Baitouweng decoction repairs the intestinal barrier in DSS-induced colitis mice via regulation of AMPK/mTOR-mediated autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is one of non-specific inflammatory bowel disease that mainly affects the colon. Recently, UC has become a significant social and economic problem worldwide. Baitouweng decoction (BD), a traditional Chinese medicine described in the "Treatise on Febrile Diseases", has been used for centuries to treat intestinal diseases. However, its underlying mechanism remains largely unexplored. AIM OF STUDY: In this study, we aimed to investigate the effect of BD on autophagy for repairing the colonic barrier in DSS-induced colitis mice and explored its role in regulating the autophagic signaling pathway AMPK/mTOR. MATERIALS AND METHODS: Mice with colitis were treated with 3% dextran sulfate sodium (DSS) for 7 days. The effectiveness of BD in treating DSS-induced colitis was evaluated through body weight, disease activity index (DAI), colon length, pathological changes, organ index, and proportion of blood cells. Moreover, intestinal epithelial permeability was analyzed by examining FITC-dextran leakage, the bacterial load of mesenteric lymph nodes (MLNs), and bacterial infiltration of colon tissues. Barrier function was evaluated by assessing the number and proportion of colonic goblet cells and the expression of tight junction proteins, including ZO-1, claudin-1, and occludin. Furthermore, the levels of autophagy were assessed by examining the number of autophagosomes and the expression of the autophagy-related proteins LC3, Beclin1, and P62. Additionally, network pharmacology research was conducted to analyze the potential mechanisms underlying the medicinal effects, as indicated by the role of AMPK/mTOR in regulating the autophagic signaling pathway. RESULTS: BD improved colitis symptoms in mice by restoring body weight and colon length and reducing inflammatory cell infiltration. Additionally, BD decreased the diffusion of FITC-dextran and bacterial translocation in MLNs, as well as bacterial infiltration of the colonic mucosa. The number and proportion of colonic goblet cells, the expression of ZO-1, Claudin-1, and Occludin, and the levels of autophagy were also increased by BD. Network pharmacology analysis suggested that BD might affect intestinal autophagy through the AMPK signaling pathway, which was confirmed by the activation of AMPK phosphorylation and the downregulation of mTOR expression following BD treatment. CONCLUSION: Our study demonstrated that BD repaired the intestinal epithelial barrier in DSS-induced colitis mice by activating AMPK phosphorylation and inhibiting mTOR expression to promote autophagy.

Toxicological safety evaluation of zengye granule through acute and 30-day toxicity studies in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zengye granule (ZYG), a traditional Chinese medicine formula composed of Radix Scrophulariae, Radix Ophiopogonis, and Radix Rehmanniae in the ratio of 1.0:0.8:0.8, is listed in the Chinese Pharmacopoeia for treating diseases associated with yin deficiency, such as inner heat, dry mouth and pharynx, and dry bound stool. However, little information is available on its toxicological safety. AIM OF THE STUDY: To evaluate the acute and subacute toxicity of ZYG after oral administration in rats. MATERIALS AND METHODS: In the acute toxicity study, ZYG was orally administered to rats at a single dose of 10 g/kg/day. In the subacute toxicity study, ZYG was administered orally to rats at repeated daily doses of 2.5, 5.0, or 10 g/kg/day for 30 days. The toxicological effects were evaluated by assessing the rats' general behavior, body weight, food intake, water consumption, blood biochemical and hematological parameters, organ coefficients, and organ histopathology. RESULTS: No obvious adverse reactions were found in the rats in the acute toxicity study, indicating that ZYG was non-toxic. In the subacute toxicity study, ZYG had no toxic effect on the rats at a dose of 2.5 g/kg/day but showed slight toxicity in the kidneys, and spleens of the rats at doses of 5 and 10 g/kg/day. Significant drug toxicity was observed in male and female rats at 5 and 10/kg/day; however, elevated WBCs counts, ALT, and LYMs levels were found in female rats. CONCLUSIONS: The oral administration of ZYG at a dose of less than 10 g/kg/day for 1 day or 2.5 g/kg/day for 30 consecutive days can be considered safe, as these doses showed no distinct toxicity or side effects in the rats in this study. Therefore, the dosage should be set according to the clinically recommended dosage to ensure its safety.

Qingjie decoction attenuated E.coli-induced diarrhea by regulating energy metabolism and alleviating inflammation based on network analysis and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Diarrhea is a frequently encountered gastrointestinal complication in clinical practice, and E. coli is one of the main causative agents. Although Qingjie decoction (QJD) has been shown to be highly effective in treating diarrhea by eliminating heat-toxin, the underlying molecular mechanisms and pathways of QJD remain unclear. AIM OF REVIEW: The aim of this research was to explore the effects and fundamental mechanism of QJD on diarrhea induced by E.coli in rats. MATERIALS AND METHODS: Initially, we used UHPLC-MS/MS analysis to identify the chemical composition of QJD. Then, we constructed a visualization network using network pharmacology. Next, we utilized metabolomics to identify differentially expressed metabolites of QJD that are effective in treating diarrhea. RESULTS: The chemical composition of QJD was analyzed using UHPLC-MS/MS, which identified a total of 292 components. Using a network pharmacology approach, 127 bioactive compounds of QJD were screened, targeting 171 potential diarrhea treatment targets. TNF-α, IL-6, IL-1ß, and CAT were identified as important targets through visualizing the PPI network. Enrichment analysis demonstrated significant enrichment in the TNF signaling pathway, IL-17 signaling pathway, and PI3K-Akt signaling pathway. QJD showed beneficial effects, such as increased body weight, decreased fecal water content, and reduced inflammatory cell infiltration in the duodenum and colon, as well as maintaining the structure of the duodenum and colon. Metabolomic analysis revealed 32 differentially expressed metabolites in the control, model and QJD-H groups, including glucose, valine, and cysteine. Functional analysis indicated that differential metabolites were related to energy metabolism, including glucose metabolism, TCA cycle, and amino acid metabolism. CONCLUSION: QJD significantly increased body weight, decreased water content in feces, relieved inflammatory cell infiltration, maintained the structure of duodenum and colon. Combining network analysis and metabolomics, QJD exerted therapeutic effects by inhibiting inflammation and oxidative stress, regulating glucose metabolism, tricarboxylic acid metabolism, and amino acid metabolism.

