Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance.

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, we first used a cellular model of skeletal muscle cell iron overload and found that endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear FoxO localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2α phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative ATG5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. We translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance where administration of salubrinal as pretreatment promoted eIF2α phosphorylation, enhanced autophagic flux in skeletal muscle and improved insulin responsiveness. Together, our results show that salubrinal elicited an eIF2α-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice.

A novel blood-based bioassay to monitor adiponectin signaling.

The diverse beneficial effects of adiponectin-receptor signaling, including its impact on the regulation of inflammatory processes in vivo, have resulted in development of adiponectin receptor agonists as a treatment for metabolic disorders. However, there are no established non-invasive bioassays for detection of adiponectin target engagement in humans or animal models. Here, we designed an assay using small amounts of blood to assess adiponectin action. Specifically, we tested effects of the small 10-amino acid peptide adiponectin receptor agonist, ALY688, in a sublethal LPS endotoxemia model in mice. LPS-induced pro-inflammatory cytokine levels in serum were significantly reduced in mice treated with ALY688, assessed via multiplex ELISA in flow cytometry. Furthermore, ALY688 alone significantly induced TGF-ß release in serum 1 h after treatment and was elevated for up to 24 h. Additionally, using a flow-cytometry panel for detection of changes in circulating immune cell phenotypes, we observed a significant increase in absolute T cell counts in mice after ALY688 treatment. To assess changes in intracellular signaling effectors downstream of adiponectin, phospho-flow cytometry was conducted. There was a significant increase in phosphorylation of AMPK and p38-MAPK in mice after ALY688 treatment. We then used human donor immune cells (PBMCs) treated with ALY688 ex vivo and observed elevation of AMPK and p38-MAPK phosphorylation from baseline in response to ALY688. Together, these results indicate we can detect adiponectin action on immune cells in vivo by assessing adiponectin signaling pathway for AMPK and p38-MAPK, as well as pro-inflammatory cytokine levels. This new approach provides a blood-based bioassay for screening adiponectin action.

Ischemia-induced cardiac dysfunction is exacerbated in adiponectin-knockout mice due to impaired autophagy flux.

Strategies to enhance autophagy flux have been suggested to improve outcomes in cardiac ischemic models. We explored the role of adiponectin in mediating cardiac autophagy under ischemic conditions induced by permanent coronary artery ligation. We studied the molecular mechanisms underlying adiponectin's cardio-protective effects in adiponectin knockout (Ad-KO) compared with wild-type (WT) mice subjected to ischemia by coronary artery ligation and H9c2 cardiomyocyte cell line exposed to hypoxia. Systemic infusion of a cathepsin-B activatable near-infrared probe as a biomarker for autophagy and detection via noninvasive three-dimensional fluorescence molecular tomography combined with computerized tomography to quantitate temporal changes, indicated increased activity in the myocardium of WT mice after myocardial infarction which was attenuated in Ad-KO. Seven days of ischemia increased myocardial adiponectin accumulation and elevated ULK1/AMPK phosphorylation and autophagy assessed by Western blotting for LC3 and p62, an outcome not observed in Ad-KO mice. Cell death, assessed by TUNEL analysis and the ratio of Bcl-2:Bax, plus cardiac dysfunction, measured using echocardiography with strain analysis, were exacerbated in Ad-KO mice. Using cellular models, we observed that adiponectin stimulated autophagy flux in isolated primary adult cardiomyocytes and increased basal and hypoxia-induced autophagy in H9c2 cells. Real-time temporal analysis of caspase-3/7 activation and caspase-3 Western blot indicated that adiponectin suppressed activation by hypoxia. Hypoxia-induced mitochondrial reactive oxygen species production and cell death were also attenuated by adiponectin. Importantly, the ability of adiponectin to reduce caspase-3/7 activation and cell death was not observed in autophagy-deficient cells generated by CRISPR-mediated deletion of Atg7. Collectively, our data indicate that adiponectin acts in an autophagy-dependent manner to attenuate cardiomyocyte caspase-3/7 activation and cell death in response to hypoxia in vitro and ischemia in mice.

