Does subclinical hypothyroidism affect the prognosis of patients with chronic systolic heart failure: A systematic review and meta-analysis.

BACKGROUND: Chronic systolic heart failure (CSHF) is a significant health burden with high morbidity and mortality. The role of subclinical hypothyroidism (SCH) in the prognosis of CSHF patients remains a critical area of inquiry. This systematic review and meta-analysis aim to elucidate the impact of SCH on the prognosis of patients with CSHF. METHODS: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, this meta-analysis employed a comprehensive search strategy across major databases including PubMed, Embase, Web of Science, and the Cochrane Library. The Patient, Intervention, Comparison, Outcome framework guided the inclusion of studies focusing on patients with CSHF, comparing those with and without SCH. Quality assessment was performed using the Newcastle-Ottawa scale. Statistical analyses assessed heterogeneity and publication bias, employing fixed-effect or random-effects models based on heterogeneity levels. RESULTS: From an initial pool of 1439 articles, 8 studies met the stringent inclusion criteria. These studies, conducted across diverse geographical regions, highlighted the relationship between SCH and all-cause mortality, cardiac events, and subgroup differences in CSHF patients. The meta-analysis revealed SCH as a significant risk factor for all-cause mortality (HR = 1.42) and cardiac events (HR = 1.46). Subgroup analysis indicated variability in risk based on region, sample size, age, and follow-up duration. Sensitivity analysis confirmed the stability of these findings, and publication bias assessment indicated symmetric funnel plot and nonsignificant Egger test results. CONCLUSIONS: SCH emerges as a predictive factor for all-cause mortality, cardiovascular events, and rehospitalization in CSHF patients. This finding underscores the importance of screening for SCH in CSHF patients, highlighting its potential role in improving patient prognosis.

New insights into the interplay between autophagy, gut microbiota and insulin resistance in metabolic syndrome.

Metabolic syndrome (MetS) is a widespread and multifactorial disorder, and the study of its pathogenesis and treatment remains challenging. Autophagy, an intracellular degradation system that maintains cellular renewal and homeostasis, is essential for maintaining antimicrobial defense, preserving epithelial barrier integrity, promoting mucosal immune response, maintaining intestinal homeostasis, and regulating gut microbiota and microbial metabolites. Dysfunctional autophagy is implicated in the pathological mechanisms of MetS, involving insulin resistance (IR), chronic inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, with IR being a predominant feature. The study of autophagy represents a valuable field of research with significant clinical implications for identifying autophagy-related signals, pathways, mechanisms, and treatment options for MetS. Given the multifactorial etiology and various potential risk factors, it is imperative to explore the interplay between autophagy and gut microbiota in MetS more thoroughly. This will facilitate the elucidation of new mechanisms underlying the crosstalk among autophagy, gut microbiota, and MetS, thereby providing new insights into the diagnosis and treatment of MetS.

CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.

CFAP58 is a testis-enriched gene that plays an important role in the sperm flagellogenesis of humans and mice. However, the effect of CFAP58 on bull semen quality and the underlying molecular mechanisms involved in spermatogenesis remain unknown. Here, we identified two single-nucleotide polymorphisms (rs110610797, A>G and rs133760846, G>T) and one indel (g.-1811_ g.-1810 ins147bp) in the promoter of CFAP58 that were significantly associated with semen quality of bulls, including sperm deformity rate and ejaculate volume. Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping. Cfap58 deficiency causes an increase in spermatozoa apoptosis. Further experiments confirmed that CFAP58 interacts with IFT88 and CCDC42. Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway. Collectively, our findings reveal that CFAP58 is required for spermatogenesis and provide genetic markers for evaluating semen quality in cattle.

CRTC2 activates the epithelial-mesenchymal transition of diabetic kidney disease through the CREB-Smad2/3 pathway.

BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a key role in tubulointerstitial fibrosis, which is a hallmark of diabetic kidney disease (DKD). Our previous studies showed that CRTC2 can simultaneously regulate glucose metabolism and lipid metabolism. However, it is still unclear whether CRTC2 participates in the EMT process in DKD. METHODS: We used protein‒protein network (PPI) analysis to identify genes that were differentially expressed during DKD and EMT. Then, we constructed a diabetic mouse model by administering STZ plus a high-fat diet, and we used HK-2 cells that were verified to confirm the bioinformatics research results. The effects that were exerted by CRTC2 on epithelial-mesenchymal transition in diabetic kidney disease through the CREB-Smad2/3 signaling pathway were investigated in vivo and in vitro by real-time PCR, WB, IHC and double luciferase reporter gene experiments. RESULTS: First, bioinformatics research showed that CRTC2 may promote EMT in diabetic renal tubules through the CREB-Smad2/3 signaling pathway. Furthermore, the Western blotting and real-time PCR results showed that CRTC2 overexpression reduced the expression of E-cadherin in HK-2 cells. The CRTC2 and α-SMA levels were increased in STZ-treated mouse kidneys, and the E-cadherin level was reduced. The luciferase activity of α-SMA, which is the key protein in EMT, was sharply increased in response to the overexpression of CRTC2 and decreased after the silencing of CREB and Smad2/3. However, the expression of E-cadherin showed the opposite trends. In the real-time PCR experiment, the mRNA expression of α-SMA increased significantly when CRTC2 was overexpressed but partially decreased when CREB and Smad2/3 were silenced. However, E-cadherin expression showed the opposite result. CONCLUSION: This study demonstrated that CRTC2 activates the EMT process via the CREB-Smad2/3 signaling pathway in diabetic renal tubules.

Loganin reduces diabetic kidney injury by inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis.

Diabetic kidney disease (DKD) is an essential cause of end-stage renal disease. The ongoing inflammatory response in the proximal tubule promotes the progression of DKD. Timely and effective blockade of the inflammatory process to protect the kidney during DKD progression is a proven strategy. The purpose of this study was to investigate the protective effect of loganin on diabetic nephropathy in vivo and in vitro and whether this effect was related to the inhibition of pyroptosis. The results indicated that loganin reduced fasting blood glucose, blood urea nitrogen and serum creatinine concentrations, and alleviated renal pathological changes in DKD mice. In parallel, loganin downregulated the expression of pyroptosis related proteins in the renal tubules of DKD mice and decreased serum levels of interleukin-1beta (IL-1ß) and interleukin-18 (IL-18). Furthermore, in vitro experiments showed that loganin attenuated high glucose-induced HK-2 cell injury by reducing the expression of pyroptosis-related proteins, and cytokine levels were also decreased. These fundings were also confirmed in the polyphyllin VI (PPVI) -induced HK-2 cell pyroptosis model. Loganin reduces high glucose induced HK-2 cells pyroptosis by inhibiting reactive oxygen species (ROS) production and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, the inhibition of pyroptosis via inhibition of the NLRP3/Caspase-1/Gasdermin D (GSDMD) pathway might be an essential mechanism for loganin treatment of DKD.

CCDC176 stabilizes microtubule doublets 1 and 9 to ensure proper sperm movement.

The molecular mechanism underlying asymmetric axonemal complexes in sperm flagella is still largely unknown. Here, we showed that the knockout of the coiled-coil domain-containing 176 (CCDC176) in mice led to male infertility due to decreased sperm motility. Ccdc176 knockout specifically destabilized microtubule doublets (MTDs) 1 and 9 during sperm maturation in the corpus epididymis. Single-sperm immunofluorescence showed that most CCDC176 was distributed along the axoneme, and further super-resolution imaging revealed that CCDC176 is asymmetrically localized in the sperm axoneme. CCDC176 could cooperate with microtubule and radial spoke proteins to stabilize MTDs 1 and 9, and its knockout results in the destabilization of some proteins in sperm flagella. Furthermore, as predicted by the sperm multibody dynamics (MBD) model, we found that MTDs 1 and 9 jutted out from the sperm flagellum annulus region in Ccdc176-/- spermatozoa, and these flagellar defects alter sperm flagellar beat patterns and swimming paths, potentially owing to the reduction and disequilibration of bending torque on the central pair. These results demonstrate that CCDC176 specifically stabilizes MTDs 1 and 9 in the sperm flagellum to ensure proper sperm movement for fertilization.

Coordinated alternation of DNA methylation and alternative splicing of PBRM1 affect bovine sperm structure and motility.

