Decreased Body Weight Research Articles

Therapeutic potentials of Hibiscus trionum: Antioxidant, anti-lipid peroxidative, hypoglycemic, and hepatoprotective effects in type 1 diabetic rats

Recent advances in diabetes treatment have primarily focused on insulin and hypoglycemic agents; however, there is growing interest in exploring herbal and synthetic alternatives. Numerous studies have highlighted the preventive effectiveness of regular plant consumption in managing chronic conditions, particularly diabetes. Hibiscus, a medicinal plant recognized in various cultures, is known for its diverse health benefits. This study investigated the impact of Hibiscus trionum on glycemic control and assessed its influence on glucose and insulin levels in diabetes-induced rats. The concentrations of antioxidant enzymes, particularly superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), were scrutinized across multiple body tissues (plasma, heart, muscle, liver, and kidney). The malondialdehyde (MDA) concentration, an indicator of lipid peroxidation, was examined in both plasma and tissue samples. Serum total cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were evaluated. Diabetic Group (D) exhibited a significant decrease in body weight, increased fluid and food consumption, elevated blood glucose levels, and increased antioxidant enzyme activity. Moreover, the diabetic group also showed increased levels of MDA, TC, TG, AST, and ALT, along with reduced insulin levels, compared to the control group. A substantial improvement in all parameters impaired by diabetes was observed following the application of Hibiscus trionum (HTT) in the Diabetes+HTT group. The antioxidative stress-reducing, lipid peroxidation-improving, and hepatoprotective potential of Hibiscus trionum in mitigating diabetes-induced oxidative stress is noteworthy. These findings indicate that HTT supplementation has valuable beneficial effects in protecting against the harmful impacts of diabetes.

Chronic lead poisoning–induced budgerigar liver damage, gut microbiota dysbiosis, and metabolic disorder

Birds are sensitive to heavy metal pollution, and lead (Pb) contamination can negatively affect their liver and gut. Therefore, we used budgerigars to examine liver and gut toxicosis caused by Pb exposure in bird, and the possible toxic mechanisms. The findings showed Pb exposure increased liver weight and decreased body weight. Moreover, histopathological and immunofluorescence assay results demonstrated obvious liver damage and cell apoptosis increased in Pb- treated budgerigars. Quantitative polymerase chain reaction (qPCR) results also showed Pb caused an increase in apoptosis by inhibiting the PPAR-γ/PI3K/Akt pathway. The gut microbe analyses indicated Firmicutes, Proteobacteria, and Bacteroidetes were dominant microbial phyla, and Network analysis results shown Arthrobacter, Bradyrhizobium and Alloprevotella as the hubs of Modules I, II, and III, respectively. Phenylpropanoids and polyketides, Organoheterocyclic compounds, Organic oxygen compounds, and Organic nitrogen compounds were dominant metabolite superclasses. Tauroursodeoxycholic acid, taurochenodeoxycholic acid (sodium salt), and 2-[2-(5-bromo-2-pyridyl)diaz-1-enyl]-5-(diethylamino)phenol were significantly enriched in the Pb-treated group. It showed that 41 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues and 183 pathways differed between the Pb-treated and control budgerigars using microbial and metabolomic data. Moreover, orthogonal partial least-squares discrimination analysis (OPLS-DA) based on microbial and metabolite indicated distinct clusters in the Pb-treated and control groups. Additionally, the correlation analysis results indicated that a positive correlation for the Pb-treated and control groups between gut microbiota and metabolomic data, respectively. Furthermore, the microenvironment of the gut and liver were found to affect each other, and this study demonstrated heavy metal especially Pb may pose serious health risks to birds through the “gut–liver axis” too.

Chlorogenic acid ameliorates intestinal inflammation via miRNA-microbe axis in db/db mice.

Chlorogenic acid improves diabetic symptoms, including inflammation, via the modulation of the gut microbiota. However, the mechanism by which the microbiota is regulated by chlorogenic acid remains unknown. In this study, we firstly explored the effects of chlorogenic acid on diabetic symptoms, colonic inflammation, microbiota composition, and microRNA (miRNA) expression in db/db mice. The results showed that chlorogenic acid decreased body weight, improved glucose tolerance and intestinal inflammation, altered gut microbiota composition, and upregulated the expression level of five miRNAs, including miRNA-668-3p, miRNA-467d-5p, miRNA-129-1-3p, miRNA-770-3p, and miRNA-666-5p in the colonic content. Interestingly, the levels of these five miRNAs were positively correlated with the abundance of Lactobacillus johnsonii. We then found that miRNA-129-1-3p and miRNA-666-5p promoted the growth of L. johnsonii. Importantly, miRNA-129-1-3p mimicked the effects of chlorogenic acid on diabetic symptoms and colonic inflammation in db/db mice. Furthermore, L. johnsonii exerted beneficial effects on db/db mice similar to those of chlorogenic acid. In conclusion, chlorogenic acid regulated the gut microbiota composition via affecting miRNA expression and ameliorated intestinal inflammation via the miRNA-microbe axis in db/db mice.