Caproic acid production from food waste using indigenous microbiota: Performance and mechanisms.

Caproic acid (CA) production from food waste (FW) is a promising way for waste recycling, while the fermentation processes need further exploration. In this study, FW acidogenic fermentation under different pH (uncontrolled, 4, 5, 6) using indigenous microbiota was investigated. Result showed that substrate hydrolysis, carbohydrate degradation and acidogenesis increased with the increase of pH. Although various microbial communities were observed in FW, lactic acid bacteria (Lactobacillus and Limosilactobacillus) were enriched at pH lower than 6, resulting in lactic acid accumulation. CA (88.24 mM) was produced at pH 6 accounting for 31.23% of the total product carbon. The enriched lactic acid bacteria were directionally replaced by chain elongators (Caproicibacter, Clostridium_sensu_stricto, unclassified_Ruminococcaceae) at pH 6, and carbohydrates in FW were firstly transformed into lactic acid, then to butyrate and CA through lactate-based chain elongation processes. This work provided a novel CA fermentation pathway and further enriched the FW valorization.

Bioenergy production from swine wastewater based on a combined process of anaerobic dynamic membrane reactor and microalgae cultivation: Feasibility and performance.

Enhanced methane production and sustainable reduction of pollutants from anaerobic digestate are crucial for swine wastewater treatment. In this study, anaerobic dynamic membrane bioreactor (AnDMBR) was introduced to enhance methane production, then microalgae were cultivated on the digestate for nutrients recovery and lipid production. Results showed that pollutants can be effectively removed under various hydraulic retention time (HRT) conditions during long-term operation. Methanogenesis was enhanced with the reduction of HRT from 20 days to 10 days (0.23 L-CH4/g-CODremoved), but inhibited by shortening HRT to 5 days (0.09 L-CH4/g-CODremoved). Ammonia and phosphate in the digestate were effectively removed after microalgae cultivation. In addition, the highest microalgal biomass and lipid productivity (1.7 g/L and 17.5 mg/(L·d), respectively) were obtained using digestate ratio of 20 %, while microalgal growth was seriously restricted at high digestate content (>50 %). This work provides a prospective pathway for pollutants control and energy production from swine wastewater through integrating of AnDMBR technology with microalgae cultivation.

[SigE inhibits DNA damage and participates in the regulation of DNA damage repair in Mycobacterium smegmatis].

Objective To investigate the anti-DNA damage role of Sigma factor E (SigE) and its regulation mechanism of DNA damage repair in Mycobacterium smegmatis(MS). Methods The SigE gene of Mycobacterium smegmatis was cloned into plasmid pMV261 to construct recombinant plasmid pMV261(+)-SigE, and the inserted gene was verified by sequencing. The recombinant plasmid was electrically transformed into Mycobacterium smegmatis to construct SigE over-expression strain, and the expression of SigE was detected by Western blot analysis. The Mycobacterium smegmatis containing pMV261 plasmid was used as the control strain. Growth differences between the two stains were monitored by measuring the 600 nm absorbance (A600) value of the bacterial culture suspension. The survival rate differences between two kinds of strains which were treated with three kinds of DNA damaging agents including ultraviolet ray (UV), cisplatin (DDP), and mitomycin C (MMC) were detected by colony forming unit (CFU) counting assay. DNA damage repair pathways of Mycobacteria were analyzed through bioinformatics and SigE-related genes were screened. The relative expression levels of these genes possibly related to the SigE against DNA damage were detected by real-time fluorescence quantitative PCR. Results SigE over-expression strain pMV261(+)-SigE/MS was constructed and the expression of SigE in Mycobacterium smegmatis was detected. Compared with the control strain, the SigE over-expression strain grew more slowly and entered the growth plateau later; survival rate analysis found that SigE over-expression strain was more resistant to three DNA damaging agents including UV, DDP, and MMC. Bioinformatic analysis indicated that SigE gene was closely related to DNA damage repair genes recA, single-strand DNA binding protein, (ssb), and dnaE2; the expression levels of recA, dnaE2, and ssb in SigE over-expression strain all increased with varying degrees compared with those in the control strain. Conclusion SigE plays an important role in inhibiting the DNA damage of Mycobacterium smegmatis, whose mechanism is closely related to the regulation of DNA damage repair.

