well as sedation in spontaneous locomotion with open field test .
We demonstrated for the first time that @ @ @ @ @ @ @ In radioligand binding to native GABAreceptors , the inclusion of ethanol enhanced humulone modulation of GABA-induced displacement of [ H ] EBOB binding in rat forebrain and cerebellum as it produced a leftward shift in [ H ] EBOB displacement curves .
Moreover , the additive modulatory effects between humulone , isoxanthohumol and 6-prenylnaringenin were evident and corresponded to the sum of [ H ] EBOB displacement by each compound individually .
In behavioral tests , humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased the spontaneous @ @ @ @ @ @ @ ( . )
.
Despite the absence of humulone effects on ethanol-induced sleep onset , sleep duration was increased dose-dependently down to 10 mg/kg ( . )
.
Our findings confirmed humulone 's positive allosteric modulation of GABAreceptor function and displayed its sedative and hypnotic behavior .
Humulone modulation can be potentially enhanced by ethanol and hops modulators suggesting a probable enhancement in the intoxicating effects of ethanol in hops-enriched beer .

L. (hops) is a major constituent of beer. It exhibits neuroactive properties that make it useful as a sleeping aid. These effects are hypothesized to be mediated by an increase in GABAreceptor function. In the quest to uncover the constituents responsible for the sedative and hypnotic properties of hops, recent evidence revealed that humulone, a prenylated phloroglucinol derivative comprising 35-70% of hops alpha acids, may act as a positive modulator of GABAreceptors at low micromolar concentrations. This raises the question whether humulone plays a key role in hops pharmacological activity and potentially interacts with other modulators such as ethanol, bringing further enhancement in GABAreceptor-mediated effects of beer. Here we assessed electrophysiologically the positive modulatory activity of humulone on recombinant GABAreceptors expressed in HEK293 cells. We then examined humulone interactions with other active hops compounds and ethanol on GABA-induced displacement of [H]EBOB binding to native GABAreceptors in rat brain membranes. Using BALB/c mice, we assessed humulone's hypnotic behavior with pentobarbital- and ethanol-induced sleep as well as sedation in spontaneous locomotion with open field test. We demonstrated for the first time that humulone potentiates GABA-induced currents inα1β3γ2 receptors. In radioligand binding to native GABAreceptors, the inclusion of ethanol enhanced humulone modulation of GABA-induced displacement of [H]EBOB binding in rat forebrain and cerebellum as it produced a leftward shift in [H]EBOB displacement curves. Moreover, the additive modulatory effects between humulone, isoxanthohumol and 6-prenylnaringenin were evident and corresponded to the sum of [H]EBOB displacement by each compound individually. In behavioral tests, humulone shortened sleep onset and increased the duration of sleep induced by pentobarbital and decreased the spontaneous locomotion in open field at 20 mg/kg (.). Despite the absence of humulone effects on ethanol-induced sleep onset, sleep duration was increased dose-dependently down to 10 mg/kg (.). Our findings confirmed humulone's positive allosteric modulation of GABAreceptor function and displayed its sedative and hypnotic behavior. Humulone modulation can be potentially enhanced by ethanol and hops modulators suggesting a probable enhancement in the intoxicating effects of ethanol in hops-enriched beer.


greenmedinfo--2020-12-04--Xanthohumol attenuates isoprenaline-induced cardiac hypertrophy and fibrosis.

Emerging evidence suggests the cardiovascular protective effects of Xanthohumol ( Xn ) , a prenylatedﬂavonoid isolated from the hops ( Humulus lupulus L. ) .
However , the cardioprotective effect of Xn remains unclear .
Present study aimed to investigate the protective role of Xn against isoprenaline ( ISO ) -induced cardiac hypertrophy and fibrosis , and elucidate the underlying mechanism .
The cardiac hypertrophy and fibrosis model were established via subcutaneously administration of ISO .
ISO reduced the left ventricular contractile function and elevated myocardial enzyme levels , suggesting cardiac dysfunction .
Moreover , the increased cardiac myocyte area @ @ @ @ @ @ @ ratio and ANP/BNP expressions indicated the ISO-induced hypertrophy , while the excessive collagen-deposition and up-regulation of fibrosis marker protein ( α-SMA , Collagen-I/III ) expression indicated the ISO-induced fibrosis .
The ISO-induced cardiac dysfunction , hypertrophy and fibrosis were signiﬁcantlyattenuated by oral administrated with Xn .
PTEN/AKT/mTOR pathway has been reported to involve in pathogenesis of cardiac hypertrophy and fibrosis .
We found that Xn administration up-regulated PTEN expression and inhibited the phosphorylation of AKT/mTOR in ISO-treated mice .
Moreover , treating with VO-ohpic , a speciﬁc PTEN inhibitor , abolished the cardioprotective @ @ @ @ @ @ @ results suggested that Xn attenuated ISO-induced cardiac hypertrophy and fibrosis through regulating PTEN/AKT/mTOR pathway .

