Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism

BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

The bio-active components of the Mongolian medicine Horcha-6 and therapeutic mechanism in the rat migraine model

Background:The active components of Horcha-6 were identified using liquid chromatography with tandem mass spectrometry.Also,we investigated the potential mechanisms that explain why Horcha-6 may be effective in treating migraines through the use of network pharmacology and a rat migraine model.Methods:After identifying the active components of Horcha-6,the corresponding genes of the active components’target were obtained from the Universal Protein database,and a“compound-target-disease”network was constructed using Cytoscape 3.9.0 software.For the in vivo experiments,nitroglycerin was injected intraperitoneally into rats to create a migraine model.Pre-treatment with Horcha-6 was administered orally for 14 days,and rats were subjected to migraine-related behavior tests.RNA sequencing was performed to identify the gene expression regulated by Horcha-6 in the trigeminal nerve.Results:A total of 903 chemical components of Horcha-6 have been collected in the liquid chromatography with tandem mass spectrometry.We discovered 55 of the Horcha-6 bio-active components that were evaluated based on their Percent Human Oral Absorption(≥30%)and DL values(≥0.185)on the traditional Chinese medicine systems pharmacology database.The“compound-target-disease”network contained 163 intersection targets with the migraine state.Gene Ontology analysis indicated that these components significantly regulated the immune response,vascular function,oxidative stress,etc.When Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed,we observed that most of the target genes were significantly enriched in the inflammation and neuro-related signaling pathway,toll-like receptor signaling pathway,neuroactive ligand-receptor interaction,etc.These predictions were further demonstrated via in vivo animal model experiments.The RNA sequencing results showed that 41 genes were down-regulated(P<0.05)and 86 genes were up-regulated(P<0.05)in the Horcha-6 treated group compared with the untreated group.Those genes were mainly involved in neuromodulation,vascular function,and hormone metabolism.Conclusion:The 55 bio-active components in Horcha-6 regulate inflammation,hormone metabolism,and neurotransmitters and have potential as a therapy to treat migraines.

Pathogenesis and research progress of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

In this editorial,we comment on the article by Mei et al.Nonalcoholic steatohep-atitis(NASH)is a severe inflammatory subtype of nonalcoholic fatty liver disease(NAFLD)with pathological features including steatosis,hepatocellular damage,and varying degrees of fibrosis.With the epidemic of metabolic diseases and obesity,the prevalence of NAFLD in China has increased,and it is now similar to that in developed countries;thus,NAFLD has become a major chronic liver disease in China.Human epidemiological data suggest that estrogen has a protective effect on NASH in premenopausal women and that sex hormones influence the development of liver disease.This review focuses on the path-ogenesis,treatment,and relationship between NASH and other diseases as well as on the relationship between NASH and sex hormone metabolism,with the aim of providing new strategies for the treatment of NASH.

Elevated thyroid stimulating hormone levels are associated with metabolic syndrome in a Chinese community-based population of euthyroid people aged 40 years and older

This study investigated whether high-normal thyrotropin（TSH） levels are associated with metabolic syndrome in euthyroid Chinese people≥40 years old.Clinical and metabolic factors were assessed in 2,356 subjects（40-77 years old） with TSH levels in the normal range（0.35-5.00 mU/L）.Using 2.50 mU/L as the cut-off point of TSH level within the normal range,we divided subjects into the high-TSH（2.50-5.00 mU/L;n= 1,064） and low-TSH（0.35-2.50mU/L;n= 1,292） group.The results showed that the mean levels of body mass index（BMI）,total cholesterol（TC）,low density lipoprotein cholesterol（LDL-C）,and fasting plasma glucose（FPG） were higher in the high-TSH group and TSH levels were significantly positively con-elated with BMI,LDL-C,TC,and FPG.The prevalence of central obesity,hypertriglyceridemia,low high density lipoprotein cholesterol（HDL-C）,and high FPG（〉5.60 mmol/L） was significantly higher in females and subjects with high-TSH levels.Metabolic syndrome was also more prevalent in the high-TSH group.People over the age of 40 years with high-normal TSH levels had a 1.2-fold increased risk of metabolic syndrome,compared with those with low-normal TSII levels,after adjusting for age and gender.In conclusion,high normal TSH is a risk factor for metabolic syndrome in people ≥40 years old.