Pickering emulsion: A multi-scale stabilization mechanism based on modified lotus root starch/xanthan gum nanoparticles.

New Pickering emulsion stabilizer LS/XG-NPs (Lotus root starch/xanthan gum nanoparticles) was prepared via autoclaving-cooling method followed by combination with XG. The LS/XG-NPs showed uniform and stable particles with particle size <500 nm, PDI <30, and zeta potential 30-40. The autoclaving-cooling treatment completely changed the crystalline form (from A-type to B-type) and structure of starch; hydrogen bonding and electrostatic interactions were proved to be existed between starch and XG in LS/XG-NPs. The addition of XG increased the contact angle of LS/XG-NPs from 58.79° to 85.42°. In the prepared Pickering emulsion, the LS/XG-NPs adsorbed well on the oil droplets surface, forming a three-dimensional gel network with evenly distributed oil droplets. The Pickering emulsion prepared with LS/XG-NPs showed excellent storage stability and auto-oxidation resistance; the EPA + DHA content in the emulsion remained at 92.46 % after 5 d of storage. The results of this study suggest that LS/XG-NPs have the potential to be food-grade Pickering emulsifiers that not only stabilize emulsions but also prevent emulsion oils from oxidizing.

Inhibition of mycobacteria proliferation in macrophages by low cisplatin concentration through phosphorylated p53-related apoptosis pathway.

BACKGROUND: Drug resistance is a prominent problem in the treatment of tuberculosis, so it is urgent to develop new anti- tuberculosis drugs. Here, we investigated the effects and mechanisms of cisplatin (DDP) on intracellular Mycobacterium smegmatis to tap the therapeutic potential of DDP in mycobacterial infection. RESULTS: Macrophages infected with Mycobacterium smegmatis were treated with DDP alone or combined with isoniazid or rifampicin. The results showed that the bacterial count in macrophages decreased significantly after DDP (≤ 6 µg/mL) treatment. When isoniazid or rifampicin was combined with DDP, the number of intracellular mycobacteria was also significantly lower than that of isoniazid or rifampicin alone. Apoptosis of infected cells increased after 24 h of DDP treatment, as shown by flow cytometry and transmission electron microscopy detection. Transcriptome sequencing showed that there were 1161 upregulated and 645 downregulated differentially expressed genes (DEGs) between the control group and DDP treatment group. A Trp53-centered protein interaction network was found based on the top 100 significant DEGs through STRING and Cytoscape software. The expression of phosphorylated p53, Bax, JAK, p38 MAPK and PI3K increased after DDP treatment, as shown by Western blot analysis. Inhibitors of JAK, PI3K or p38 MAPK inhibited the increase in cell apoptosis and the reduction in the intracellular bacterial count induced by DDP. The p53 promoter Kevetrin hydrochloride scavenges intracellular mycobacteria. If combined with DDP, Kevetrin hydrochloride could increase the effect of DDP on the elimination of intracellular mycobacteria. In conclusion, DDP at low concentrations could activate the JAK, p38 MAPK and PI3K pathways in infected macrophages, promote the phosphorylation of p53 protein, and increase the ratio of Bax to Bcl-2, leading to cell apoptosis, thus eliminating intracellular bacteria and reducing the spread of mycobacteria. CONCLUSION: DDP may be a new host-directed therapy for tuberculosis treatment, as well as the p53 promoter Kevetrin hydrochloride.