2024 update in heart failure.

In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4mg once weekly administered for 1year decreased body weight and significantly improved quality of life and the 6min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

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Anaerobic productivity is characterized by the body’s ability to perform muscle work due to anaerobic processes of energy supply and is characterized by their power and capacity. Data on the age-related dynamics of the body’s anaerobic productivity are contradictory. Studying the anaerobic capabilities of girls in the mountainous regions of Zakarpattia Oblast, we understand that the somatotype and functional capabilities of the body are formed in this category of persons in conditions of relative hypoxia. Szymczak R.K. et al researching the effect on the physiology of the body of a long stay at a very high altitude (over 3500 m), male climbers note that in conditions of hypoxia, the anaerobic productivity of the body decreases, the maximum respiratory volume increases, and the relative content of the fat component of the body weight decreases. Therefore, the study of indicators of anaerobic productivity of the body’s energy supply in healthy girls may allow developing individual and population medical prognosis in the future. The level of physical health was assessed by indicators of anaerobic productivity of the body, assessing the ability of women living in mountainous regions to adapt to performing physical work in an anaerobic mode. For this purpose, we used the Wingat anaerobic test method described by Yu.M. Furman et al, the method of Shogy A., Cherebetin G. and somatotype was determined according to Heath-Carter. Having studied the anaerobic capabilities of 102 girls aged 16 to 20, residents of the mountainous regions of the Transcarpathian region. we noted that the performance of physical work in the anaerobic regime of the body’s energy supply depends on the somatotype. The power of anaerobic alactate and lactate processes turned out to be the highest in girls with an endomesomorphic somatotype. The power of anaerobic alactate and lactate processes turned out to be the lowest in girls with an ectomorphic somatotype. Studying the level of anaerobic productivity of females based on the relative indicator of the capacity of anaerobic lactate processes of energy supply showed that girls with a balanced somatotype have the lowest level of anaerobic capacity compared to girls of other somatotypes.

Reduced congestion and improved response to a fluid/sodium challenge in chronic heart failure patients after initiation of sacubitril/valsartan: The NATRIUM-HF study.

The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

Unrevealing the therapeutic potential of artesunate against emerging zoonotic Babesia microti infection in the murine model.

Babesiosis, a zoonotic blood protozoal disease, threatens humans and animals and is difficult to treat due to growing antimicrobial resistance. The study aimed to investigate the therapeutic efficacy of artesunate (AS), a well-known derivative of artemisinin, against Babesia microti (B. microti) using a murine infection model. Male BALB/c mice (6 weeks old; 15 per group) were chosen and randomly divided into 1) the control group, 2) the B. microti group, and 3) the B. microti + artesunate treatment groups. AS treatment at 2 mg/kg, 4 mg/kg, and 8 mg/kg of body weight significantly (p < 0.05) reduced the B. microti load in blood smears in a dose-dependent manner. Additionally, AS treatment mitigated the decrease in body weight and restored the normal state of the liver and spleen viscera index compared to the B. microti-infected group after 28 days. Hematological analysis revealed significant increases in RBC, WBC, and PLT counts post-AS treatment compared to the B. microti-infected group. Furthermore, AS administration resulted in significant reductions in total protein, bilirubin, ALT, AST, and ALP levels, along with reduced liver and spleen inflammation and lesions as observed through histopathological analysis. AS also elicited dose-dependent changes in mRNA and protein expression levels of apoptotic, proinflammatory, and anti-inflammatory cytokines in the liver compared to the control and B. microti-infected groups. Immunolabeling revealed decreased expression of apoptotic and inflammation-related proteins in AS-treated hepatic cytoplasm compared to the B. microti-infected group. AS also in dose-dependent manner decreased apoptotic protein and increased Bcl-2. Overall, these findings underscore the potential of AS as an anti-parasitic candidate in combating B. microti pathogenesis in an in vivo infection model, suggesting its promise for clinical trials as a treatment for babesiosis.