DNA methylation and gene alternative splicing drive spermatogenesis. In screening DNA methylation markers and transcripts related to sperm motility, semen from three pairs of full-sibling Holstein bulls with high and low motility was subjected to reduced representation bisulphite sequencing. A total of 948 DMRs were found in 874 genes (gDMRs). Approximately 89% of gDMR-related genes harboured alternative splicing events, including SMAD2, KIF17, and PBRM1. One DMR in exon 29 of PBRM1 with the highest 5mC ratio was found, and hypermethylation in this region was related to bull sperm motility. Furthermore, alternative splicing events at exon 29 of PBRM1 were found in bull testis, including PBRM1-complete, PBRM1-SV1 (exon 28 deletion), and PBRM1-SV2 (exons 28-29 deletion). PBRM1-SV2 exhibited significantly higher expression in adult bull testes than in newborn bull testes. In addition, PBRM1 was localized to the redundant nuclear membrane of bull sperm, which might be related to sperm motility caused by sperm tail breakage. Therefore, the hypermethylation of exon 29 may be associated with the production of PBRM1-SV2 in spermatogenesis. These findings indicated that DNA methylation alteration at specific loci could regulate gene splicing and expression and synergistically alter sperm structure and motility.

Comparing the bioequivalence and safety of liraglutide in healthy Chinese subjects: an open, single-dose, randomized, repeated, two-sequence, two-cycle phase I clinical trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. CONCLUSION: The study shows that the two drugs had similar bioequivalence and safety. CLINICAL TRIAL REGISTRATION: DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076.

Jiedu Tongluo Baoshen formula enhances renal tubular epithelial cell autophagy to prevent renal fibrosis by activating SIRT1/LKB1/AMPK pathway.

Renal fibrosis, an important pathological change in the development of diabetic kidney disease (DKD), urgently needs new treatment methods clinically. The Jiedu Tongluo Baoshen (JTBF) formula was created based on the theory of toxic damage to the kidney collaterals, and a variety of active ingredients in JTBF have inhibitory effects on epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM). In this study, the Ultra Performance Liquid Chromatography (UPLC) was employed to analyze the effective ingredients in the JTBF formula. After screening in the PubChem database, we identified 94 active compounds of JTBF and predicted the SIRT1 pathway as potential targets through network pharmacology. In addition, in the high fat diet (HFD)+Streptozocin (STZ)-induced DKD rat model and high glucose (HG)-induced NRK-52E cell model, JTBF treatment activates the phosphorylation of LKB1 and AMPK and enhances the autophagy activity of NRK-52E cells, thereby reducing the accumulation of EMT and ECM. These results have been confirmed in vivo and in vitro experiments. JTBF enhances the autophagy activity of renal tubular epithelial cells and inhibits the progression of DKD renal fibrosis by activating the SIRT1/LKB1/AMPK signal pathway. This study provides new insights into the molecular mechanism of JTBF to prevent and treat DKD renal fibrosis.

Signatures of selection in indigenous Chinese cattle genomes reveal adaptive genes and genetic variations to cold climate.

Cold climate shapes the genome of animals and drives them to carry sufficient genetic variations to adapt to changes in temperature. However, limited information is available about the genome-wide pattern of adaptations to cold environments in cattle. In the present study, we used 777K SNP genotyping (15 Chinese cattle breeds, 198 individuals) and whole genome resequencing data (54 cattle breeds of the world, 432 individuals) to disentangle divergent selection signatures, especially between the cold-adapted (annual average temperature of habitat, 6.24 °C to 10.3 °C) and heat-adapted (20.2 °C to 24.73 °C) Chinese native cattle breeds. Genomic analyses revealed a set of candidate genes (e.g., UQCR11, DNAJC18, EGR1, and STING1) were functionally associated with thermogenesis and energy metabolism. We also characterized the adaptive loci of cattle exposed to cold temperatures. Our study finds new candidate genes and provides new insights into adaptations to cold climates in cattle.

Cold climates can affect cattle performance, survival, and health. Local cattle breeds have been adapted to the local environments including extremely cold temperatures after a long period of natural and artificial selection. Selection and local adaptation are shaping populations. However, identifying loci associated with cold adaptation has been a major challenge. We used high-density SNP arrays and resequencing data to comprehensively analyze and compare the genomic selection signatures of Chinese northern and southern cattle, and elucidated several adaptive genes and alleles involved in cold adaptation. The complexity of genetic adaptation mechanism among different low-temperature adapted cattle breeds was also emphasized.

Contribution of Chinese herbal medicine in the treatment of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of randomized controlled trials.