The discovery of subunit-selective GluN1/GluN2B NMDAR antagonist via pharmacophere-based virtual screening.

The incidence and mortality rates of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are gradually increasing worldwide. Numerous studies have demonstrated that N-methyl-D-aspartic acid receptor (NMDAR)-mediated excitotoxicity contributes to neurodegenerative diseases. Ifenprodil, a subtype-selective NMDAR antagonist, showed strong therapeutic potential. However, it suffers from low oral bioavailability and off-target side effects. In this study, natural compounds were identified for selective inhibition of GluN1/GluN2B NMDAR of human. We obtained a set of natural compounds (n = 81,366) from COCONUT, TIPdb, PAMDB, CMNPD, YMDB, and NPAtlas databases, and then virtually screened by an ifenprodil-structure-based pharmacophore model and molecular docking. The top 100 compounds were selected for binding affinity prediction via batch drug-target affinity (BatchDTA). Then, the top 50 compounds were analyzed by absorption, distribution, metabolism, excretion, toxicity (ADMET). Molecular dynamics involving molecular mechanics/position-Boltzmann surface area (MM-PBSA) calculation were performed to further screening. The top 15 compounds with strong binding affinity and ifenprodil, a proven GluN2B-selective NMDAR antagonist, were subjected to molecular dynamic simulations (100 ns), root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), H-bonds, solvent accessible surface area (SASA), principal component analysis (PCA), and binding free energy calculations. Based on these analyses, one possible lead compound carrying positive charges (CNP0099440) was identified, with great binding affinity and less off-target activity by contrast to ifenprodil. CNP0099440 has great potential to be a GluN1/GluN2B NMDAR antagonist candidate and can be further detected via in vitro and in vivo experiments.

The Mechanism of Alisol B23 Acetate Inhibiting Lung Cancer: Targeted Regulation of CD11b/CD18 to Influence Macrophage Polarization.

Background: Tumor microenvironment has attracted more and more attention in oncology. Alisol B23 acetate (AB23A) inhibits the proliferation of tumor cells including non-small cell lung cancer (NSCLC) cells. However, whether AB23A plays a role in the tumor microenvironment of NSCLC still remains obscure. Methods: After THP-1 cells were polarized to M0 type by PMA, M0 macrophages were differentiated into M1 by LPS and IFNγ, and were differentiated into M2 by IL-4 and IL-13. The differentiation of THP-1 cells was detected by flow cytometry. After AB23A was given to macrophage RT-qPCR and ELISA detected the expressions of IL-6, IL-1ß, IL-10 and TGF-ß. Western blot and RT-qPCR detected the expressions of CD11b and CD18 at both mRNA and protein levels. Lung cancer cell A549 cells were induced by above related macrophage culture medium. Cell proliferation was detected by CCK-8. Tunel, wound healing and Transwell detected the apoptotic, migration and invasion capabilities. Next, M0 and M1-type macrophages were cultured in the cell culture medium of conventional A549 cells, to which AB23A was added. Subsequently, cell differentiation and inflammatory response were measured. Finally, the expression of CD18 in A549 cells was knocked down to construct NSCLC tumor-bearing mice and AB23A was applied for intragastric administration. Immunohistochemistry detected the polarization of macrophages in tumor tissues. Western blot detected the expressions of CD11b, CD18, invasion-, migration- and apoptosis-related proteins. Results: AB23A promoted the polarization of macrophages towards M1, thus promoting the apoptosis and inhibiting the invasion and migration of A549 cells. The tumor cell culture medium induced M0 macrophages to M2, while AB23A reversed this effect. AB23A targeted CD11b/CD18 and improved the polarization of macrophages, thereby affecting tumor invasion, migration and apoptosis. Conclusion: AB23A affected the polarization of tumor-associated macrophages through the targeted regulation of CD11b/CD18, thus inhibiting the development of lung cancer.