Emerging evidence suggests the cardiovascular protective effects of Xanthohumol (Xn), a prenylatedﬂavonoid isolated from the hops (Humulus lupulus L.). However, the cardioprotective effect of Xn remains unclear. Present study aimed to investigate the protective role of Xn against isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis, and elucidate the underlying mechanism. The cardiac hypertrophy and fibrosis model were established via subcutaneously administration of ISO. ISO reduced the left ventricular contractile function and elevated myocardial enzyme levels, suggesting cardiac dysfunction. Moreover, the increased cardiac myocyte area, heart weight/body weight (HW/BW) ratio and ANP/BNP expressions indicated the ISO-induced hypertrophy, while the excessive collagen-deposition and up-regulation of fibrosis marker protein (α-SMA, Collagen-I/III) expression indicated the ISO-induced fibrosis. The ISO-induced cardiac dysfunction, hypertrophy and fibrosis were signiﬁcantlyattenuated by oral administrated with Xn. PTEN/AKT/mTOR pathway has been reported to involve in pathogenesis of cardiac hypertrophy and fibrosis. We found that Xn administration up-regulated PTEN expression and inhibited the phosphorylation of AKT/mTOR in ISO-treated mice. Moreover, treating with VO-ohpic, a speciﬁc PTEN inhibitor, abolished the cardioprotective effect of Xn. Collectively, these results suggested that Xn attenuated ISO-induced cardiac hypertrophy and fibrosis through regulating PTEN/AKT/mTOR pathway.


greenmedinfo--2020-12-04--Can Vaccines Alter a Child’s Health Trajectory?

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greenmedinfo--2020-12-04--Puerarin increases survival and protects against organ injury by suppressing NF-κB/JNK signalling in

Puerarin increases survival and protects against organ injury by suppressing NF-κB/JNK signalling in experimental sepsis.

Puerarin , an isoflavonoid rich in Radix , has been reported to be a broadly effective regulator in various biological processes and clinic conditions .
However , the role of puerarin in sepsis-induced mortality with multiple-organ injury remains unknown .
Herein , we showed that puerarin potently attenuated organ injury and increased survival rate in both lipopolysaccharides ( LPS ) and cecal ligation and puncture ( CLP ) induced mouse sepsis models .
It greatly suppressed systemic inflammation , determined by the serum levels of proinflammatory factors TNF-α , IL-6 , IL-1β , IL-10 , as well as monocyte chemotactic @ @ @ @ @ @ @ ( CRP ) .
Flow cytometry analysis indicated that puerarin settled overall inflammation mainly by normalizing expanded macrophages with limited effects on dendritic cells and CD4T cells in the circulation of sepsis mice .
In the liver , puerarin inhibited the transcription of inflammatory factor TNF-α , IL-6 , and IL-1β and protected hepatocyte apoptosis in sepsis mouse models .
In vitro , puerarin inhibited LPS-induced inflammation in LO2 hepatocytes , prevented TNF-α-mediated cell apoptosis and promoted an M2 phenotype revealed by M2 marker IL-10 and Arginase-1 ( Arg-1 ) in LPS challenged @ @ @ @ @ @ @ of TLR4/NF-κB/JNK pathway .
In conclusion , puerarin reduced systemic inflammation and protected organ injury in sepsis mice , thus , it might provide a new modality for a better treatment of sepsis .