Remission of type 2 diabetes: opportunities of different nutrition styles

Last time there are a lot of date, published systematic reviews and meta-analyses about relationship between eating behavior and incidence type 2 diabetes. It is known that more than 80% of cases of type 2 diabetes are associated with obesity. In this regard, the nutritional factor is of particular importance in the formation of treatment goals for patients with type 2 diabetes. Today, the disease is no longer a sentence, because achieving remission of type 2 diabetes is possible with the help of nutritional correction. The results of studies shown that a significant decrease in body weight is a predictor of remission of type 2 diabetes. However, the question of the best dietary recommendations for patients with type 2 diabetes remains open. Various dietary patterns (Mediterranean, paleo diet, DASH system, etc.) contribute to the improvement of glycemia, however, there is not enough data indicating a regression of symptoms of type 2 diabetes. In all likelihood, achieving remission is possible only with a significant reduction in daily caloric intake. The ketogenic diet, especially popular in recent times, also improves glycemic control. At the same time, according to the results of a meta-analysis, carbohydrates from whole grains and cereal fibers should not be neglected, because this category of products helps reduce the risk of developing diabetes.

Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome

BackgroundShort bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. Methods and resultsThrough testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. ConclusionsOCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.

Abstract PO1-25-12: Metformin enhances response to chemotherapy combined with immunotherapy in a triple negative breast cancer in vivo model

Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous group comprising several well-defined molecular subtypes. Classical chemotherapy remains the standard of care for advanced TNBC, although blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity. Atezolizumab is an immune checkpoint inhibitor targeting PD-L1 that has been approved for use in combination with paclitaxel for the treatment of advanced TNBC. Metformin (MTF) is a prescribed drug for type 2 diabetes with well-tolerated side-effects and has been reported to have anticancer effects. Xenograft mouse models studies of breast, lung and prostate cancer, have reveal a synergistic effect of MTF when combined with paclitaxel, carboplatin or doxorubicin and has been reported to enhance the efficacy of immunotherapy. In this work we want to explore the effect of including MTF in a chemo-immunotherapy scheme using an in vivo model. Methods 1x106 EMT6 TNBC cell line (ATCC® CRL-2755™) were implanted subcutaneously in the back of immunocompetent BALB/c mice. Treatment began when tumours reached a volume size of 30-100 mm3. At that moment, mice received the drug, or drugs combinations, for 21 days. All drugs were administered intraperitoneally, except for MTF, which was given orally in drinking water at a concentration of 1g/L. The anti PD-L1 drug anti-hPD-L1-mIgG1 (mATZ, 300 mg/week) was administered twice per week and doxorubicin (DOXO) every three days (0.3 mg/Kg or 6 mg/kg). The primary outcome will be tumour response. Tumour size was measured using a digital caliper every day until mice were euthanized. For tumour volume determination (mm3), two measures were taken (length and width). Volume was calculated as (length x wide2)/2. We tested three different arms: DOXO(0,3mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ+MTF, and DOXO(6mg/Kg)+m-ATZ. Each arm included 10 mice. Differences in tumour volume and mice weight were assessed by Kruskall-Wallis analysis. Results EMT6 cells produced a tumour mass in twenty seven out of thirty mice. Follow-up in mice in the DOXO(0.3mg/Kg)+m-ATZ and DOXO(6mg/Kg)+m-ATZ arms was interrupted in two weeks due to extended tumour growth and quality of live criteria, respectively. Mice in the DOXO(0.3mg/Kg)+m-ATZ+MTF arm were followed for three weeks. Increase of tumoral volume was assessed at 14 days. Mean increase was 205, 1096 and 365 mm3in the DOXO(6mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ, and DOXO(0,3mg/Kg)+m-ATZ+MTF arms respectively, being the volume increase between DOXO(0,3mg/Kg)+m-ATZ treated mice significantly higher. Regarding mice, mean weight at the beginning of the treatments was 19.8 gr for the complete mice population, whereas mean weight after 14 days of treatment was 15.4, 20.9 and 21.7 gr in the DOXO(6mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ, and DOXO(0,3mg/Kg)+m-ATZ+MTF arms respectively, showing a significant decrease of body weight in mice receiving a high dose of DOX, while no differences associated to the inclusion of MTF in the treatment scheme was found. Conclusions MTF addition to a combination of chemotherapy and immunotherapy in the treatment of TNBC increased therapy efficacy, with no added side effects. These result paves the way to explore treatment schemes with lower chemotherapy doses, decreasing toxicity side effects. Citation Format: Pilar Zamora, Angelo Gamez Pozo, Luz Vega-Clemente, Elena Lopez-Camacho, Lucia Trilla-Fuertes, David Alonso-Martin, Juan Angel Fresno Vara, Mariano Garcia-Arranz, Enrique Espinosa. Metformin enhances response to chemotherapy combined with immunotherapy in a triple negative breast cancer in vivo model [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-25-12.