Progress of Alzheimer＇s disease related glucose metabolism regulating hormones and a research perspective in nootropics of herbal medicine

Alzheimer’s disease as one of the neurodegenerative diseases, its pathological mechanisms still remains unclear. There’s evidence that diabetes is associated with Alzheimer’s disease. However, the fundamental cause of diabetes is abnormal glucose metabolism. There may be an inseparable relationship between glucose metabolism regulating hormones and Alzheimer’s disease. Here, we review the studies that connect the glucose metabolism regulating hormones to Alzheimer’s disease, and that suggest the quality of Alzheimer’s patients is improved by regulating glucose metabolism.

Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)has reached epidemic proportions globally in parallel to the rising prevalence of obesity.Despite its significant burden,there is no approved pharmacotherapy specifically tailored for this disease.Many potential drug candidates for MAFLD have encountered setbacks in clinical trials,due to safety concerns or/and insufficient therapeutic efficacy.Nonetheless,several investigational drugs that mimic the actions of endogenous metabolic hormones,including thyroid hormone receptorβ(THRβ)agonists,fibroblast growth factor 21(FGF21)analogues,and glucagon-like peptide-1 receptor agonists(GLP-1RAs),showed promising therapeutic efficacy and excellent safety profiles.Among them,resmetirom,a liver-targeted THRβ-selective agonist,has met the primary outcomes in alleviation of metabolic dysfunction-associated steatohepatitis(MASH),the advanced form of MAFLD,and liver fibrosis in phase-3 clinical trials.These hormone-based pharmacotherapies not only exhibit varied degrees of therapeutic efficacy in mitigating hepatic steatosis,inflammation and fibrosis,but also improve metabolic profiles.Furthermore,these three hormonal agonists/analogues act in a complementary manner to exert their pharmacological effects,suggesting their combined therapies may yield synergistic therapeutic benefits.Further in-depth studies on the intricate interplay among these metabolic hormones are imperative for the development of more efficacious combination therapies,enabling precision management of MAFLD and its associated comorbidities.

Impact of Metabolic disrupting chemicals on redox homeostasis,energy sensors,receptor modulation,and hormone metabolism:A comparative account in Teleost and mammalian model organisms

Endocrine-disrupting chemicals(EDCs)may mimic the endogenous neuroendocrine and endocrine messengers and interfere with developmental,reproductive,immune,metabolic and other physiological functions.Modulation of basal metabolic rate,energy metabolism,food intake and engorgement by endocrine disruptors may lead to loss of metabolic equilibrium.EDC-induced loss of metabolic homeostasis and obesity gave rise to the concept of metabolic-disrupting chemicals(MDC)and environmental obesogens.Elevated oxidative stress,alterations in the circadian clock,and energy-sensing homeostasis are some of the major pathophysiological conditions implicated in promoting metabolic disruption.Reportedly,fish are the most vulnerable candidate due to their direct exposure to metabolic disruptors in aquatic habitats.Though limited,studies conducted using piscine models have helped to identify MDCs in the aquatic environment.Notably,the molecular mechanisms through which MDCs can negatively influence the metabolism of hormones,epigenetic alteration,gut dysbiosis,and changes in endocrine and metabolic receptor expression and functions have recently gained considerable attention.In this review,we provide an update on the impact of MDCs on the initiators,cellular mediators,and hormone receptors related to the maintenance of metabolic homeostasis,with particular emphasis on fish models.