Total flavonoids of Hippophae rhamnoides L. improves type 2 diabetes symptoms in rats through down-regulating of the DAG/PRKCA/MAPK10/p65/TNF-α signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dry mature fruits of Hippophae rhamnoides L. (HRL), Elaeagnaceae, have traditional functions of invigorating spleen and improving spleen insufficiency. Traditional Chinese medicine (TCM) clinics have been proved that HRL is in favor of diabetes treatment. Modern pharmacological studies demonstrated that total flavones of Hippophae rhamnoides (TFH) are the main substance for HRL to develop anti-inflammation and anti-diabetes functions. However, chemical features, active ingredients and anti-diabetes pharmacological mechanism of HRL still remain unclear. AIM OF THE STUDY: Key targets and metabolites in anti-type-II diabetes mellitus (T2DM) of TFH have been explored based on AGE-RAGE signaling pathway in diabetic complications. The anti-T2DM mechanism of TFH has been elaborated from comprehensive perspectives, including target prediction, metabolites, potential metabolic pathways, and so on. MATERIALS AND METHODS: In this study, a qualitative test of chemical composition of HRL was carried out based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The anti-T2DM targets and pathways of HRL were predicted through network pharmacological approach. The T2DM rat model was induced by high-fat and high-glucose diet combined with streptozotocin (STZ). The T2DM model was evaluated through fasting blood glucose level, body weight, serum biochemical indicators, insulin levels and homeostatic model assessment of insulin resistance. The key metabolic pathways were screened through the correlation between metabolites and key targets. Finally, the quantitative analysis of key targets and metabolites was verified through experiments. RESULTS: After TFH intervention, the fasting blood-glucose level of T2DM rats induced by high-fat and high-glucose diet combined with streptozotocin (STZ) was downregulated significantly, while body weight, serum liquid level, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were improved. According to ELISA, Western blotting (WB) and reverse transcriptase polymerase chain reaction (RT-PCR), TFH significantly downregulates expression levels of diglyceride (DAG)-activated protein kinase C (PRKCA), mitogen activated protein kinase 10 (MAPK10), human nuclear factor κB subunit p65 (NF-κB p65) and tumor necrosis factor-α (TNF-α) in pancreas of STZ-induced rats. CONCLUSIONS: TFH downregulates expressions of PRKCA, MAPK10 and p65 TNF-α as well as level of the key metabolite DA in the DAG/PRKCA/MAPK10/TNF-α/p65 pathways, improves lipid metabolism disorder, inhibits inflammatory response and thereby relieves symptoms of T2DM.

Effects of Cornus mas L. on anthropometric and biochemical parameters among metabolic associated fatty liver disease patients: Randomized clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus mas L. (Cornelian cherry, CM) fruits have been utilized for decades in numerous European and Asian countries as traditional cuisine and folk medicine. CM has antioxidant, anti-diabetic, anti-inflammatory, anti-obesity, and hypolipidemic activities due to its rich bioactive compounds, and CM fruits and other parts have been used for the prevention and treatment of a diverse variety of diseases in folk medicine. Obesity, insulin resistance, and inflammation are strongly associated with metabolic-associated fatty liver disease (MAFLD), therefore, CM may be hope for MAFLD patients. AIM OF THE STUDY: The study aimed to evaluate the effect of lyophilized CM fruit powder with/without diet therapy on biochemical parameters and anthropometric measurements in patients with MAFLD. MATERIALS AND METHODS: This randomized clinical trial was conducted on 87 patients with MAFLD and 21 healthy individuals. Patients were randomly assigned into 4 groups: group-1 receiving 30 g/d lyophilized CM fruit powder plus diet therapy, group-2 receiving only diet therapy, group-3 receiving only 30 g/d lyophilized CM fruit powder, and group-4 had not undertaken any pharmacological treatment and diet therapy or lyophilized CM fruit powder for 8 weeks. Biochemical parameters, and anthropometric measurements at baseline and after the intervention were taken. RESULTS: After 8 weeks of intervention, a significant decrease in body weight, body mass index, body fat mass, waist and hip circumferences, fasting blood glucose, insulin, hbA1c, liver enzymes, total triglycerides, low-density lipoprotein, total cholesterol were found in group-1, 2 and 3. CONCLUSION: Lyophilized CM fruit powder in addition to diet therapy and only diet therapy had a positive and similar effect on anthropometric measurements and biochemical parameters in MAFLD patients. Furthermore, only lyophilized CM fruit powder improved glycemic parameters. Therefore, lyophilized CM fruit powder may be beneficial for adult patients with MAFLD.