Enhanced energy production and biological treatment of swine wastewater using anaerobic membrane bioreactor: Fouling mechanism and microbial community.

This study aimed to reveal the membrane fouling mechanisms during anaerobic membrane bioreactor (AnMBR) operation for swine wastewater treatment under different organic loading rates (OLR). Results showed that AnMBR could achieve high pollutant removal (71.9-83.6 %) and energy recovery (0.18-0.23 L-CH4/g-COD) at an OLR range of 0.25-0.5 g-COD/g-VSS.d, realizing energy production. However, higher OLR would aggravate the membrane fouling due to accumulation of fine sludge particles, organic foulants, and extracellular polymeric substances (EPS) on cake layer. Based on the high-throughput sequencing, microbial communities significantly changed and fouling-causing bacteria (e.g. Pseudomonas, Methanosarcina and Methanothrix) enriched in the cake layer at higher OLR conditions, leading to lower membrane permeability. Backwash can effectively remove the cake layer from the membrane surface and recover membrane permeability. The present study provides important information about membrane fouling and microbial information that could have significant impact on large-scale AnMBR application.

Effects of physical exercise on body fat and laboratory biomarkers in cancer patients: a meta-analysis of 35 randomized controlled trials.

BACKGROUND: A growing number of articles had reported the beneficial effects of physical exercise on reduced risks of cancer recurrence and mortality. However, the associations between physical exercise and laboratory biomarkers still had controversy. As we knew, this meta-analysis of randomized controlled trials (RCTs) was the first time for us to comprehensively clarify their relationships in cancer patients. METHODS: We comprehensively searched the PubMed, Cochrane Central, EMBASE, Web of Science, and SportDiscus online databases to identify eligible articles, up to June 1, 2021. Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were utilized to clarify their associations. Sensitivity analysis was performed to assess the impact of the individual on overall and Begg's/Egger's plot was utilized to evaluate potential publication bias. RESULTS: Finally, 35 randomized controlled trials (RCTs) were finally enrolled in this meta-analysis. Our results indicated that physical exercise could significantly reduce BMI (pooled SMD = -0.32 - 0.56 to -0.09)), body weight (pooled SMD = -0.31 (-0.54 to -0.08)), body fat (pooled SMD = -0.44 (-0.70 to -0.18)), waist circumference (pooled SMD = -0.50 (-0.76 to -0.23)), hip circumference (pooled SMD = -0.54 (-0.80 to -0.28)), triglyceride (pooled SMD = -0.35 (-0.69 to -0.02)), fasting insulin (pooled SMD = -0.38 (-0.54 to -0.22)), glucose (pooled SMD = -0.56 (-0.84 to -0.28)), insulin resistance (pooled SMD = -0.40 (-0.72 to -0.07)), CRP (pooled SMD = -0.97 (-1.48 to -0.46)), IGF-1 levels (pooled SMD = -0.56 (-0.83 to -0.29)) and remarkably increase IGFBP-3 levels (pooled SMD = 0.81 (0.45 to 1.17)). Further sensitivity analysis and Begg's or Egger's test suggested that our results were robust with no significant publication bias. CONCLUSIONS: Our results shed light on the beneficial effects of physical exercise on cancer patients by means of BMI/weight change and various biomarkers alteration (insulin-glucose pathways or inflammatory biomarkers). Our results were anticipated for clinical application to improve cancer patients' prognosis.

Corrigendum: The Effect of High-Diet and Exercise Intervention on the TNF-α Level in Rat Spleen.

[This corrects the article DOI: 10.3389/fimmu.2021.671167.].

Enhanced methane production coupled with livestock wastewater treatment using anaerobic membrane bioreactor: Performance and membrane filtration properties.