Puerarin, an isoflavonoid rich in Radix, has been reported to be a broadly effective regulator in various biological processes and clinic conditions. However, the role of puerarin in sepsis-induced mortality with multiple-organ injury remains unknown. Herein, we showed that puerarin potently attenuated organ injury and increased survival rate in both lipopolysaccharides (LPS) and cecal ligation and puncture (CLP) induced mouse sepsis models. It greatly suppressed systemic inflammation, determined by the serum levels of proinflammatory factors TNF-α, IL-6, IL-1β, IL-10, as well as monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP). Flow cytometry analysis indicated that puerarin settled overall inflammation mainly by normalizing expanded macrophages with limited effects on dendritic cells and CD4T cells in the circulation of sepsis mice. In the liver, puerarin inhibited the transcription of inflammatory factor TNF-α, IL-6, and IL-1β and protected hepatocyte apoptosis in sepsis mouse models. In vitro, puerarin inhibited LPS-induced inflammation in LO2 hepatocytes, prevented TNF-α-mediated cell apoptosis and promoted an M2 phenotype revealed by M2 marker IL-10 and Arginase-1 (Arg-1) in LPS challenged Raw 264.7 macrophages, through the inhibition of TLR4/NF-κB/JNK pathway. In conclusion, puerarin reduced systemic inflammation and protected organ injury in sepsis mice, thus, it might provide a new modality for a better treatment of sepsis.


greenmedinfo--2020-12-04--Puerarin ameliorated pressure overload-induced cardiac hypertrophy.

Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy .
Previous evidence suggests that puerarin , a phytoestrogen , exerts beneficial effects on cardiac function in patients with cardiac hypertrophy .
In this study , we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized , aortic-banded rats .
Female SD rats subjected to bilateral ovariectomy ( OVX ) plus abdominal aortic constriction ( AAC ) .
The rats were treated with puerarin ( 50 mg·kg ·d , ip ) for 8 weeks .
Then @ @ @ @ @ @ @ were sacrificed , their heart tissues were extracted and allocated for further experiments .
We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats , which could be attributed to activation of PPARα/PPARγ coactivator-1 ( PGC-1 ) pathway .
Puerarin administration significantly increased the expression of estrogen-related receptor α , nuclear respiratory factor 1 , and mitochondrial transcription factor A in hearts .
Moreover , puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats .
Hypertrophic changes could be induced in neonatal rat cardiomyocytes ( @ @ @ @ @ @ @ angiotensin II ( Ang II , 1 μM ) , which was attenuated by co-treatemnt with puerarin ( 100 μM ) .
We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids ( NEFAs ) and deletion of ATP , attenuated the Ang II-induced dissipation of the mitochondrial membrane potential , and improved the mitochondrial dysfunction in NRCM .
Furthermore , addition of PPARα antagonist GW6471 ( 10 μM ) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM .
In conclusion , puerarin prevents cardiac hypertrophy @ @ @ @ @ @ @ PPARα/PGC-1 pathway and regulation of energy metabolism remodeling .
This may provide a new approach to prevent the development of heart failure in postmenopausal women .

Estrogen deficiency induces cardiac dysfunction and increases the risk of cardiovascular disease in postmenopausal women and in those who underwent bilateral oophorectomy. Previous evidence suggests that puerarin, a phytoestrogen, exerts beneficial effects on cardiac function in patients with cardiac hypertrophy. In this study, we investigated whether puerarin could prevent cardiac hypertrophy and remodeling in ovariectomized, aortic-banded rats. Female SD rats subjected to bilateral ovariectomy (OVX) plus abdominal aortic constriction (AAC). The rats were treated with puerarin (50 mg·kg ·d, ip) for 8 weeks. Then echocardiography was assessed, and the rats were sacrificed, their heart tissues were extracted and allocated for further experiments. We showed that puerarin administration significantly attenuated cardiac hypertrophy and remodeling in AAC-treated OVX rats, which could be attributed to activation of PPARα/PPARγ coactivator-1 (PGC-1) pathway. Puerarin administration significantly increased the expression of estrogen-related receptor α, nuclear respiratory factor 1, and mitochondrial transcription factor A in hearts. Moreover, puerarin administration regulated the expression of metabolic genes in AAC-treated OVX rats. Hypertrophic changes could be induced in neonatal rat cardiomyocytes (NRCM) in vitro by treatment with angiotensin II (Ang II, 1 μM), which was attenuated by co-treatemnt with puerarin (100 μM). We further showed that puerarin decreased Ang II-induced accumulation of non-esterified fatty acids (NEFAs) and deletion of ATP, attenuated the Ang II-induced dissipation of the mitochondrial membrane potential, and improved the mitochondrial dysfunction in NRCM. Furthermore, addition of PPARα antagonist GW6471 (10 μM) partially abolished the anti-hypertrophic effects and metabolic effects of puerarin in NRCM. In conclusion, puerarin prevents cardiac hypertrophy in AAC-treated OVX rats through activation of PPARα/PGC-1 pathway and regulation of energy metabolism remodeling. This may provide a new approach to prevent the development of heart failure in postmenopausal women.


greenmedinfo--2020-12-05--Effect of concomitant treatment of curcumin and melatonin on cisplatin-induced nephrotoxicity.