Feed restriction affects milk performances and decreases milk lipolysis in dairy ewes

Spontaneous lipolysis results in the breakdown of milk fat by the lipoprotein lipase (LPL; EC: 3.1.1.34), an enzyme present in milk. Free fatty acids (FFA) and by-products released in milk during lipolysis can alter both the organoleptic value of milk (off-flavours release) and technological properties of dairy products (decrease in creaming capabilities). Current climate change is having significant impacts on the feeding of grazing animals, with negative consequences on the availability and quality of grass. We and others have demonstrated that dietary restriction increases milk lipolysis in the cow species. However, no data about the impact of feed restriction on milk lipolysis is available in the ewe species. Thus, this paper aims to investigate the effect of feed restriction on milk characteristics with regard to lipolysis values in dairy ewes. Two groups of 24 multiparous Lacaune ewes in mid-lactation received a “non-restricted” (NON RESTR) control diet (100 % of ad libitum DM intake) or a “restricted” (RESTR) diet (65 % of ad libitum DM intake) according to a 2 X 2 crossover design. Milk gross composition together with lipolysis analyses were performed. Blood samples were also screened for metabolites or hormones concentrations. The RESTR treatment induced a decrease in milk production (- 21 % compared with control treatment) and a modification of the metabolism of dairy ewes characterized by an increase in plasma non-esterified fatty acids (NEFA), which represents the balance between adipose tissue mobilization and the use of NEFA by other tissues (+ 153 %), cholesterol (+ 17 %) and β-hydroxybutyrate (+ 4 %) levels. As a result, a decrease in body weight of dairy ewes was observed (-7 %). Feed restriction also resulted in a decrease in milk lipolysis estimated by the milk FFA measured by the copper-soap method (- 63 % and - 62 %, respectively for morning and evening milking) or by the reference Bureau of Dairy Industry (BDI) method (- 51 % and – 57 %, respectively for morning and evening milking). The decrease in milk spontaneous lipolysis under feed restriction was not associated with a decrease in lipoprotein lipase activity in ewes. These results will be completed with proteomic and lipidomic studies in milk samples to better understand mechanisms initiated in the ewe species specifically with regard to lipolysis in milk.

Petroleum ether extract of Schisandra sphenanthera prevents hyperglycemia and insulin resistance in association with modulation of sweet taste receptors and gut microbiota in T2DM rats

Ethnopharmacological relevanceSchisandra sphenanthera (Schisandra sphenanthera Rehd. et Wils.) is the dried mature fruit of Schisandra sphenanthera, a plant in the Magnoliaceae family. It was used in the treatment of diabetes mellitus in the Jade Fluid Decoction and the Xiaoke pills, which were recorded in ancient books. However, its mechanism of action in the treatment of type 2 diabetes mellitus (T2DM) was unclear and needs further study. Aim of the studyThis research aimed to investigate the chemical composition and lignan content of Schisandra sphenanthera petroleum ether parts (SPEP) and to evaluate the effects of SPEP on sweet taste receptors (STRs) and intestinal flora in rats on a high-fat diet (HFD). Additionally, the relationships between SPEP and hyperglycemia and insulin resistance were examined. Materials and methodsGC-MS was used to determine the chemical composition of SPEP, and HPLC was used to determine the lignin content. A combination of the HFD and the administration of streptozotocin (STZ) was employed to generate a rat model of T2DM. Petroleum ether extracts from Schisandra sphenanthera were used as the focus of the research to evaluate the effects of these extracts on the glucolipid metabolism of T2DM rats, as well as the underlying mechanisms. ResultsAnalysis of the GC-MS spectrum of SESP revealed a total of 58 compounds. HPLC analysis revealed that SPEP had the highest concentration of Schisandrin A and the lowest concentration of Schisandrol A. The drug administration intervention resulted in a significant decrease in body weight and pancreatic weight of diabetic rats compared to the Normal group. When compared to the Model group, the body weight of rats in the drug administration group and the Metformin group had a more moderate decrease, while the pancreatic weight and pancreatic-to-body ratio increased. The Model group shown significant increases in FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, and NEFA, as well as significant decreases in HDL-C and SOD, when compared to the Normal group (P<0.05). The administration of each group was found to be significantly effective in decreasing FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, NEFA, while increasing HDL-C and SOD when compared to the Model group. The application of SPEP had a positive impact on hepatocyte swelling, hepatocyte degeneration, and necrosis, as well as the morphological structure of pancreatic islet cells. Furthermore, the protein expression levels of T1R2, TRPM5 and GLP-1 in the small intestine of the Model group were reduced. After a period of six weeks, the protein expression levels began to align more closely with those of the Normal group of rats. Analysis of 16S rRNA sequencing revealed that the intestinal microbiota of diabetic rats was significantly disrupted, with a decrease in the abundance of the Firmicutes phylum and an increase in the abundance of the Bacteroidetes phylum. Furthermore, the composition of the dominant genus was distinct from that of the control group. After the drug intervention, the microbiota of diabetic rats was significantly altered, exhibiting a higher abundance and diversity, as well as a significant enrichment of the community. The SPEP treatment resulted in a significant increase in acetic acid, propionic acid, and butyric acid. ConclusionsThe findings of this research indicated that SPEP could be effective in treating T2DM through the regulation of STRs, the adjustment of disturbed metabolite levels, and the alteration of intestinal flora.