The present study introduced a new method for enhanced biomethane production and pollution control of swine wastewater (SW) using anaerobic membrane bioreactor (AnMBR). Results confirmed 35 °C as the optimum temperature for enhanced anaerobic digestion which resulted in relatively higher methane production rate and potential. In AnMBR system, robust pollutants removal and conversion rate were achieved under various hydraulic retention time (HRT) ranging from 20 to 10 days, while the highest methane yield (0.24 L/g-CODremoved) and microbial activity (6.65 mg-COD/g-VSS·h) were recorded at HRT of 15 days. Reduction of HRT to 10 days resulted in serious membrane fouling due to accumulation of extracellularpolymericsubstances(EPS) and cake layer on the membrane. However, cake layer as the dominant membrane foulant could be effectively removed through periodic physical backwash to recover the membrane permeability. Overall, the suggested AnMBR is a promising technology to enhance SW treatment and energy recovery.

High throughput sequencing of whole transcriptome and construct of ceRNA regulatory network in RD cells infected with enterovirus D68.

BACKGROUND: With the advancement of sequencing technologies, a plethora of noncoding RNA (ncRNA) species have been widely discovered, including microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs). However, the mechanism of these non-coding RNAs in diseases caused by enterovirus d68 (EV-D68) remains unclear. The goal of this research was to identify significantly altered circRNAs, lncRNAs, miRNAs, and mRNAs pathways in RD cells infected with EV-D68, analyze their target relationships, demonstrate the competing endogenous RNA (ceRNA) regulatory network, and evaluate their biological functions. METHODS: The total RNAs were sequenced by high-throughput sequencing technology, and differentially expressed genes between control and infection groups were screened using bioinformatics method. We discovered the targeting relationship between three ncRNAs and mRNA using bioinformatics methods, and then built a ceRNA regulatory network centered on miRNA. The biological functions of differentially expressed mRNAs (DEmRNAs) were discovered through GO and KEGG enrichment analysis. Create a protein interaction network (PPI) to seek for hub mRNAs and learn more about protein-protein interactions. The relative expression was verified using RT-qPCR. The effects of Fos and ARRDC3 on virus replication were confirmed using RT-qPCR, virus titer (TCID50/ml), Western blotting. RESULTS: 375 lncRNAs (154 upregulated and 221 downregulated), 33 circRNAs (32 upregulated and 1 downregulated), 96 miRNAs (49 upregulated and 47 downregulated), and 239 mRNAs (135 upregulated and 104 downregulated) were identified as differently in infected group compare to no-infected group. A single lncRNA or circRNA can be connected with numerous miRNAs, which subsequently coregulate additional mRNAs, according to the ceRNA regulatory network. The majority of DEmRNAs were shown to be connected to DNA binding, transcription regulation by RNA polymerase II, transcription factor, MAPK signaling pathways, Hippo signal pathway, and apoptosis pathway, according to GO and KEGG pathway enrichment analysis. The hub mRNAs with EGR1, Fos and Jun as the core were screened through PPI interaction network. We preliminarily demonstrated that the Fos and ARRDC3 genes can suppress EV-D68 viral replication in order to further verify the results of full transcriptome sequencing. CONCLUSION: The results of whole transcriptome analysis after EV-D68 infection of RD cells were first reported in this study, and for the first time, a ceRNA regulation network containing miRNA at its center was established for the first time. The Fos and ARRDC3 genes were found to hinder viral in RD cells. This study establishes a novel insight host response during EV-D68 infection and further investigated potential drug targets.

Exercise prevents HFD-induced insulin resistance risk: involvement of TNF-α level regulated by vagus nerve-related anti-inflammatory pathway in the spleen.