Cisplatin ( CP ) is a potent anticancer drug used to treat solid tumors .
Its use , however , is dose-limited by its nephrotoxicity .
We aimed to compare the effect of melatonin and curcumin given singly , with that of a combination of these two agents on CP-induced nephrotoxicity in rats .
CP ( 6 mg/kg , given once intraperitoneally ) induced nephrotoxicity as evidenced by several significant adverse physiological , biochemical and histopathological actions that included a reduction in body weight , increased urine production , and significant alterations in some conventional and novel renal damage indices @ @ @ @ @ @ @ CP also elevated several pro-inflammatory cytokines and caused renal oxidative/nitrosative stress .
Supplementation with either curcumin ( 200 mg/kg ) or melatonin ( 10 mg /kg ) given singly by oral gavage for eight consecutive days prior to CP injection and four days thereafter , significantly mitigated the adverse renal effects of CP , by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in renal tissues of CP- treated rats .
When curcumin and melatonin were given together , the ameliorative effect was augmented in some of the measured indices e.g @ @ @ @ @ @ @ C , uric acid , phosphorus in plasma and , urine creatinine and creatinine clearance .
Renal platinum concertation was reduced more with curcumin than that with melatonin , while the reduction was maximized when both melatonin and curcumin were given .
Pending further pharmacological and toxicological studies , a combination of these two agents is likely to be mor effective in mitigating the adverse renal effects of CP administered to cancer patients .

Cisplatin (CP) is a potent anticancer drug used to treat solid tumors. Its use, however, is dose-limited by its nephrotoxicity. We aimed to compare the effect of melatonin and curcumin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in rats. CP (6 mg/kg, given once intraperitoneally) induced nephrotoxicity as evidenced by several significant adverse physiological, biochemical and histopathological actions that included a reduction in body weight, increased urine production, and significant alterations in some conventional and novel renal damage indices in plasma, urine and kidneys. CP also elevated several pro-inflammatory cytokines and caused renal oxidative/nitrosative stress. Supplementation with either curcumin (200 mg/kg) or melatonin (10 mg /kg) given singly by oral gavage for eight consecutive days prior to CP injection and four days thereafter, significantly mitigated the adverse renal effects of CP, by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in renal tissues of CP- treated rats. When curcumin and melatonin were given together, the ameliorative effect was augmented in some of the measured indices e.g. tumor necrosis factor alpha, cystatin C, uric acid, phosphorus in plasma and, urine creatinine and creatinine clearance. Renal platinum concertation was reduced more with curcumin than that with melatonin, while the reduction was maximized when both melatonin and curcumin were given. Pending further pharmacological and toxicological studies, a combination of these two agents is likely to be mor effective in mitigating the adverse renal effects of CP administered to cancer patients.


greenmedinfo--2020-12-05--Melatonin may have protective and therapeutic effects on hypercholesterolaemia.

The aim of this study was to investigate the effects of melatonin on the serum asymmetric dimethylarginine ( ADMA ) @ @ @ @ @ vaspin , visfatin , dimethylarginine dimethylaminohydrolase ( DDAH ) , and signal transducer and activator @ @ @ @ @ for evaluation of endothelial function and inflammation in the hypercholesterolemic rats .
Rats were divided @ @ @ @ @ 1 ) control , ( 2 ) hypercholesterolaemia , ( 3 ) melatonin administrated concurrently @ @ @ @ @ 4 ) melatonin administrated only last 2 weeks and fed with cholesterol diet , ( @ @ @ @ @ last 2 weeks fed with cholesterol diet .
Although an increase was observed in the @ @ @ @ @ and the serum ADMA levels , the vaspin and DDAH protein expressions were found to @ @ @ @ @ Melatonin was determined to restore all the parameters to the normal levels .
In conclusion @ @ @ @ @ and therapeutic effects on hypercholesterolaemia by regulating vaspin , STAT-3 , DDAH , and ADMA @ @ @ @ @ effects with atorvastatin .