Coronavirus disease 2019 (COVID-19) has become a global epidemic, and there is no specific treatment for anti-COVID-19 drugs. However, treatment of COVID-19 using Chinese herbal medicine (CHM) has been widely practiced in China. PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP databases were searched to evaluate the efficacy and safety of CHM in the treatment of COVID-19. Twenty-six studies were included in this meta-analysis. The included cases were all patients diagnosed with COVID-19 according to the "New Coronary Virus Pneumonia Diagnosis and Treatment Program," with a total of 2,407 cases. Patients were treated with CHM, including 36 prescriptions, and 105 flavors of CHM were included. The results of the meta-analysis showed that the CHM group improved in lung CT, clinical cure rate, clinical symptom score and time to negative for viral nucleic acid. However, this study still has many limitations due to the limited number of included studies. Therefore, high-quality RCT studies are needed to provide more reliable evidence for CHM treatment of COVID-19. In conclusion, CHM may significantly improve the clinical manifestations and laboratory indicators of patients with COVID-19. In addition, no serious adverse reactions were found after CHM treatment. Therefore, CHM may be used as a potential candidate for COVID-19. HIGHLIGHTS: COVID-19 has become a global epidemic, and there is no specific treatment for anti-COVID-19 drugs. CHM has made a new breakthrough in the treatment of COVID-19. CHM may relieve lung CT images of COVID-19 patients. CHM may improve clinical symptoms of COVID-19 patients. CHM may inhibit the expression of inflammatory factors in patients with COVID-19.

The effects of Ophiocordyceps sinensis combined with ACEI/ARB on diabetic kidney disease: A systematic review and meta-analysis.

BACKGROUND: Ophiocordyceps sinensis (OS), a medicinal fungus, has been made into OS preparations, which are frequently used as adjunctive therapy for patients with Diabetic Kidney Disease (DKD) in China. It is necessary to assess the efficacy and safety of OS preparations in the adjunctive treatment of DKD by conducting a systematic review and meta-analysis. OBJECTIVE: Ophiocordyceps sinensis preparations were evaluated for their efficacy and safety as adjunctive therapy to conventional drugs (angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)) for DKD. METHODS: We searched seven electronic literature databases for randomized controlled trials (RCTs) comparing ACEI/ARB and OS combined with ACEI/ARB from inception up to March 2022. Two reviewers extracted data and assessed the risk of bias independently. Evidence certainty was rated using the GRADE system. Standardized mean difference (SMD) or mean difference (MD) was pooled with random effects models and was reported with corresponding 95% confidence intervals (CIs). Meta-analysis, sensitivity analysis and Egger's test were performed using R software (version 14.2) (PROSPERO registration no. CRD42021248634). RESULTS: Thirty eight RCTs involving 3167 patients met the inclusion criteria. No trials were reported with outcomes about kidney disease progression and cardiovascular events. In meta-analysis, compared with the control group of ACEI/ARB alone, OS combined with ACEI/ARB can achieve better effects in the treatment of DKD on reducing serum creatinine (Scr) [MDScr =-11.48 95% CI [-15.78, -7.18], p < 0.01], blood urea nitrogen (BUN) [MDBUN= -1.00, 95% CI [-1.44, -0.55], p < 0.01], ß2-microglobulin (ß2-MG) [SMDß2-MG= -1.32, 95% CI [-2.27, -0.37], p < 0.01], cystatin C (CysC) [MDCysC=-0.64, 95% CI [-0.83, -0.45], p < 0.01], 24-h urine proteinuria (24hUP) [SMD24hUP= -1.99, 95% CI [-2.68; -1.31], p < 0.01], urine microalbumin (UALB) [MDUALB= -37.41, 95% CI [-44.76, -30.06], p < 0.01] and decreasing urinary albumin excretion rate (UAER) [MDUAER= -24.11, 95% CI [-30.54, -17.68], p < 0.01] and albumin creatinine ratio (ACR) [SMDACR = 1.01, 95% CI [-1.73, -0.29], p < 0.01]. The OS adjuvant treatment also improved outcomes of blood pressure, blood glucose, blood lipid, inflammation and oxidative stress. No significant change in fasting blood glucose (FPG), glycated hemoglobin (HbA1c), malondialdehyde (MDA), and transforming growth factor beta 1 (TGF-ß1) was detected. Yet, no significant difference was found about the adverse events between the two groups. CONCLUSIONS: Ophiocordyceps sinensis preparation combined with ACEI/ARB has beneficial influence on renal function, decrease proteinuria, dyslipidemia, and even oxidative stress and inflammation in DKD patients. However, there is no trial that evaluated outcomes of kidney disease progression and cardiovascular events. Future study should move beyond surrogate endpoints to actual cardiovascular or renal outcome benefits with an aim to explore effects of OS preparation in the long-term.