OBJECTIVES: Regular physical exercise can improve insulin resistance in insulin target tissues. However, the mechanisms about the beneficial effect of exercise on insulin resistance are not yet fully resolved. This study was carried out to address whether insulin resistance improvement by exercise is involved in an anti-inflammatory pathway in the spleen in high-fat diet (HFD) feeding mice. METHODS: Male C57Bl/6J mice with or without subdiaphragmatic vagotomy (sVNS) were subjected to medium-intensity treadmill exercise during HFD feeding. Glucose tolerance test and insulin tolerance test were detected, and spleen acetylcholine level, choline acetyltransferase activity (ChAT), protein kinase C (PKC) and tumor necrosis factor-alpha (TNF-α) were assayed. RESULTS: We found that exercise significantly improves HFD-induced glucose intolerance and insulin resistance, along with an increase in acetylcholine level, ChAT activity, and PKC activity, and decrease in TNF-α level in the system and the spleen from HFD-fed mice. However, sVNS abolished the beneficial effect of exercise on glucose intolerance and insulin resistance, decreased acetylcholine level, ChAT activity, and PKC activity, and increase TNF-α level of the spleen in HFD-mice exercise intervention. CONCLUSIONS: These data reveal that the prevention of HFD-associated insulin resistance by exercise intervention involves reducing splenic TNF-α level, which is mediated by cholinergic anti-inflammatory activity via influencing PKC activity, ChAT activity, and acetylcholine concentration in mice spleen.

The Therapeutic Effects of Mild to Moderate Intensity Aerobic Exercise on Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Trials.

INTRODUCTION: It has been recommended that physical activity be a part of treatment and management regimens of type 2 diabetes mellitus (T2DM), and research has shown that regular physical exercise facilitates glycemic control in these patients. In this analysis, our aim was to systematically show the therapeutic effects of mild to moderate intensity aerobic exercise on glycemic control in patients with T2DM. METHODS: From February to April 2021, we searched the https://www.clinicaltrials.gov , EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Google Scholar databases for trials that showed the effects of aerobic exercise on glycemic control in patients with T2DM. Glycated hemoglobin (HbA1c) was the endpoint in the analysis. The RevMan version 5.4 statistical program was used for statistical analysis, and the mean difference (MD) and 95% confidence intervals (CI) used to represent the data following analysis. RESULTS: Eighteen trials involving 972 participants with T2DM were included in this meta-analysis, of whom 523 were assigned to an exercise group and 449 were assigned to a control group. A comparison pre- versus post-aerobic exercise showed that aerobic exercise significantly improved glycemic control (HbA1c) (MD 0.35, 95% CI 0.23-0.48; P = 0.00001) in these patients with T2DM. A second comparison, T2DM participants in the experimental group post-exercise versus T2DM participants from the control group at the end of the follow-up, also showed that aerobic exercise significantly improved glycemic control (MD - 0.46, 95% CI - 0.69 to - 0.22; P = 0.0001). However, a comparison of HbA1c of T2DM participants in the control group at the beginning of the study compared to those at the end of follow-up did not show any significant improvement in glycemic control (MD 0.08, 95% CI - 0.05 to 0.21; P = 0.21). CONCLUSION: The current analysis showed that mild to moderate intensity aerobic exercise significantly improved glycemic control in patients with T2DM. Patients with T2DM who regularly participated in aerobic exercise activities had a better control of their disease than those who were not on a regular aerobic exercise regimen. These results lead to the recommendation that at least mild to moderate intensity aerobic exercise should be included in the treatment and management regimens of patients with T2DM.