Liraglutide’s Effect on Weight Management in Subjects with Pre-Diabetes: A Systematic Review & Meta-analysis

BackgroundDespite the growing literature, the effectiveness of liraglutide in weight management among individuals with pre-diabetes and in preventing the disease remains controversial. This study aims to critically evaluate the extent of liraglutide’s impact on weight management in this population and assess the heterogeneity among extant studies. MethodsA systematic literature search was conducted across MEDLINE, Embase, ClinicalTrials.gov, and the reference list of retrieved studies to identify eligible English language randomized controlled trials (RCTs) evaluating liraglutide’s effect on weight in individuals with pre-diabetes. Non-randomized studies, studies not reporting relevant outcomes, and those conducted on patients with type 2 diabetes were excluded from this review. Outcomes included a change from baseline in absolute body weight in kg, body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), and low-density lipoprotein cholesterol (LDL-C) levels. Additional safety outcomes were also reported. Data were analyzed using R statistical software version 4.3.1. A fixed-effect model was used when pooling crude numbers for study outcomes. Moreover, a sensitivity analysis using random-effect model was performed, and heterogeneity was assessed using I2 statistics. ResultsFive eligible studies were included, with a total of 1604 subjects in the liraglutide arm and 859 subjects in the control arm. Participants exposed to liraglutide showed a decrease in body weight (MD= -4.95 kg; 95%CI -5.16, -4.73; I2= 93%), BMI (MD= -2.06 kg/m2; 95%CI -2.22, -1.89; I2= 97%), waist circumference (MD= -4.61 cm; 95%CI -4.79, -4.43; I2= 82%), HbA1c (MD= -0.33%; 95%CI -0.34, -0.31; I2= 100%), and LDL-C levels (MD= -0.36 mmol/L; 95%CI -0.39, -0.33; I2= 99%). The overall effect size remained similar when using a random-effects model for all outcomes. In addition, the rate of adverse events was higher with liraglutide when compared to the control; however, the dropout rates were relatively lower in the former arm. ConclusionWhile our meta-analysis suggests that liraglutide can reduce body weight, BMI, waist circumference, and HbA1c levels in pre-diabetic individuals, the findings should be interpreted cautiously due to limitations such as the small number of trials, the study’s short duration, and variability in dosages. Further randomized controlled trials examining long-term outcomes are essential to validate these findings and address the high heterogeneity among the studies included in this analysis.

The effects of short-term environment-induced heat stress on the myocardium in male mice

Environment-induced heat stress (EIHS) is caused by a sustained elevation in body temperature due to prolonged exposure to excess heat and humidity. Given the current and increasing frequency of EIHS and the large gap in knowledge regarding EIHS-mediated impacts to the myocardium, the purpose of this investigation was to determine the extent EIHS alters cardiac health. We hypothesized EIHS would cause myocardial injury and cellular dysfunction. To test this hypothesis, 13 w old male C57 mice were exposed to EIHS for 4 h or 8 h (n=7; 37.7 ± 0.10 °C, 38.3 ± 0.5 % humidity) or thermoneutral (TN) (n=7, 27.7 ± 0.15 °C, 42.5 ± 0.43% humidity) conditions, hearts were removed, weighed, and portions of the heart were fixed for histology or frozen for biochemical measures. Environment-induced HS increased subcutaneous temperature following 4 and 8 h by 0.9 °C (p&lt; 0.01) compared to respective TN temperatures and decreased body weight by 6.8% (p=0.01) at 4 h and 13% (p&lt;0.01) at 8 h compared to TN. Histological inspection revealed that EIHS increased anisokaryosis by 1.4-fold following 4 h (p&lt;0.01) and by 75% following 8 h (p=0.01) compared to TN animals. Environment-induced HS increased relative abundance of malondialdehyde-modified proteins (35%, p=0.02), a marker of oxidative stress, and increased relative protein abundance of SOD2 (72%, p=0.05) following 4 h compared to TN. Eight hours of EIHS increased relative protein abundance of SOD1 (69%, p=0.01) compared to TN and increased catalase and GPX1 compared to TN (91%, p&lt;0.01; 2-fold, p&lt;0.01) and compared to 4 h of EIHS (72%, p=0.03; 34%, p=0.01), though MDA-modified proteins were similar to TN. Following 4 h of EIHS, markers of mitochondrial abundance, including electron transport chain complexes II (69%, p=0.02) and V (36%, p=0.03), VDAC2 (79%, p=0.01) and PHB1 (65%, p=0.03) were increased compared to TN, and PDH (35%, p=0.04) and Cox IV (55%, p=0.01) were increased compared to 8 hrs of EIHS. Environment-induced HS appeared to alter mitochondrial fusion and fission as DRP1 (51%, p=0.05), phosphorylated (p)-DRP1 (47%, p=0.04), FIS1 (57%, p=0.01) and Mfn1 (26%, p=0.03) were increased compared to TN following 4 h and Mfn2 was increased (37%, p=0.02) following 8 h of EIHS compared to TN. Mitophagy markers BNIP3L/NIX and Pink1 were increased by EIHS following 4 h compared to TN (78%, p=0.02; 41%, p=0.03). Environment-induced HS increased autophagy markers ULK1 (36%, p&lt;0.01), PI3K (80%, p&lt;0.01), and ATG7 (49%, p&lt;0.01) following 4 h compared to TN and ULK1 (33%, p&lt;0.01) and ATG7 (41%, p=0.02) following 4 h compared to 8 h of EIHS. However, p-ULK1, Beclin, p-Beclin, ATG12, and ATG16 were similar between groups. Relative protein abundance of p62 and LC3 II were similar between groups; however, using a colchicine-inhibition approach, 8 h of EIHS caused a significant accumulation of p62, suggestive of increased flux. These data suggest that in a murine model of EIHS, 4 h was suffcient to cause cellular injury and dysfunction in the myocardium; however, as EIHS continued, it was associated with changes reflective of a cellular stress response that may contribute to acclimation. This work was supported by USDA 2020-02716. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The consequences of environment-induced heat stress on the kidney in female mice