Ferroptosis and its role in skeletal muscle diseases.

Ferroptosis is characterized by the accumulation of iron and lipid peroxidation products, which regulates physiological and pathological processes in numerous organs and tissues. A growing body of research suggests that ferroptosis is a key causative factor in a variety of skeletal muscle diseases, including sarcopenia, rhabdomyolysis, rhabdomyosarcoma, and exhaustive exercise-induced fatigue. However, the relationship between ferroptosis and various skeletal muscle diseases has not been investigated systematically. This review's objective is to provide a comprehensive summary of the mechanisms and signaling factors that regulate ferroptosis, including lipid peroxidation, iron/heme, amino acid metabolism, and autophagy. In addition, we tease out the role of ferroptosis in the progression of different skeletal muscle diseases and ferroptosis as a potential target for the treatment of multiple skeletal muscle diseases. This review can provide valuable reference for the research on the pathogenesis of skeletal muscle diseases, as well as for clinical prevention and treatment.

Qizhi Kebitong Formula Ameliorates Streptozocin-Induced Diabetic Osteoporosis through Regulating the PI3K/Akt/NF-κB Pathway.

Background: Diabetic osteoporosis (DOP) is a progressive osteoblast dysfunction induced by high glucose, which has negative impacts on bone homeostasis. Qizhi Kebitong formula (QKF) is a traditional Chinese medicine (TCM) formula for treating DOP. However, its role in the protection of DOP has not been clarified yet. Here, we aimed to explore the potential mechanisms of QKF on DOP development via in vivo experiment. Methods: Network pharmacology was used to detect the key targets and signaling pathways of QKF on DOP. The effects of QKF on DOP were examined by the phenotypic characteristics, micro-CT, and hematoxylin-eosin (H&E) staining. The predicted targets and pathways were validated by a streptozocin- (STZ-) induced mouse model. Subsequently, the levels of the selected genes and proteins were analyzed using qRT-PCR and Western blot. Finally, AutoDock and PyMOL were used for molecular docking. Results: In this study, 90 active compounds and 2970 related disease targets have been found through network pharmacology. And QKF could improve the microstructures of femur bone mass, reduce inflammatory cell infiltration, and downregulate the levels of TNF-α, IKBKB, IL-6, and IL-1ß. Moreover, the underlying effect of PI3K/Akt/NF-κB pathways was also recommended in the treatment. Conclusion: Altogether, our findings suggested that QKF could markedly alleviate osteoblast dysfunction by modulating the key targets and PI3K/Akt/NF-κB signaling pathway.

The Impact of lncRNA on Diabetic Kidney Disease: Systematic Review and In Silico Analyses.

Background: Long noncoding RNA (lncRNA) is involved in the occurrence and development of diabetic kidney disease (DKD). It is necessary to identify the expression of lncRNA from DKD patients through systematic reviews, and then carry out silico analyses to recognize the dysregulated lncRNA and their associated pathways. Methods: The study searched Pubmed, Embase, Cochrane Library, WanFang, VIP, CNKI, and CBM to find lncRNA studies on DKD published before March 1, 2021. Systematic review of the literature on this topic was conducted to determine the expression of lncRNA in DKD and non-DKD controls. For the dysregulated lncRNA in DKD patients, silico analysis was performed, and lncRNA2Target v2.0 and starBase were used to search for potential target genes of lncRNA. The Encyclopedia of Genomics (KEGG) pathway enrichment analysis was performed to better identify dysregulated lncRNAs in DKD and determine the associated signal pathways. Results: According to the inclusion and exclusion criteria, 28 publications meeting the eligibility criteria were included in the systematic evaluation. A total of 3,394 patients were enrolled in this study, including 1,238 patients in DKD group, and 1,223 diabetic patients, and 933 healthy adults in control group. Compared with the control, there were eight lncRNA disorders in DKD patients (MALAT1, GAS5, MIAT, CASC2, NEAT1, NR_033515, ARAP1-AS2, and ARAP1-AS1). In addition, five lncRNAs (MALAT1, GAS5, MIAT, CASC2, and NEAT1) participated in disease-related signal pathways, indicating their role in DKD. Discussion. This study showed that there were eight lncRNAs in DKD that were persistently dysregulated, especially five lncRNAs which were closely related to the disease. Although systematic review included 28 studies that analyzed the expression of lncRNA in DKD-related tissues, the potential of these dysregulated lncRNAs as biomarkers or therapeutic targets for DKD remains to be further explored. Trial registration. PROSPERO (CRD42021248634).