TGS1/PIMT knockdown reduces lipid accumulation in adipocytes, limits body weight gain and promotes insulin sensitivity in mice.

PRIP Interacting protein with Methyl Transferase domain (PIMT/TGS1) is an integral upstream coactivator in the peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional apparatus. PPARγ activation alleviates insulin resistance but promotes weight gain. Herein, we show how PIMT regulates body weight while promoting insulin sensitivity in diet induced obese mice. In vitro, we observed enhanced PIMT levels during adipogenesis. Knockdown of PIMT in 3T3-L1 results in reduced lipid accumulation and alters PPARγ regulated gene expression. Intraperitoneal injection of shPIMT lentivirus in high fat diet (HFD)-fed mice caused reduced adipose tissue size and decreased expression of lipid markers. This was accompanied by significantly lower levels of inflammation, hypertrophy and hyperplasia in the different adipose depots (eWAT and iWAT). Notably, PIMT depletion limits body weight gain in HFD-fed mice along with improved impaired oral glucose clearance. It also enhanced insulin sensitivity revealed by assessment of important insulin resistance markers and increased adiponectin levels. In addition, reduced PIMT levels did not alter the serum free fatty acid and TNFα levels. Finally, the relevance of our studies to human obesity is suggested by our finding that PIMT was upregulated in adipose tissue of obese patients along with crucial fat marker genes. We speculate that PIMT may be a potential target in maintaining energy metabolism, thus regulating obesity.

UPLC-Q-Exactive/MS based analysis explore the correlation between components variations and anti-influenza virus effect of four quantified extracts of Chaihu Guizhi decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu Guizhi decoction (CGD) is a classic Traditional Chinese Medicine (TCM) prescription for the treatment of influenza and fever, composes of Bupleuri Radix (Chaihu), Cinnamomi Ramulus (Guizhi), Scutellariae Radix (Huangqin), Codonopsis Radix (Dangshen), Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle (Zhigancao), Pinelliae Rhizoma Praeparatum (Fabanxia), Zingiberis Rhizoma Recens (Shengjiang), Paeoniae Radix Alba (Baishao) and Jujubae Fructus (Dazao) in the ratio of 12:4.5:4.5:4.5:3:6:4.5:4.5:4. The efficacy of TCM, if there are differences, depends on the different extraction methods and extracted components. AIM OF THE STUDY: This study was to evaluate the anti-influenza virus effect of CGD extracts with different extraction methods, analyze the components and explore their correlation. MATERIALS AND METHODS: CGD were prepared with four extraction methods respectively, the traditional decoction (TD), two steps alcohol-water extraction (AWE), alcohol reflux extraction (AE) and water reflux extraction (WE). Based on the influenza mouse model, the efficacy of anti-influenza virus in vivo of the four CGD extracts were evaluated with the therapeutic index of body weight, rectal temperature, lung index, thymus index and lung viral load of mice. The chemical components in four CGD extracts, and compounds absorbed in rats blood with prototypes or metabolites were identified by UPLC-Q-Exactive/MS. The partial least squares (PLS) method was used to explore the correlation between the components variation in CGD extracts and the comprehensive efficacy index. The potential effective components were further accessed by molecular docking. RESULTS: Comparing with the other three extracts, AWE has the best anti-influenza effect. It could ameliorate the symptoms caused by influenza virus infection in mice, increase body weight and rectal temperature, reduce the lung index and virus load in lung tissue. 129, 144, 140 and 129 components were identified from TD, AWE, AE, and WE respectively. The identified components were mainly including flavonoids, terpenoids, organic acids, phenylpropanoids, amino acids, nucleosides, phenols, alkaloids, etc. 43 prototypes and 49 metabolites of CGD were detected in rat plasma after oral administration. Seven components, cinnamaldehyde, wogonoside, baicalin, baicalein, gallic acid, oroxylinA-7-O-glucuronide and coumarin, showed significant correlation with anti-influenza effects, all of which had good binding activity with NA, IL-6, STAT3, AKT1, EGFR and TNF. CONCLUSION: Two steps alcohol-water extraction was optimal for CGD preparation. Cinnamaldehyde, wogonoside, oroxylinA-7-O-glucuronide, coumarin, gallic acid, baicalein and baicalin play a certain essential role in anti-influenza effects and may be taken as a potential maker compounds for quality evaluation of CGD.

Assessment of cytotoxicity, acute, subacute toxicities and antioxidant activities (in vitro) of Sanghuangporus vaninii crude polysaccharide.