The aim of this study was to investigate the effects of melatonin on the serum asymmetric dimethylarginine (ADMA) levels and the expressions of vaspin, visfatin, dimethylarginine dimethylaminohydrolase (DDAH), and signal transducer and activator of transcription-3 (STAT-3) for evaluation of endothelial function and inflammation in the hypercholesterolemic rats. Rats were divided into 5 groups: (1) control, (2) hypercholesterolaemia, (3) melatonin administrated concurrently with cholesterol diet, (4) melatonin administrated only last 2 weeks and fed with cholesterol diet, (5) atorvastatin administered only last 2 weeks fed with cholesterol diet. Although an increase was observed in the expressions of visfatin and STAT-3 and the serum ADMA levels, the vaspin and DDAH protein expressions were found to decrease with hypercholesterolemic diets. Melatonin was determined to restore all the parameters to the normal levels. In conclusion, melatonin may have protective and therapeutic effects on hypercholesterolaemia by regulating vaspin, STAT-3, DDAH, and ADMA signalling pathways and create similar effects with atorvastatin.


greenmedinfo--2020-12-05--Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia.

BACKGROUND : The aim of this study was to determine the efficacy of exogenous melatonin supplementation for sleep disturbances in patients with middle-aged primary insomnia .
METHODS : This is a randomized double-blind , placebo-controlled parallel study .
Participants were recruited from Tianlin community , Xuhui district , Shanghai .
Ninety-seven consecutive middle-aged patients with primary insomnia were randomized to receive 3 mg fast-release melatonin ( n = 51 ) or placebo ( n = 46 ) for four-weeks .
Objective sleep parameters tested by overnight polysomnography , subjective sleep performance and daytime somnolence obtained from the Pittsburgh Sleep Quality @ @ @ @ @ @ @ Index ( ISI ) and Epworth Sleepiness Scale ( ESS ) were obtained at baseline and after treatment .
Treatment was taken daily 1 h before bedtime .
Serious adverse events and side-effects were monitored .
RESULTS : Melatonin supplementation significantly decreased early wake time [ -30.63min ( 95 % CI , -53.92 to -7.34 ) ; P = 0.001 ] and percentage of N2 sleep [ -7.07 % ( 95 % CI , -13.47 % to -0.68 % ) ; P = 0.031 ] .
However , melatonin had no significant effect @ @ @ @ @ @ @ latency , sleep efficiency , wake during the sleep and percent of N1 , N3 and REM sleep .
Melatonin had no effect on insomnia symptoms and severity on the PSQI [ 1.53 ( 95 % CI , -0.55 to 3.61 ) ; p = 0.504 ] ; ISI [ 0.81 ( 95 % CI , -2.27 to 3.88 ) ; p = 0.165 ] and ESS [ -0.83 ( 95 % CI , -3.53 to 1.88 ) ; p = 0.147 ] .
No serious adverse events were reported .
CONCLUSIONS : @ @ @ @ @ @ @ effective and safe in improving some aspects of objective sleep quality such as total sleep time , percentage of rapid eye movement and early morning wake time in middle-aged patients with insomnia .

BACKGROUND: The aim of this study was to determine the efficacy of exogenous melatonin supplementation for sleep disturbances in patients with middle-aged primary insomnia.
METHODS: This is a randomized double-blind, placebo-controlled parallel study. Participants were recruited from Tianlin community, Xuhui district, Shanghai. Ninety-seven consecutive middle-aged patients with primary insomnia were randomized to receive 3 mg fast-release melatonin (n = 51) or placebo (n = 46) for four-weeks. Objective sleep parameters tested by overnight polysomnography, subjective sleep performance and daytime somnolence obtained from the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) were obtained at baseline and after treatment. Treatment was taken daily 1 h before bedtime. Serious adverse events and side-effects were monitored.
RESULTS: Melatonin supplementation significantly decreased early wake time [-30.63min (95% CI, -53.92 to -7.34); P = 0.001] and percentage of N2 sleep [-7.07% (95% CI, -13.47% to -0.68%); P = 0.031]. However, melatonin had no significant effect on other objective sleep parameters including sleep latency, sleep efficiency, wake during the sleep and percent of N1, N3 and REM sleep. Melatonin had no effect on insomnia symptoms and severity on the PSQI [1.53(95% CI, -0.55 to 3.61); p = 0.504]; ISI [0.81 (95% CI, -2.27 to 3.88); p = 0.165] and ESS [-0.83 (95% CI, -3.53 to 1.88); p = 0.147]. No serious adverse events were reported.
CONCLUSIONS: Melatonin supplementation over a four-week period is effective and safe in improving some aspects of objective sleep quality such as total sleep time, percentage of rapid eye movement and early morning wake time in middle-aged patients with insomnia.
TRIAL REGISTRATION: Identifier: ChiCTR-TRC-13003997; Prospectively registered on 2 December 2013.


greenmedinfo--2020-12-05--Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin.