Expression Analysis of Genes Related to Auxin Metabolism at Different Growth Stages of Pak Choi

Pak choi is a low-temperature vernalized plant that readily undergoes premature bolting during spring, but little is known about the governing molecular regulation of vernalization. In order to enhance our understanding of mechanism about premature bolting, we discussed the relationship between auxin(indole-3-acetic acid, IAA) and flowering of pak choi. During vernalization, hormone metabolism is an important regulatory pathway, and IAA plays a specific role. IAA metabolism has been studied in Arabidopsis thaliana and other plants, but not in pak choi. In this paper, the IAA content in pak choi shoot apices during vernalization and different growth stages was compared. The IAA content decreased significantly after low-temperature treatment(4 °C) and then increased rapidly during vegetative growth. During floral bud initiation,the IAA content decreased rapidly and was the lowest. Expressions of genes encoding key IAA metabolic enzymes were analyzed, and a major synthetase-encoding gene was downregulated, while a key degrading enzyme-encoding gene was upregulated during each comparison period,resulting in decreased IAA content. Expressions of four genes(Bra034975, Bra030246, Bra012239 and Bra040296) were consistent with changes in the IAA content. The functions of differentially expressed genes(DEGs) were analyzed, and 15 DEGs were found to be related to IAA metabolism.The findings illuminated the molecular mechanism regulating IAA content during vernalization in pak choi.

Stocking density affects the growth performance and metabolism of Amur sturgeon by regulating expression of genes in the GH/IGF axis

The effects of stocking density on the growth and metabolism of Amur sturgeon were assessed. Amur sturgeon were grown for 70 days at three dif ferent stocking densities(low stocking density, LSD: 5.5 kg/m^3; medium stocking density, MSD: 8.0 kg/m^3; and high stocking density, HSD: 11.0 kg/m^3), and the biometric index, muscle composition, and serum biochemical parameters were evaluated. In addition, pituitary, liver, and muscle samples were collected for gene cloning and expression analyses. After 70 days of growth, the fish maintained at HSD had significantly lower fi nal body weight and specifi c growth rate, and a higher feed conversion ratio than those of the fish in the MSD and LSD groups. The HSD group had the lowest lipid and protein concentrations in serum and muscle. The serum cortisol concentration increased significantly in the HSD group, indicating that the stress-response system was activated in these fish. There was no change in the concentration of serum insulin-like growth factor 2(IGF-2), while the concentrations of serum growth hormone(GH) and insulin-like growth factor 1(IGF-1) decreased in the HSD group. The full-length cDNAs of G H and IGF-2 genes(995-bp and 1 207-bp long, respectively), were cloned and analyzed. In the HSD group, the expressions of GH in the pituitary and growth hormone receptor( GHR) and IGF-1 in the liver were down-regulated at the end of the 70-day experiment. In the HSD group, the transcript level of IGF-2 significantly decreased in the liver, but did not change in muscle. Overall, our results indicated that a HSD negatively af fects the growth performance and leads to changes in lipid and protein metabolism in Amur sturgeon. The down-regulated expression of genes related to the GH/IGF axis may be responsible for the poor growth performance of Amur sturgeon under crowding stress.

Meta Analysis of the Efficacy of Nonpharmaceutical Chinese Medicine Therapy in the Treatment of Obese Polycystic Ovary Syndrome

Objective:To systematically evaluate the effects of acupuncture,auricular point sticking,acupoint catgut embedding,cupping and other non-pharmaceutical Chinese medicine therapies on sex hormone as well as glucose and lipid metabolism in patients with obese polycystic ovary syndrome.Method:The databases such as China National Knowledge Infrastructure were searched by computer to collect the literature on the treatment of obese polycystic by non-pharmaceutical Chinese medicine therapy combined with western medicine or lifestyle change,and the literature quality of the included literature was evaluated,and finally the data were analyzed.A total of 15 randomized controlled trial(RCT)literature were included in this study,with a total of 1263 patients.Results:Non-pharmaceutical Chinese medicine therapy combined with metformin or lifestyle can reduce body mass index,insulin resistance index,fasting plasma insulin,fasting blood glucose,luteinizing hormone,ratio of luteinizing hormone to follicle stimulating hormone,testosterone,but it has no obvious advantage over follicle stimulating hormone(FSH).Conclusion:Compared with simple application of metformin or lifestyle change,traditional Chinese medicine non drug therapy combined with metformin or lifestyle change can better improve sex hormone and blood glucose metabolism in obese PCOS patients.