ETHNOPHARMACOLOGY RELEVANCE: Sanghuangporus vaninii (S. vaninii), as a traditional large medicinal fungus, has a history of more than 2000 years in Chinese history and has been widely used to treat female diseases such as vaginal discharge, amenorrhea, and uterine bleeding, and recent pharmacological studies have also found that it has antioxidant, anti-inflammatory, and anti-tumor physiological activity, which has received more and more attention. AIM OF THE STUDY: The objective was to evaluate cytotoxicity and the acute, subacute toxicity, and in vitro antioxidant activity of S. vaninii crude polysaccharide (SVP). MATERIALS AND METHODS: The monosaccharide composition of SVP was determined by HPLC (high-performance liquid chromatography). The cytotoxicity of different concentrations of SVP on three types of cells (HT-22, Kupffer macrophages, HEK293) was assessed using CCk-8. The acute toxicity in vivo was evaluated for 14 days after the administration of SVP (2500,5000, or 10,000 mg/mL). For the evaluation of subacute toxicity, mice were daily treated for 28 days with SVP (2500,5000, or 10,000 mg/mL). In addition, DPPH, hydroxyl radical, and superoxide anion radical were used to evaluate the in vitro antioxidant activity of SVP. RESULTS: SVP was not toxic in all three cell lines tested. In vitro antioxidant tests on the extracts showed that SVP possessed a strong antioxidant capacity in vitro. In the acute study, the no-observed-adverse-effect level (NOAEL) in male and female rats was 10，000 mg/kg body weight. There were also no deaths or severe toxicity associated with SVP in subacute studies. However, SVP treatment had a decreasing effect on body weight in mice of both sexes (2500, 5000, and 10000 mg/kg). At doses (5000 and 10,000 mg/kg), SVP had a reduced effect on food intake in both male and female mice. In addition, there were significant effects on organ coefficients of the liver, lung, and kidney. Hematological analysis showed significantly lower LYM (%) values in mice of both sexes, with significantly lower MCH (pg) values obtained in males (5000 mg/kg and 10000 mg/kg) and higher GRAN (%) values in females. In addition, the RDW-SD (fL) values were significantly lower in the male mice given the highest dose. Biochemical tests showed that there were no significant changes in ALT, AST, TP, and Cr levels after SVP treatment. In histopathological analysis, mild liver toxicity was observed in both female mice treated with 10,000 mg/kg SVP. CONCLUSION: The extract of SVP showed a predominance of polysaccharide compounds, with non-toxic action in vivo. Our approach revealed SVP on the chemical composition and suggests a high margin of safety in the popular use of medicinal fungi. In conclusion, our results suggest that SVP is safe, and can be used as health care products and food.

Sex-dependent effects of rice cadmium exposure on body weight, gut microflora, and kidney metabolomics based on a mouse model.

Consumption of cadmium (Cd) contaminated rice is the main dietary source of Cd exposure and toxicity. To protect humans from Cd toxicity, it is pivotal to fully understand the sex-dependent toxicity of subchronic rice-Cd exposure. However, the sex-dependent effects of subchronic rice-Cd exposure on body weight gain, gut microflora, and kidney metabolomics are still unclear. In this study, a Cd-free and a Cd-contaminated rice (0.005 and 0.74 mg Cd kg-1) were fed to both female and male mice for one month, with changes in body weight gain, Cd accumulation in tissue, bone mineral concentration, expression of intestinal channels involving in Cd and calcium (Ca) absorption, gut microbiota, and kidney metabolites assessed for both genders. Results showed that female mice had normal body weight gain after rice-Cd exposure, while body weight of male mice was decreased from 19.8 to 17.5 g over the one-month consumption of the Cd-contaminated rice (0.74 mg kg-1), suggesting specific toxicity on growth of male mice. Rice-Cd exposure had limited effects on gut microbiota for both genders. However, higher Cd accumulation in liver and femur was observed in male mice than in females, which may be due to higher intestinal expression of Ca channels involving in intestinal Cd absorption in male mice with rice-Cd exposure. Greater risk of osteoporosis was also observed in male mice. In addition, kidney metabolomic profiling showed special disruption of adrenocortical hormone homeostasis for male mice with rice-Cd exposure. Particularly, expression of cortisol in kidneys of male mice was elevated 37.1-fold with rice-Cd exposure, likely resulting in Cushing's syndrome and contributing to growth retardation. This study advances our understanding of the sex-dependent toxicity of rice-Cd exposure, and highlights the priority of protecting males from the adrenocortical hormone disrupting effects of rice-Cd exposure.

Effects of a Theory-Based Educational Program on Health Behaviors and Cardiovascular Health Outcomes Among Overweight Postmenopausal Women: A Randomized Controlled Trial.

BACKGROUND: With the natural cessation of estrogen, after menopause, women, especially those who are overweight, are at a high risk for cardiovascular disease. Diet control and adequate physical activity (PA) are recommended as the essence of promoting cardiovascular health for women after menopause. OBJECTIVE: The aim of this study was to examine the effects of a theory-based educational program on health behaviors and cardiovascular health outcomes among overweight postmenopausal Chinese women compared with conventional didactic education. METHODS: In this randomized controlled trial, 288 participants were randomly allocated to intervention (n = 144) or control (n = 144) groups. The control group received conventional didactic education. The intervention group received a 3-month theory-based educational program. Primary outcomes were PA and dietary behavior. Secondary outcomes included cardiovascular health knowledge, self-efficacy in PA and diet, and cardiovascular health outcomes. Data were collected at baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3). RESULTS: The intervention group demonstrated significantly greater improvements in PA, dietary behavior, self-efficacy in PA and diet, and several cardiovascular health outcomes (body weight, body mass index, waist circumference, blood pressure, and Framingham risk score [body mass index]) at postintervention compared with the control group (all P s < .05). These significant effects maintained at T2, and the effects on self-efficacy in PA and diet also were maintained at T3. CONCLUSIONS: A theory-based educational program may be an effective strategy for improving PA, dietary behavior, self-efficacy in PA and diet, and several cardiovascular health outcomes for overweight postmenopausal Chinese women. However, further strategies are needed to enhance the sustainability of the positive changes.