Environment-induced heat stress (EIHS) is caused by a sustained elevation in body temperature, due to prolonged exposure to excess heat and humidity. Given the present and increasing frequency of EIHS and the gap in knowledge regarding EIHS-mediated impacts to the kidney, the purpose of this investigation was to determine the extent to which EIHS alters kidney health. We hypothesized EIHS would cause kidney injury and cellular dysfunction. To test this hypothesis, 7 wk old C57 female mice were assigned to either EIHS (n=14; 36.7 ± 0.16 °C, 36.3 ± 0.5 % humidity) or thermoneutral (TN) conditions (n=12, 31.2 ± 1.01 °C, 35 ± 0.7% humidity) for 24 h, kidneys were removed, weighed, and were either fixed for histology or frozen for biochemical measures. Environment-induced HS increased rectal temperature by 2.1 °C (p&lt; 0.001), decreased body weight by 10% (p=0.03), and decreased absolute kidney weight (10%; p=0.02) compared to TN. Environment-induced HS increased relative protein abundance of heat shock proteins 70 (48%, p&lt;0.01), 90 (37%, p&lt;0.01), and 60 (36%, p=0.02), as well as heat shock factor 1 (2-fold, p=0.02) compared to TN. Histological inspection revealed EIHS animals had increased vacuolation in the proximal convoluted tubules (p&lt;0.01) compared to TN animals. Using a western blot approach, we measured biomarkers of kidney tubular health and discovered EIHS increased protein abundance of NGAL (88%, p&lt;0.01), IL-10 (36%, p=0.05), IL-6 (46%, p&lt;0.01), MCP-1 (74%, p=0.04), and L-FABP (99%, p&lt;0.01), which are suggestive of kidney injury. Environment-induced HS increased markers of inflammatory signaling including TLR4 (44%, p=0.04), phosphorylated (p-) NFκB (93%, p&lt;0.01), p-JNK (54 kD; 51%, p=0.02), p-JNK (46 kD, 35%, p=0.02), AP-1 (33%, p=0.02), and TNFα (39%, p=0.05). Endoplasmic reticulum stress was increased by EIHS as Bip, p-IRE1α, Perk, XBP1s, ATF4, and CHOP were increased 27-190% (p&lt;0.05-0.01) compared to TN animals. Markers of mitochondrial abundance remained similar between groups; however, EIHS may alter mitochondrial fusion and fission as Opa1 (71%, p=0.01), MFN2 (29%, p=0.04) and DRP1 (59%, p=0.04) were increased compared to TN; however, MFN1, FIS1, and p-DRP1 were similar between groups. Collectively, these data suggest that 24 h of EIHS causes kidney injury, but may also be suffcient to initiate changes that contribute to acclimation. This study was supported by USDA 2020-02716. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of high doses of zearalenone on some antioxidant enzymes and locomotion of Tenebrio molitor larvae (Coleoptera: Tenebrionidae).