CCDC38 is required for sperm flagellum biogenesis and male fertility in mice.

The sperm flagellum is essential for male fertility, and defects in flagellum biogenesis are associated with male infertility. Deficiency of coiled-coil domain-containing (CCDC) 42 (CCDC42) is specifically associated with malformation of mouse sperm flagella. Here, we find that the testis-specific protein CCDC38 interacts with CCDC42, localizing on the manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in a distorted manchette, multiple morphological abnormalities of the flagella of spermatozoa and eventually male sterility. Furthermore, we find that CCDC38 interacts with intraflagellar transport protein 88 (IFT88), as well as outer dense fibrous 2 (ODF2), and the knockout of Ccdc38 reduces transport of ODF2 to the flagellum. Altogether, our results uncover the essential role of CCDC38 in sperm flagellum biogenesis, and suggest that some mutations of these genes might be associated with male infertility in humans.

Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has been applied to diabetic kidney disease (DKD). A large number of animal trials each year focus on TCM for DKD, but the evidence for these preclinical studies is not clear. AIM OF THE STUDY: The aim of this study was to study the therapeutic effect of Jiedu Tongluo Baoshen formula (JTBF) on DKD proteinuria and renal protection. At the same time, it is verified that JTBF can reduce podocyte injury by enhancing autophagy function, and then achieve the effect of proteinuria. MATERIALS AND METHODS: We use high performance liquid chromatography to detect and analyze the fingerprint of JTBF to find the chemical composition. Subsequently, we constructed a DKD rat model induced by high-fat diet and streptozocin (HFD + STZ). Urine and blood biochemical automatic analyzer were used to detect 24-h urine protein quantification (24 h-UP) and renal function. The renal pathological changes were observed by H&E and transmission electron microscopy (TEM), and the levels of autophagy-related proteins and mRNA in podocytes were detected by immunohistochemistry, RT-qPCR and Western Blot. The chemical composition of JTBF was screened from traditional Chinese medicine systems pharmacol (TCMSP) and PubChem databases, and the potential targets and associated pathways of JTBF were predicted using kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI) network analysis in network pharmacology, and confirmed in animal experiments and histopathological methods. RESULTS: We discovered 77 active ingredients of JTBF. Through animal experiments, it was found that JTBF reduced 24 h-UP and promoted the expression of podocin, nephrin, and WT-1 in podocytes, thereby reducing podocyte damage. At the same time, JTBF activates the expression of podocyte autophagy-related proteins (beclin-1, LC3 and P62). Subsequently, through network pharmacology predictions, 208 compounds were obtained from JTBF, and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) was a potential signal pathway. JTBF was obtained in DKD rat kidney tissue to inhibit the expression of PI3K, Akt and mTOR related proteins. CONCLUSIONS: JTBF enhance podocyte autophagy to reduce podocyte damage, thereby effectively treating DKD proteinuria and protecting kidney function.

The Influence of Different Types of Diabetes on Vascular Complications.

The final outcome of diabetes is chronic complications, of which vascular complications are the most serious, which is the main cause of death for diabetic patients and the direct cause of the increase in the cost of diabetes. Type 1 and type 2 diabetes are the main types of diabetes, and their pathogenesis is completely different. Type 1 diabetes is caused by genetics and immunity to destroy a large number of ß cells, and insulin secretion is absolutely insufficient, which is more prone to microvascular complications. Type 2 diabetes is dominated by insulin resistance, leading to atherosclerosis, which is more likely to progress to macrovascular complications. This article explores the pathogenesis of two types of diabetes, analyzes the pathogenesis of different vascular complications, and tries to explain the different trends in the progression of different types of diabetes to vascular complications, in order to better prevent diabetes and its vascular complications.