Probiotic-fermented tomato alleviates high-fat diet-induced obesity in mice: Insights from microbiome and metabolomics.

Probiotic-fermented plant-based foods are associated with weight loss. Here, we hypothesized probiotic-fermented tomato (FT) as a functional food with potential to alleviate obesity, thus the obesity-alleviating effects and mechanisms of FT on high-fat diet-induced obese mice were explored via biochemical, gut microbiome, and serum metabolomics analysis. The results showed that FT performed better than unfermented tomato in reducing body weight gain and fat accumulation, improving dyslipidemia and glucose homeostasis, and relieving inflammation and adipocytokine dysregulation. Particularly, live probiotic-fermented tomato (LFT) was associated with improved diversity, composition, and structure of gut microbiota, suppressed obesity-related genera growth (e.g., Clostridium, Olsenella, and Mucispirillum), and promoted beneficial genera growth (e.g., Roseburia, Coprococcus, and Oscillospira), which were associated negatively with body weight, TC, TG, and TNF-α levels. Additionally, LFT was associated with positive changes in glycerophospholipids, sphingolipids, unsaturated fatty acids, and amino acids levels. Collectively, as a functional food, LFT possessed potential for obesity alleviation.

Jianpi Shengqing Huazhuo Formula improves abnormal glucose and lipid metabolism in obesity by regulating mitochondrial biogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Shengqing Huazhuo Formula (JSH) is a modified prescription based on traditional Chinese medicine theory and classic prescriptions (Buzhong Yiqi Decoction and Yuye Decoction). It has been found that JSH has a good effect on obese patients with early abnormal glucose and lipid metabolism. Therefore, this experiment was conducted to study its clinical efficacy and pharmacological effect. AIM OF THE STUDY: To observe the clinical efficacy of JSH and explore the mechanism of the formula to improve glucose and lipid metabolism in obese rats. MATERIALS AND METHODS: 1. CLINICAL OBSERVATION: 10 overweight/obese patients with abnormal glucose and lipid metabolism were selected to observe the indicators of serum glucose, serum lipids and liver damage of the patients before and after treatment with JSH. 2. Animal experiments: Fifty Sprague-Dawley (SD) rats were randomly divided into control group, model group, Metformin group (120 mg/kg/day), JSH-L group (5 g/kg/day) and JSH-H group (20 g/kg/day), with 10 rats in each group. The obese SD rat model was produced by feeding 60% high-fat diet for 8 weeks, and the drug group was given prophylactic administration for 8 weeks. At the end of the experiment, body weight, abdominal fat, plasma glucose, plasma lipids, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. The levels of interleukin-6 (IL-6), interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in plasma were detected by Elisa, and the changes of malondialdehyde (MDA), glutathione (GSH) and catalase (CAT) in plasma and liver tissue were detected by kits. The pathological changes and lipid deposition in liver were observed by HE staining and oil red O staining, and the changes in the number of mitochondria in liver cells were observed by transmission electron microscopy. RT-qPCR and Western Blot (WB) were used to detect the mitochondrial regulation-related indicators PGC-1α, NRF1, TFAM, MFN2, DRP1 and apoptosis-related indicators Bcl-2, Bax, caspase 8 in liver tissue. RESULTS: 1. CLINICAL OBSERVATION: After one month administration, the patient's body weight, BMI, 2 h oral glucose tolerance test (2hOGTT), glycated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) decreased significantly, and the indicators of liver damage AST and ALT also decreased significantly. 2. Animal experiments: JSH can significantly reduce body weight and abdominal fat area, improve glucose and lipid metabolism, and also reduce plasma IL-6, IL-1ß and TNF-α content in obese rats, and improve oxidative stress; HE staining and oil red O staining also showed that JSH can alleviate liver damage and lipid deposition in the liver. Further observations of liver cell ultrastructure showed that JSH can ameliorate the reduction of liver mitochondria caused by a high-fat diet and promote the expression of indicators of mitochondrial biogenesis related to PGC-1α, NRF1, and TFAM. Moreover, JSH could promote the expression of MFN2 and DRP1, decrease Bcl-2 and increase Bax in the liver. CONCLUSIONS: 1. CLINICAL OBSERVATION: JSH can reduce body weight, serum glucose, serum lipid, and liver injury in overweight/obese patients. 2. Animal experiments: JSH regulates PGC-1α/NRF1/TFAM signaling pathway promotes liver mitochondrial biogenesis, improves glucose and lipid metabolism in obese rats, and regulates mitochondrial dependent apoptosis indicators Bcl-2/Bax to reduce liver injury.