The mealworm Tenebrio molitor L. (Coleoptera: Tenebrionidae) feeds on wheat bran and is considered both a pest and an edible insect. Its larvae contain proteins and essential amino acids, fats, and minerals, making them suitable for animal and human consumption. Zearalenone (ZEA) is the mycotoxin most commonly associated with Fusarium spp. It is found in cereals and cereal products, so their consumption is a major risk for mycotoxin contamination. One of the most important effects of ZEA is the induction of oxidative stress, which leads to physiological and behavioral changes. This study deals with the effects of high doses of ZEA (10 and 20mg/kg) on survival, molting, growth, weight gain, activity of antioxidant enzymes superoxide dismutase (SOD) and glutathione S-transferase (GST), and locomotion of mealworm larvae. Both doses of ZEA were found to (i) have no effect on survival, (ii) increase molting frequency, SOD, and GST activity, and (iii) decrease body weight and locomotion, with more pronounced changes at 20mg/kg. These results indicated the susceptibility of T. molitor larvae to high doses of ZEA in feed.

Long-term intermittent fasting induces sex-dependent changes in small intestine from SAMP8 aged mice

Background: Intermittent fasting (IF) is a popular and effective method to decrease body weight. Yet, the effects of IF on aged intestine is unknown. SAMP8 (Senescence Accelerated Mouse-Prone 8) mice are used as a model for studying aging. This study aimed to examine the potential for IF to ameliorate age-associated disturbances in murine jejunum. Methods: Two-month-old male and female SAMP8 mice were randomly assigned to either an IF protocol or an ad-libitum diet (AL) for the 8-month study (n=7-10 group). Fasted mice followed a 24-hour alternate day fasting protocol. At the end of the study mice were euthanized and jejunum stored at −80°C until use for western blot or other assay, and a segment was fixed for histology. Results: IF resulted in significantly less weight gain in both males (22% less, n=7-10, p&lt;0.05) and females (33% less, n=7-8, p&lt;0.05) and response to glucose load (glucose tolerance testing) was comparable in both sexes: area under curve for AL &gt; IF. Interestingly, IF significantly reduced fasting serum glucose levels in males (30% less, n=6, p&lt;0.05), but IF had no effect on fasting serum glucose in females. In jejunum, we assessed: protein expression, health, and morphology. In females, IF led to a 57% decrease in GLUT2 expression (n=5-6, p&lt;0.05) versus AL. GLUT2 moves glucose/galactose and fructose out of the enterocyte into the blood, suggesting restructuring of monosaccharide transport due to IF. IF had no effect on jejunum GLUT5 or SGLT1 expression. Cleaved Caspase-3 expression was decreased by IF in both sexes versus AL. This reduction was greater in females, suggesting a sex-dependent protective role of IF against apoptosis. Moreover, IF induced a significant increase 1.4-fold (n=5=6, p&lt;0.05) in jejunum superoxide dismutase (SOD) activity in both sexes. Jejunum morphology was significantly changed in females only: IF induced both a decrease in villi length (by 21%, n=4/group, p&lt;0.05) and a decrease in wall thickness (by 7%, n=4/group, p&lt;0.05). Conclusions: In both sexes, IF decreased body weight, yet in females resting glucose levels were unchanged by IF. In females, IF reduced monosaccharide absorption out of intestines, yet improved overall intestinal health, increasing antioxidant levels with SOD. These findings collectively highlight the complex effects of IF on cellular processes and demonstrate significant sex-dependent aged intestinal responses. Unraveling the underlying molecular mechanisms driving these sex-dependent IF-induced effects is currently under evaluation. Midwestern-Arizona Alzheimer’s Consortium Grant, Midwestern University Intramural Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Zinc(II) coordination compound with N′-(pyridin-2-ylmethylene)nicotinohydrazide: Synthesis, crystal structure, computational and cytotoxicity studies

In this work, we report on the synthesis of a novel zinc(II) coordination compound [ZnL2] (1), which was readily obtained from the reaction of Zn(OAc)·2H2O and N′-(pyridin-2-ylmethylene)nicotinohydrazide (HL) in methanol. Recrystallization of 1 from dimethylformamide under ambient conditions allowed to produce yellow block-like crystals of 1·H2O. Complex 1·H2O was characterized by FT-IR and 1H NMR spectroscopy, while its optical properties were studied by UV–vis and spectrofluorimetry in methanol. The crystal structure of the title complex was revealed by single crystal X-ray diffraction and further explored in detail by the Hirshfeld surface analysis. Theoretical investigations based on the DFT calculations have also been applied to show the electronic properties of complex 1. The antitumor activities of the parent ligand HL and complex 1 were studied using Dalton's lymphoma malignant cancer model. Both compounds were found to induce concentration-dependent cytotoxicity and apoptotic cell death, leading to a decrease in cell viability, body weight, and tumor volume in mice with the superior activity of complex 1 over HL. Mice treated with complex 1 demonstrated an increase in life span with a survival period of 23 days. Finally, using a molecular docking approach, we have probed complex 1 to inhibit the recombinant mouse tumor-necrosis factor alpha (mTNF).