Studies on the Free Radicals and Thyroid Hormone Metabolism in Cattle with Iodine and Selenium Deficicncy

In order to interpret pathologic mechanism of free radicals and thyroid hormone metabolism in cattle iodine and selenium deficiency, 20 heads of yellow cattle were selected from NiuJia town, Wu Chang City, Heilongjiang Province, China, and were randomly devided into 4 groups with 5 for each. ① supplemented with 0.7 mg·kg -1 iodine(potassium iodine), ② supplemented with 0.2 mg·kg -1 selenium (sodium selenite), ③ supplemented with 0.7 mg·kg -1 iodine(potassium Iodine) plus 0.2 mg·kg -1 selenium (sodium selenite) per day for 30 days, respectively. ④control group. The whole blood glutathione peroxidase (GSH-px) and catalase (CAT) activities, free radicals (FR) concentration, erythrocyte superoxide dismutase (SOD) activity and molonaldehyde (MDA) concentration, the serum triiodothyronine (T 3)、thyroxine (T 4) and thyrotropin (TSH) were determined on the day of supplementation day-0 and day-30, respectively. It was showed that average iodine concentration in drinking water and diet were 3.82 μg·L -1 and 0.285mg·kg -1 , respectively, Diet selenium was 0.0498mg·kg -1 , Serum protein bound iodine(PBI) was 7.02 μg·100 mL, Blood selenium was 0.14 mg·L -1 , the schoolchildren′s goiter was 21.8%. It indicated that iodine and selenium were deficient in the investigated area. Whole blood GSH-px and CAT activities and serum T 3 concentration were significantly higher (P< 0.01 ), FR concentration and serum TSH were significantly lower(P<0.01) in the first three groups than that of the control, T 4 content in the first group was higher(P<0.05), T 4 was also higher (P>0.05) in the second group. and lower in the third group. The SOD and MDA in erythrocyte were not changed during the experimental period, The results also showed that GSH-px and CAT activities were increased, and FR decreased oberviously in the third group more than the other two groups, In addition, Thyroid hormone metabolism was more coincided with the physiologic status in the third group. the iodine and the selenium played an important role in the pathologic process of free radical metabolic disorder. selenium not only had the function of antioxidation by derectly scavenging free radicals, but also affected through GSH-px and CAT activities. iodine deficiency results in the Goiter, selenium deficiency aggravated iodine deficiency, Iodine and the selenium were dependent and restrained each other in the course of free radicals and thyroid hormone metabolism with a synergistic state.

Metabolic actions of FGF21:molecular mechanisms and therapeutic implications

Fibroblast growth factor 21(FGF21)is an atypical member of the FGF family that functions as an endocrine factor.In obese animals,elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight,decreases hyperglycemia and hyperlipidemia,alleviates fatty liver and increases insulin sensitivity.FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets,including adipose tissue,liver,brain and pancreas.The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma(PPARγ)and peroxisome proliferator.-activated receptor alpha(PPARα).A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21.In humans,plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes,but are reduced in patients with autoimmune diabetes.This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions,and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

Metabolic syndrome and androgen deprivation therapy in metabolic complications of prostate cancer patients