Safety and antidiabetic activity of Lagenaria siceraria (Molina) Standl. juice in streptozotocin -induced diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes and its complications have overwhelmed India's healthcare system. Current therapies are expensive and have adverse side effects, thus dietary changes and alternative treatments are needed. Lagenaria siceraria (Molina) Standl. Juice is used mainly for its nutritional and medicinal values, however toxicity of the juice and antidiabetic effects have been poorly characterized. AIM OF THE STUDY: To investigate the toxicity, anti-diabetic and anti-inflammatory efficacy of Lagenaria siceraria (Molina) Standl. (LS) juice. MATERIALS AND METHODS: In vitro antidiabetic (α-glucosidase, α-amylase and DPP-4 inhibitory) activities were screened using standard procedures. The glucose uptake test was carried out by using L6 rat skeletal muscle cell line. In vivo sub-acute toxicity of LS juice was assessed on Wistar rats. Wistar rats were induced with diabetes by a single intraperitoneal (I.P) injection of freshly prepared streptozotocin (55 mg/kg body weight). The animals were randomly divided into 6 groups: normal control, untreated diabetic control, diabetic rats. Different dose of 200 mg/kg, 400 mg/kg and 600 mg/kg body weight of LS juice were administered, one group of diabetic rats were administered with 2 IU/mL insulin. The rats were sacrificed on the 31st day of the experiment and various in vivo biochemical parameters were evaluated in the serum and tissue homogenates of diabetic rats. RESULTS: Significant dose-dependent inhibition of α-amylase (22.6%), α-glucosidase (50.13%), and DPP-4 (61.50%) activity was observed by LS juice. LS juice (10 µg/mL) increased insulin-mediated 2NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose) absorption in L6 cells. Animals treated with LS juice showed no toxicity or unfavorable pharmacological effects. Lagenaria siceraria (Molina) Standl. Juice improved glucose tolerance in diabetic rats with reduced fasting blood glucose. Lipopolysaccharide induced NF-κB, TNF-α and IL-1ß production was also decreased in rats fed with LS juice. CONCLUSION: Lagenaria siceraria (Molina) Standl. Juice has demonstrated promising anti-inflammatory properties as well as the capacity to inhibit the digestion enzymes glucosidase and amylase. Our findings thus open new avenues for further research into the antidiabetic potential of LS juice.

Kuijie decoction ameliorates ulcerative colitis by affecting intestinal barrier functions, gut microbiota, metabolic pathways and Treg/Th17 balance in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Currently, the clinical treatment is limited and difficult to achieve satisfactory results for ulcerative colitis (UC). The role of traditional Chinese medicine (TCM) in the treatment of UC is very complex. Kuijie decoction (KJD) as a classic TCM, is widely used in the clinical treatment of UC, but the mechanism of its action is still unclear. AIM OF THE STUDY: This study is to investigate the protective effects of KJD on UC and the underlying mechanisms. MATERIALS AND METHODS: The experimental model of UC was induced by DSS, and KJD was introduced into the model at the same time. Clinical symptoms, including the body weight, colon length and colon histopathological, were used to measure the severity of colitis. The expression of inflammatory cytokines and tight junction proteins was quantified. The effect of KJD on intestinal flora and intestinal metabolism was determined by 16S rRNA and untargeted metabolomics analysis, respectively. The proportion of Th17 cells and Tregs in the spleen was examined by flow cytometry. RESULTS: Mice treated with KJD showed significantly alleviated clinical symptoms and histological damage, such as more body weight gain, lower disease activity index (DAI) score, and longer colon length. The administration of KJD also led to the down-regulation of inflammatory mediators, upregulation of the expression of ZO-1, occludin and decreased claudin-2, as well as altered microbiota composition against DSS challenges (especially an increase of Lachnospiraceae). KJD enhanced the percentage of Treg cells but decreased the proportion of Th17 cells to maintain intestinal homeostasis by improving gut microbiota metabolism. CONCLUSIONS: In summary, KJD maintained intestinal epithelial homeostasis by regulating epithelial barrier function, intestinal flora, and restoring Th17/Treg balance. KJD has the potential to be a Chinese medicine treatment for UC.

Xinmaikang (XMK) tablets alleviate atherosclerosis by regulating the SREBP2-mediated NLRP3/ASC/Caspase-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinmaikang (XMK) tablets, a Chinese patent medicine, have been used for the prevention and treatment of atherosclerosis (AS) clinically. However, the underlying mechanism of XMK is far from completely illustrated. AIM OF THE STUDY: This study aimed to determine whether XMK alleviates AS in Apolipoprotein E-knockout (ApoE-/-) mice and to explore the potential mechanism of action in bone marrow-derived macrophages (BMDMs). MATERIALS AND METHODS: XMK decoction was analyzed by an LC‒MS/MS assay. Molecular docking was conducted to determine the interaction of XMK molecular ligands and AS targets. In vivo, 10 ApoE-/- mice were selected as the control group. Fifty ApoE-/- mice were randomly divided into 5 groups: the model group, low-, medium-, and high-dose XMK groups and the simvastatin group. Mice in the control group were fed a chow diet, and the other 5 groups were fed a high-fat diet (HFD) for 12 weeks. After 12 weeks, the treatment groups were administered low-dose XMK (2.28·kg-1·d), medium-dose XMK (4.55·kg-1·d), high-dose XMK (9.1 kg-1 d) and simvastatin (91 mg-1 d) for another 12 weeks. Serum enzymology assays tested AST/ALT, Cr, LDH and CK-MB levels. The atherosclerotic plaques and lipid deposition were measured by Oil red O (ORO) staining and Hematoxylin and Eosin (H&E) staining. Then, we examined the body weight and serum lipids (TC, TG, LDL-C and HDL-C) of the mice. ELISA was performed to determine the levels of inflammatory factors (IL-6, TNF-ɑ, VCAM-1, CXCL8 and CCL2). SREBP2/NLRP3 signaling pathway-related genes (SREBP2, NLRP3, ASC, IL-1ß and Caspase-1) were analyzed by RT‒qPCR and western blotting. In vitro, LPS-stimulated BMDMs were treated with different concentrations of XMK (1, 2.5, 5, 10, 20, and 40 µg/ml). Immunofluorescence staining (SREBP2, NLRP3), adenovirus infection and siRNA knockdown (SREBP2, NLRP3, Caspase-1 and ASC) were conducted as complements to the in vivo experiment. RESULTS: Molecular docking showed a stable interaction between the effective components of XMK and SREBP2 and NLRP3. Serum enzymology assays revealed the medication safety of XMK in cardiac, hepatic and renal function. Studies in vivo indicated that XMK improved serum lipids (TC, TG, LDL-C and HDL-C) and reduced plaque area. Body weight decreased, and the expression of inflammatory cytokines (IL-6, TNF-ɑ and VCAM-1) was inhibited. Then, XMK downregulated the mRNA and protein expression of SREBP2, NLRP3, ASC, IL-1ß and Caspase-1. In vitro, the above findings were reinforced in BMDMs, and knocking down SREBP2 restrained the effect of XMK on the NLRP3/ASC/Caspase-1 signaling pathway. CONCLUSIONS: XMK restrains AS by improving inflammation through the SREBP2-mediated NLRP3/ASC/Caspase-1 signaling pathway.