Traditional Chinese Medicine formula FTZ protects against polycystic ovary syndrome through modulating adiponectin-mediated fat-ovary crosstalk in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: FuFang ZhenZhu TiaoZhi (FTZ) is a hospitalized traditional Chinese medicine herbal formula with documented metabolic benefits. Polycystic ovary syndrome (PCOS) characterized by ovarian dysfunction and insulin resistance represents one of the most common endocrine disorders in close association with metabolic dysfunction in premenopausal women. AIM OF THE STUDY: The present study aimed to investigate the preventive effect of FTZ on letrozole-induced experimental PCOS and its associated insulin resistance in mice. MATERIALS AND METHODS: Prepubertal female mice in the experimental groups (letrozole and FTZ) received continuous infusion of letrozole (50 µg/day) for 35 days. FTZ was administrated to mice by oral gavage daily at dosage of 2.892 g/kg body weight for 5 weeks. All groups of mice were fed a high-fat diet (HFD). Ovary and adipose tissue were collected from all mice after 5 weeks and adiponectin, testosterone, estradiol, and luteinizing hormone level determined. RESULTS: Letrozole-induced morphological changes in the ovary, including a decreased number of corpora lutea and antral follicles, and increased cystic follicles, were significantly attenuated in FTZ-treated mice. Additionally, FTZ treatment notably reversed PCOS-related disruption of estrous status. PCOS-related insulin resistance was markedly alleviated. Mechanistically, FTZ treatment notably enhanced circulating level and transcriptional abundance of adiponectin in adipose tissue, thereby orchestrating fat-ovary crosstalk. CONCLUSIONS: Our data collectively demonstrate that FTZ exerted preventive benefits in an experimental model of PCOS, at least partially by potentiating the production of adiponectin from adipose tissues. This suggests that FTZ is a promising treatment for PCOS.

The Effect of High-Fat Diet and Exercise Intervention on the TNF-α Level in Rat Spleen.

High-fat diet (HFD) consumption can trigger chronic inflammation in some tissues. However, it remains unclear if HFD induces chronic inflammation in the spleen. This investigation aims to address the effect of HFD consumption and exercise intervention on the level of tumor necrosis factor alpha (TNF-α) in the spleen. Rats were subjected to HFD feeding and/or moderate-intensity treadmill running. The TNF-α levels in plasma and spleen were detected by ELISA. The mass and total cell numbers of the spleen were measured. In addition, the expression of TNF-α and its relevant gene mRNAs in macrophages from the spleen were analyzed by qRT-PCR. We found that HFD consumption did not significantly affect the mass and total cell numbers of the spleen. However, HFD consumption significantly increased splenic TNF-α level, the expression of TNF-α, toll-like receptor 4, and nuclear factor κB p65 mRNAs. In contrast, the expression of nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) mRNA in macrophages was downregulated. Additionally, exercise abolished the increase in splenic TNF-α level as well as the abnormal expression of TNF-α and related gene mRNAs in macrophages in HFD-fed rats. In conclusion, our results reveal that HFD consumption increases TNF-α level in the spleen, which is along with upregulation of the expression of TLR4 and NF-κB mRNAs as well as downregulation of the expression of α7nAChR mRNA in splenic macrophages in rats. Exercise abolished detrimental effects of HFD on TNF-α level in the spleen and prevented abnormal expression of these genes in the macrophages from rat spleen.

Acute glucose load induced islet ß cells dysfunction in TLR4 dependent manner in male mice.

Recent studies highlighted the significance of chronic inflammation, which is mediated in part by toll-like receptors 4 (TLR4), in islet ß cell dysfunction by high-glucose exposure. However, about it is unclear whether islet ß cell dysfunction in response to high glucose is associated with TLR4. This investigation was designed to address the effect of TLR4 deficiency on insulin secretion in mice in response to acute intravenous glucose load. Hyperglycemic clamp was used to impair insulin secretion, and intraperitoneal glucose tolerance test was carried out to analyze insulin secretion function of islet ß cells. Our results showed that TLR4 deficiency repressed insulin secretion impairment in response to acute intravenous glucose load. Compared to wild-type mice, TLR4-/- mice did not exhibit increase of IL-1ß and TNF-α level in plasma and pancreatic tissue in response to acute intravenous load of high glucose. However, recombinant IL-1ß or TNF-α administration restored insulin secretion impairment induced by high glucose in TLR4-/- mice. Taken together, our results demonstrated that TLR4 activation and subsequent IL-1ß and TNF-α production contribute to islet ß cell dysfunction in mice in response to acute intravenous load of high glucose, which may provide a theoretical basis for diabetes complication improvement by physical exercise.