Background Incidence of prostate cancer in Chinese males grows significantly in the past decades. Androgen deprivation therapy has been generally employed in the treatment of locally advanced and metastatic prostate cancer for many years, yet only little data was known about the metabolic syndrome in patients receiving hormonal therapy. This study described the prevalence and the changing trends of hormone-related metabolic complications, and analyzed their correlation with different therapies. Methods In 125 patients treated with castration or maximal androgen blockage for at least 12 months, metabolic indicators were analyzed. Results Totally, 13.5% patients in castration group and 30.1% patients in maximal androgen blockage group were diagnosed metabolic syndrome 12 months after the beginning of treatments （X2=4.739, P=0.029）. In castration group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 12, increased fasting plasma glucose and blood pressure were significant at the month 4. In maximal androgen blockage group, increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 4, increased fasting plasma glucose and blood pressure were significant at the month 8. Total testosterone and free testosterone in maximal androgen blockage group were significantly lower than castration group at all visits, which were proved to show positive or negative correlations with metabolic indications. Severity of metabolic complications in maximal androgen blockage group was generally more serious than people received castration, with significantly statistical difference or not. Trends of high-density lipoprotein-cholesterol and fasting plasma glucose were significant different between two kinds of therapy （P=0.005, P=-0.019, respectively）.

Hibernation with rhythmicity:the circadian clock and hormonal adaptations of the hibernating Asiatic toads(Bufo gargarizans)

Hibernation is one of the fundamental strategies in response to cold environmental temperatures.During hibernation,the endocrine and circadian systems ensure minimal expenditure of energy for survival.The circadian rhythms of key hormones,melatonin(MT),corticosterone(CORT),triiodothyronine(T3),and thyroxine(T4),and the underlying molecular regulatory mechanisms of hibernation have been well determined in mammals but not in ectotherms.Here,a terrestrial hibernating species,Asiatic toad(Bufo gargarizans),was employed to investigate the plasma CORT,MT,T3,and T4;and the retina,brain,and liver mRNA expression of the core clock genes,including circadian locomotor output cycles kaput(Clock),brain and muscle ARNT-like 1(Bmal1),cryptochrome(Cry)1 and 2,and period(Per)1 and 2,at 7-time points over a 24-h period under acute cold(1 day at 4℃),and hibernation(45 days at 4℃).Our results showed that the circadian rhythms of the core clock genes were rather unaffected by acute cold exposure in the retina,unlike the brain and liver.In contrast,during hibernation,the liver clock genes displayed significant circadian oscillations,while those in the retina and brain stopped ticking.Furthermore,plasma CORT expressed circadian oscillations in both groups,and T3 in acute cold exposure group,whereas T4 and MT did not.Our results reveal that the plasma CORT and the liver sustain rhythmicity when the brain was not,indicating that the liver clock along with the adrenal clock synergistically maintains the metabolic requirements to ensure basic survival in hibernating Asiatic toads.

Jasmonic Acid Oxidase 2 Hydroxylates Jasmonic Acid and Represses Basal Defense and Resistance Responses against Botrytis cinerea Infection

Jasmonates （JAs） orchestrate immune responses upon wound/herbivore injury or infection by necrotro- phic pathogens. Elucidation of catabolic routes has revealed new complexity in jasmonate metabolism. Two integrated pathways attenuate signaling by turning over the active hormone jasmonoyl-isoleucine （JA-Ile） through w-oxidation or deconjugation, and define an indirect route forming the derivative 12OH-JA. Here, we provide evidence for a second 12OH-JA formation pathway by direct jasmonic acid （JA） oxidation. Three jasmonic acid oxidases （JAOs） of the 2-oxoglutarate dioxygenase family catalyze spe- cific oxidation of JA to 12OH-JA, and their genes are induced by wounding or infection by the fungus Botrytis cinerea. JA02 exhibits the highest basal expression, and its deficiency in jao2 mutants strongly enhanced antifungal resistance. The resistance phenotype resulted from constitutive expression of antimi- crobial markers rather than from their higher induction in infected jao2 plants and could be reversed by ectopic expression of any of the three JAOs injao2. Elevated defense injao2 was dependent on the activity of JASMONATE RESPONSE 1 （JAR1） and CORONATINE-INSENSITIVE 1 （COI1） but was not correlated with erihanced JA-Ile accumulation. Instead, jao2 mutant lines displayed altered accumulation of several JA species in healthy and challenged plants, suggesting elevated metabolic flux through JA-Ile. Collectively, these data identify the missing enzymes hydroxylating JA and uncover an important metabolic diversion mechanism for repressing basal JA defense responses.