Population pharmacokinetic/pharmacodynamic modeling and exposure-response analysis of ciprofol in the induction and maintenance of general anesthesia in patients undergoing elective surgery: A prospective dose optimization study.

AIM: This study aimed to establish a population pharmacokinetic and pharmacodynamic (PK-PD) model to explore the optimal maintenance dose and appropriate starting time of maintenance dose after induction of ciprofol and investigate the efficacy and safety of ciprofol for general anesthesia induction and maintenance in patients undergoing elective surgery. METHOD: A total of 334 subjects with 3092 concentration measurements from nine clinical trials and 115 subjects with 5640 bispectral index (BIS) measurements from two clinical trials were used in the population PK-PD analysis. Exposure-response relationships for both efficacy endpoints (duration of anesthesia successful induction, time to recovery from anesthesia, time to respiratory recovery, and time from discontinuation to the 1st/3rd consecutive Aldrete score ≥ 9) and safety variables (hypotension, bradycardia, and injection site pain) were evaluated based on the data gathered from 115 subjects in two clinical trials. RESULT: Ciprofol pharmacokinetics (PK) were adequately described by a three-compartment model with first-order elimination from the central compartment and redistribution from the deep and shallow peripheral compartments. An inhibitory sigmoidal Emax model best described the relationship between ciprofol effect-site concentrations and BIS measurements. Body weight, age, sex, blood sampling site, and study type (short-term infusion vs long-term infusion) were identified as statistically significant covariates on the PK of ciprofol. No covariates were found to have a significant effect on the pharmacodynamic (PD) parameters. The PK-PD simulation results showed that the optimal maintenance dose was 0.8 mg/kg/h and the appropriate time to start the maintenance dose was 4-5 mins after the induction dose of ciprofol. Within the exposure range of this study, no meaningful correlations between ciprofol exposures and efficacy or safety endpoints were observed. CONCLUSION: A population PK-PD model was successfully developed to describe the ciprofol PK and BIS changes. Efficacy was consistent across the exposure range with a well-tolerated safety profile indicating no maintenance dose adjustment is required for patients undergoing elective surgery.

The effect of regular running on body weight and fat tissue of individuals aged 18 to 65.

BACKGROUND: Age and reduction in performed physical activity cause physiological changes that include an increase in body fat (BF) and visceral fat (VF) during aging. These parameters, together with increased body mass (BM), are some of the risk factors of several noninfectious diseases. However, changes in body composition can be influenced by regular physical activity. Running is a suitable, accessible, and the most effective physical activity cultivating people. The objective of this study is to investigate the effects of long-term, regular PA, specifically recreational running, on changes in body composition among recreational adult runners covering a weekly distance of at least 10 km, compared with inactive adult individuals within the same age bracket. METHODS: The study included 1296 runners and inactive individuals (691 male and 605 female), divided into 5 age groups: 18-25, 26-35, 36-45, 46-55, and 56-65 years. Runners are as follows: ran ≥ 10 km/week, and inactive is as follows: did not follow the WHO 2020 physical activity recommendations. The measured parameters included BM, BF, and VF. To check statistical significance, the Mann-Whitney U-test was used. Practical significance was assessed using the effect of size. RESULTS: All age groups of runners were selected to include individuals who run at least 10 km per week. In fact, they ran, on average, from 21.6 to 31.4 km per week in relation to age and showed significantly lower values of BM, BMI, BF, and VF (p < 0.05) than inactive individuals. Exceptions included insignificant differences (p > 0.05) in BM and BMI in males in the age category of 18-25 and in females in the age category of 18-25 and 26-35. CONCLUSION: The selected runners had to run at least 10 km per week. Their actual average volume was significantly higher (from 21.6 to 31.4 km/week), and the results showed that it could lead to significantly better body composition values. It may lead to significant changes in body mass, body fat, and visceral fat. It may meet the contemporary societal expectations for physical activities that are both achievable and effective at the lowest possible volume.