BACKGROUND : Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma ( DLBCL ) , but the overexpression of multidrug resistance ( MDR ) transporter proteins , especially P-glycoprotein ( P-gp ) , renders epirubicin ineffective .
Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR .
METHODS : The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide ( AO/EB ) fluorescence staining assay .
Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues .
Rhodamine-123 @ @ @ @ @ @ @ pump function of P-gp .
The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting , cytochrome C release , and pulldown assay .
RESULTS : Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression , epirubicin-induced apoptosis , and reduced the IC50 value of epirubicin .
Further , melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp .
Immunohistochemical staining studies revealed that P-gp expression was positively @ @ @ @ @ @ @ subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells .
Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter , decisively suppressing P-gp expression .
CONCLUSIONS : Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp , ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth .

BACKGROUND: Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR.
METHODS: The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay.
RESULTS: Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression.
CONCLUSIONS: Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.


greenmedinfo--2020-12-05--Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperf

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury.

Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy ( DCM ) , although the underlying mechanisms remain largely undefined .
Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM .
Using high-fat diet-streptozotocin-induced diabetic rat model , we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels , reduced the expressions of cardiac melatonin membrane receptors , and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling .
16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion @ @ @ @ @ @ @ fission , enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling .
After the induction of diabetes , adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals .
We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy .
Additionally , SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions .
Collectively , we demonstrated that long-term melatonin treatment attenuated the @ @ @ @ @ @ @ to MI/R injury through preserving mitochondrial quality control .
Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process .
Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients .

Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high-fat diet-streptozotocin-induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling. After the induction of diabetes, adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long-term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients.


greenmedinfo--2020-12-05--The protective effect of melatonin on radiofrequency electromagnetic fields of mobile phone-induced

The protective effect of melatonin on radiofrequency electromagnetic fields of mobile phone-induced testicular damage.

Radiofrequency electromagnetic radiation ( RF-EMR ) from mobile devices has undesirable effects on the male reproductive organs .
Melatonin with antioxidant potential can help to prevent these damages .
Therefore , the aim of this study was to evaluate the protective effect of melatonin on testicular damage induced by RF-EMR of mobile phone .
In this experimental study , 32 adult male BALB/c mice were divided randomly into four groups : control , melatonin ( 2 mg/kg , for 30 consecutive days , intraperitoneally ) , RF-EMR ( 900 MHz , 100 to 300 MT , 54 to 160 W/m @ @ @ @ @ @ @ whole body ) and melatonin + RF-EMR groups .
One day after the last prescription were evaluated oxidative stress parameters , testosterone level and histopathological assays of the testis .
EMR of mobile phone led to the induction of oxidative stress , testicular tissue damage and decreased testosterone .
Treatment with melatonin improved oxidative stress parameters such as MDA and GSH , and testis injury score , increased the thickness of the germinal epithelial thickness and diameter of the seminiferous tubule , and decreased testosterone hormone in the EMR-exposed mice , and these @ @ @ @ @

Radiofrequency electromagnetic radiation (RF-EMR) from mobile devices has undesirable effects on the male reproductive organs. Melatonin with antioxidant potential can help to prevent these damages. Therefore, the aim of this study was to evaluate the protective effect of melatonin on testicular damage induced by RF-EMR of mobile phone. In this experimental study, 32 adult male BALB/c mice were divided randomly into four groups: control, melatonin (2 mg/kg, for 30 consecutive days, intraperitoneally), RF-EMR (900 MHz, 100 to 300 MT, 54 to 160 W/m) (4 hr per day, whole body) and melatonin + RF-EMR groups. One day after the last prescription were evaluated oxidative stress parameters, testosterone level and histopathological assays of the testis. EMR of mobile phone led to the induction of oxidative stress, testicular tissue damage and decreased testosterone. Treatment with melatonin improved oxidative stress parameters such as MDA and GSH, and testis injury score, increased the thickness of the germinal epithelial thickness and diameter of the seminiferous tubule, and decreased testosterone hormone in the EMR-exposed mice, and these differences were significant(p < .05). Data showed that melatonin with its antioxidant property can decrease oxidative damage induced by RF-EMR of mobile phones on testis tissue.