Interventional Clinical Trials on Diabetic Peripheral Neuropathy: A Retrospective Analysis.

AIMS/INTRODUCTION: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. At present, there is no comprehensive summary of the clinical trials related to DPN. In this article, we summarized the basic characteristics of the interventional clinical trials pertaining to DPN to determine the current status of research in this field and the existing issues. MATERIALS AND METHODS: We searched the World Health Organization International Clinical Trial Registration Platform (ICTRP), PubMed and Web of Science for clinical trials from 2005 to April 2021 and extracted 149 registered and 459 published clinical trials on DPN. We summarized the characteristics of the clinical trials, including the source registration, recruitment status, stage, age group, allocation method, intervention, end point classification, funding source, and treatment. RESULTS: After excluding noninterventional and nontreatment trials, 149 registered clinical trials out of 292 records from 12 registration centers and 459 published articles were included in this study. Among the registered trials, 43% had been completed, and 34.4% had been published in peer-reviewed journals. Among these trials, more than half used random allocation and blinded placebo-controlled methodologies. A total of 40.3% of the trials were multicenter studies, 63.8% of the treatments were drug therapies, and the endpoint classifications of 49% were efficacy and safety. Of the 459 published interventional clinical trials on DPN, 69.7% of the trials used drug treatments; more than half were randomized, double-blind, placebo-controlled clinical trials; 94.1% had positive outcomes; 46.4% had a target size of 50; and 22.9% were multicenter. CONCLUSION: This paper systematically summarizes the current status of interventional trials on DPN registered in the ICTRP and published clinical trials and provides a reference for the development of high-quality intervention strategies for DPN in the future.

Efficacy of Tripterygium wilfordii Hook F on animal model of Diabetic Kidney Diseases: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook F (TwHF) has been clinically applied in the treatment of Diabetic Kidney Diseases (DKD). A large number of animal experiments focused on the TwHF treatment of DKD were conducted every year, but the evidence for these preclinical studies is unclear. AIM OF THE STUDY: This study aims to evaluate the efficacy of TwHF on diabetic nephropathy through a stematic reviews and meta-analysis of animal models, and whether it has an effect on improving kidney pathology, renal function indicators and blood sugar levels, it also summarizes the use of TwHF for treatment the underlying mechanism of DKD. MATERIALS AND METHODS: We systematically searched studies from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang database from inception to May 2020. Chinese studies from the list of Chinese Core Journals would be included. SYRCLE's risk of bias tool for animal studies was applied to assess the methodological quality of studies. A meta-analysis was performed by using RevMan 5.3. RESULTS: Out of 429 records identified in the initial search, 32 studies were selected. The results indicated that, compared with control group, TwHF treatment improved 24 h urine protein (24 h-UP) level (SMD - 4.21, 95% CI - 5.38 to - 3.04, P < 0.001), serum creatinine (Scr) (MD - 14.97, 95% CI - 20.42 to - 9.53, P < 0.001), blood urea nitrogen (BUN) (MD - 4.07, 95% CI - 5.49 to - 2.66, P < 0.001), blood glucose (Glu) (MD - 2.40, 95% CI - 4.304 to - 0.49, P = 0.01), Triglyceride (TG) (MD - 1.57, 95% CI - 2.06 to - 1.08, P < 0.001), and Cholesterol (TC) (MD - 1.49, 95% CI - 2.23 to - 0.75 P < 0.001); and increased the level of albumin (Alb) (MD 3.40, 95% CI 1.69 to 5.11, P < 0.001) and weight (MD 30.89, 95% CI 24.35 to 37.42, P < 0.001). There were no statistical difference on Alanine aminotransferase (ALT) (MD 3.00, 95% CI - 7.80 to 13.81, P = 0.59) and Aspartate aminotransferase (AST) (MD 0.77, 95% CI -15.05 to 16.60, P = 0.92) after TwHF. Meta regression analysis showed that the DKD model induced by different methods (type I/II), the dose of Tripterygium wilfordii and the intervention time were not the reasons for the heterogeneity of 24 h-UP, Alb, Glu, Scr, and BUN (p > 0.05). CONCLUSIONS: TwHF is an effective and safe to treat DKD, which can protect the kidneys through anti-inflammation, improving oxidative stress and podocyte damage, and inhibiting mesangial cell proliferation and extracellular matrix proliferation.