Efficacy of zinc acetate hydrate for hypozincemia in the elderly is influenced by the initial accumulated exposure dose after taking zinc acetate hydrate.

This study aimed to determine the efficacy of zinc acetate hydrate (ZAH) for hypozincemia in elderly hospitalized patients with an accumulated exposure of < 1000 mg of ZAH and to explore the factors affecting the therapeutic efficacy of ZAH. Seventy-four patients (mean age, 82 years) were enrolled in this study. All patients (n = 74) had low serum zinc levels (< 80 µg/dL), and the mean serum zinc concentration before ZAH administration was 53.6±10.7 µg/dL. The median serum zinc level (µg/dL) elevated per tablet (25 mg) of ZAH was 1.26 µg/dL, and the patients were divided into two groups, the slightly increased (< 1.26) and significantly increased (≥ 1.26) groups, based on the median cutoff value for the median increase in serum zinc level. A significant difference was found between the slightly increased (0.63±0.35 µg/dL, n = 36) and significantly increased (2.37±0.95 µg/dL, n = 38) groups (p < 0.0001, Wilcoxon rank-sum test). Logistic regression analysis with the accumulated exposure dose of ZAH, sex, and body weight as multivariate variables showed a significant difference in the accumulated exposure dose (total number of tablets per 25 mg: odds ratio, 1.119; 95% confidence interval, 1.052???1.203; p = 0.0009). There was no effect of underlying disease or of diet or zinc-containing intravenous or enteral nutrition on serum zinc levels. These results suggest that at an accumulated exposure of < 1000 mg of ZAH, serum zinc levels tend to increase with smaller accumulated doses. Therefore, serum zinc concentrations should be measured at the accumulated exposure to 500-1000 mg after ZAH initiation for the treatment of zinc deficiency in elderly hospitalized patients.

Knowledge, experiences, and perceptions relating to obesity management among primary care physicians in the Lazio Region, Italy.

Background: Primary care providers (PCPs) play an essential role in obesity care as they represent the first contact for patients seeking weight loss interventions. Objective: This study explored the knowledge, experiences, and perceptions of PCPs in the Lazio Region of Italy in the management of obesity. Design and subjects: We conducted an anonymous survey delivered from March to July 2022 via the newsletter of Rome Provincial Order of Physicians and Dentists and at the annual meeting of the regional section of the Italian Obesity Society. Approach: The survey consisted of 24 closed-ended questions grouped into 5 sections: sociodemographic and work information; assessment of obesity; management of obesity; connections with regional Centres for Obesity Management; attitudes towards obesity. Key results: A total of 92 PCPs accessed the survey. Of those, 2.2% were excluded because they did not see any patients with obesity. A total of 68 PCPs (75.6%) had complete questionnaires and were included in this analysis. All participants reported asking their patients about their eating habits, lifestyle, and clinical complications at the first assessment. Body weight and blood pressure were measured by 98.5% of participants and 82% calculate body mass index (BMI), while a small proportion of PCPs analysed body composition and fat distribution. Over 80% prescribed laboratory tests and ECG. Approximately 40% of PCPs did not refer patients for nutritional counselling, and most prescribed a low-calorie diet. Sixty-three percent referred patients to an endocrinologist, 48.5% to a psychotherapist, and a minority to specialists for obesity complications. Twenty-three percent prescribed anti-obesity medications and 46.5% referred patients for bariatric surgery only in severe cases. Ninety-one percent stated that obesity is "a complex and multifactorial disease" and 7.4% considered obesity to be secondary to other conditions. Conclusions: Despite most PCPs adopt a correct approach to manage patients with obesity, many aspects could be improved to ensure optimal and multidisciplinary management.

Effects of different volumes of ovariectomy on fertility and offspring development of rats.

Objective: The purpose of this study was to explore the effect of removal of different volumes of ovarian tissue on fertility and offspring development of SD rats. Methods: SD rats were randomly divided into 6 groups according to different volumes of ovariectomy: Sham group (n=6), non-ovariectomized; 25%-OVX group (n=6), with half of the left ovary excised; 50%-OVX group (n=5), with the left ovary excised; 75%-OVX group (n=5), with the left ovary and half of the right ovary excised; 87.5%-OVX group (n=6), with the left ovary and three quarters of the right ovary excised; 100%-OVX group (n=6), with bilateral ovaries excised. These female rats (F0) were mated with healthy male rats one and four months after the surgery, and the offspring of F0 rats were named F11mon and F14mon, respectively. The number of days from mating to delivery and number of live cubs were recorded. At postnatal day 21 (P21), the body weight, length and anogenital distance (AGD) of the cubs were measured. Results: There were no differences in the number of live cubs between 25%-OVX, 50%-OVX and sham groups. Rats in the 87.5%-OVX group did not give birth at 1 month and 4 months after the operation. When compared with the sham group, the body weight and length of F11mon at P21 were increased in 25%-OVX group and 50%-OVX group. However, after the second delivery, we controlled each mother's lactation to no more than eight pups. As a result, there were no differences in the body weight, length and AGD of F14mon compared with sham group. Conclusion: Removal of less than 50% of the ovaries did not affect the fertility of rats and offspring development of rats.