Effects of Cross-Sex Hormone Therapy on Metabolic Parameters and Aortic Relaxation in Castrated Male Rats

With the rising awareness, the number of individuals identifying themselves as transgender in the US is increasing over the years. Cross-sex hormone therapy (CSHT) may alter numerous cardiometabolic parameters leading to the increased risk of cardiovascular diseases (CVD) in transgender population. Epidemiological studies suggest that transgender females (male to female, MtF) on estrogen therapy develop higher risk of CVD compared to transgender males (female to male, FtM) taking testosterone. Underlying mechanisms of impaired cardiovascular functions in MtF are not well documented. This study was undertaken to examine the effects of 17β-estradiol (E2) on certain cardiometabolic parameters and aortic reactivity in castrated (CAS) male Sprague Dawley (SD) rats. The 8-10-weeks old CAS rats were subcutaneously implanted with either 1.5 mg of E2 (CAS+E2) or placebo (CAS+PL) containing pellets for ~35 days. The age-matched SD intact male (IM) rats were also included in the experimental groups. After performing the glucose tolerance test, animals were sacrificed, and the blood was collected for later measurements of the HbA1C and triglyceride (TG) levels. Endothelium-dependent vasorelaxation (EDV) to acetylcholine (ACh) in aortic rings pre-contracted with phenylephrine (PE) was measured before and after treatment with indomethacin (a cyclooxygenase inhibitor), followed by L-NAME [a nonselective nitric oxide (NO) synthase (NOS) inhibitor]. Contractile responses to PE before and after L-NAME in aortic rings and sodium nitroprusside (SNP)-induced relaxation responses in endothelium-denuded rings were also measured. Here, we report the decreased body weight and visceral white adipose tissue, and improved HbA1C and glucose tolerance in E2-treated CAS rats. However, the E2-treated CAS rats exhibited elevated plasma level of TG. Furthermore, the vascular relaxation to ACh was significantly impaired in aortas from this group compared to those in CAS+PL and IM rats. The impairment of ACh responses in CAS+E2 rats was accompanied by a significant decrease in NO contribution to ACh vasorelaxation. The basal NO levels and the smooth muscle sensitivity to NO were not altered, whereas the maximum contractile responses to PE were enhanced in aortas of CAS+E2 group compared to IM. In conclusion, our data suggests that the glucose homeostasis was improved in CAS+E2 rats. Regardless, this group exhibited increased level of TG in plasma and decreased aortic vasorelaxation to ACh. The impairment of EDV in E2-treated CAS rats might be due to reduced NO-mediated vasorelaxation or increased contractile responses observed in this group. Additional studies are needed to document the underlying mechanisms for improvement of glucose homeostasis and impairment of EDV in CAS+E2 rats. NIDA/NIGMS, 1SC1DA052120-01 to MF and Bridge Grant from University of the Pacific to RR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Astragalus mongholicus Polysaccharides Alleviate Insulin Resistance through Modulation of PI3K/AKT, TLR4/NF-kB Signaling Pathway and Microbiota in Rats with Type 2 Diabetes Mellitus

Background and aimAstragali Radix has been widely used in traditional Chinese medicine to treat diabetes and a variety of other diseases. This study aims to evaluate the alleviating effects and mechanisms of Astragalus mongholicus Polysaccharide (mAPS) against diet combined with streptozotocin (STZ)-induced Type 2 Diabetes Mellitus (T2DM). Experimental procedureT2DM rats were orally administrated either with 200 mg/kg mAPS or 300 mg/kg Metformin (MET) once daily for four weeks. Body weight and Fasting Blood Glucose (FBG) were detected every 6 days. Serum fasting insulin (FINS) was measured by ELISA and the homeostatic model assessment of insulin resistance (HOMA-IR) was calculated accordingly. Histological change was studied by Hematoxylin and eosin (HE) staining. 16S rDNA sequencing was used to detect the changes in gut microbiota. Results and conclusionOral administration of mAPS significantly decreased body weight, FBG, and HOMA-IR in T2DM rats (p＜0.05). Moreover, HE staining showed that mAPS could alleviate histological distortion in the liver and pancreas. Treatment with mAPS elevated the hepatic levels of phosphatidylinositol-3 kinase (PI3K), phospho-protein kinase B (AKT), and glucose transporter type 4 (GLUT4), while reducing phospho-nuclear factor kappa-B (NF-κB), Toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) (p＜0.05). Furthermore, mAPS supplementation could reverse the ratio of Firmicutes/Bacteroidetes (F/B) and reduce the abundance of Clostridia and Proteobacteria (p＜0.05). These results indicate that mAPS have the potential to enhance insulin sensitivity in diabetic rats by modifying gut microbiota and controlling the hepatic glycolipid metabolism and inflammation.