Jinlida for Diabetes Prevention in Impaired Glucose Tolerance and Multiple Metabolic Abnormalities: The FOCUS Randomized Clinical Trial.

Importance: Previous studies have shown that Jinlida (JLD) granules, an approved treatment for type 2 diabetes in China, can reduce blood glucose level, reduce glycated hemoglobin (HbA1c), and improve insulin resistance in people with type 2 diabetes. Objective: To evaluate the effect of long-term administration of JLD vs placebo on the incidence of diabetes in participants with impaired glucose tolerance (IGT) and multiple metabolic abnormalities. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial (FOCUS) was conducted across 35 centers in 21 cities in China from June 2019 to February 2023. Individuals aged 18 to 70 years with IGT and multiple metabolic abnormalities were enrolled. Intervention: Participants were randomly allocated 1:1 to receive JLD or placebo (9 g, 3 times per day, orally). They continued this regimen until they developed diabetes, withdrew from the study, were lost to follow-up, or died. Main Outcomes and Measures: The primary outcome was the occurrence of diabetes, which was determined by 2 consecutive oral glucose tolerance tests. Secondary outcomes included waist circumference; fasting and 2-hour postprandial plasma glucose levels; HbA1c; fasting insulin level; homeostatic model assessment for insulin resistance (HOMA-IR); total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels; ankle-brachial index; and carotid intima-media thickness. Results: A total of 889 participants were randomized, of whom 885 were in the full analysis set (442 in the JLD group; 443 in the placebo group; mean [SD] age, 52.57 [10.33] years; 463 [52.32%] female). Following a median observation period of 2.20 years (IQR, 1.27-2.64 years), participants in the JLD group had a lower risk of developing diabetes compared with those in the placebo group (hazard ratio, 0.59; 95% CI, 0.46-0.74; P < .001). During the follow-up period, the JLD group had a between-group difference of 0.95 cm (95% CI, 0.36-1.55 cm) in waist circumference, 9.2 mg/dL (95% CI, 5.4-13.0 mg/dL) in 2-hour postprandial blood glucose level, 3.8 mg/dL (95% CI, 2.2-5.6 mg/dL) in fasting blood glucose level, 0.20% (95% CI, 0.13%-0.27%) in HbA1c, 6.6 mg/dL (95% CI, 1.9-11.2) in total cholesterol level, 4.3 mg/dL (95% CI, 0.8-7.7 mg/dL) in low-density lipoprotein cholesterol level, 25.7 mg/dL (95% CI, 15.9-35.4 mg/dL) in triglyceride levels, and 0.47 (95% CI, 0.12-0.83) in HOMA-IR compared with the placebo group. After 24 months of follow-up, the JLD group had a significant improvement in ankle-brachial index and waist circumference compared with the placebo group. Conclusions and Relevance: The findings suggest that JLD can reduce the risk of diabetes in participants with IGT and multiple metabolic abnormalities. Trial Registration: Chinese Clinical Trial Register: ChiCTR1900023241.

Effectiveness and safety of Sanhan Huashi granules versus nirmatrelvir-ritonavir in adult patients with COVID-19: A randomized, open-label, multicenter trial.

Sanhan Huashi granules (SHG) demonstrated therapeutic effects against coronavirus disease 2019 (COVID-19) in observational studies. In order to compare the effectiveness and safety of SHG and nirmatrelvir-ritonavir in treating adults with mild-to-moderate COVID-19, we conducted a randomized, active-controlled, open-label, multi-center trial conducted between February and July in 2023. The patients were randomized in a 1:1 ratio to the SHG group and the nirmatrelvir-ritonavir group. A total of 400 participants were randomized, among which 200 participants ultimately received SHG and 198 received nirmatrelvir-ritonavir. The primary outcome was time to sustained clinical recovery through day 28. SHG significantly shortened the median time to sustained clinical recovery compared to nirmatrelvir-ritonavir (6.0 (95% CI, 5.0 to 6.0) vs. 8.0 (95% CI, 6.0 to 9.0) d; P = 0.001), particularly for individual symptoms including fever, sore throat, cough and fatigue. No participants in either group died and incidence of severe COVID-19 showed no difference between two groups. Participants who received nirmatrelvir-ritonavir demonstrated a higher rate of virus clearance on day 5 compared to those received SHG (46.4% (95% CI, 39.1 to 53.7) vs. 65.6% (95% CI, 58.3 to 72.4); P < 0.001). Most adverse events were mild in both groups. In summary, SHG was superior to nirmatrelvir-ritonavir in shortening the time to sustained clinical recovery in participants with mild-to-moderate COVID-19, despite a lower virus clearance rate observed after 5 d of treatment (Chinese Clinical Trial Registry Identifier: ChiCTR2300067872).

Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis.

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.

Mitochondrial regulation of diabetic endothelial dysfunction: Pathophysiological links.

Micro- and macrovascular complications frequently occur in patients with diabetes, with endothelial dysfunction playing a key role in the development and progression of the complications. For the early diagnosis and optimal treatment of vascular complications associated with diabetes, it is imperative to comprehend the cellular and molecular mechanisms governing the function of diabetic endothelial cells. Mitochondria function as crucial sensors of environmental and cellular stress regulating endothelial cell viability, structural integrity and function. Impaired mitochondrial quality control mechanisms and mitochondrial dysfunction are the main features of endothelial damage. Hence, targeted mitochondrial therapy is considered promising novel therapeutic options in vascular complications of diabetes. In this review, we focus on the mitochondrial functions in the vascular endothelial cells and the pathophysiological role of mitochondria in diabetic endothelial dysfunction, aiming to provide a reference for related drug development and clinical diagnosis and treatment.

Advances in secondary prevention mechanisms of macrovascular complications in type 2 diabetes mellitus patients: a comprehensive review.

Type 2 diabetes mellitus (T2DM) poses a significant global health burden. This is particularly due to its macrovascular complications, such as coronary artery disease, peripheral vascular disease, and cerebrovascular disease, which have emerged as leading contributors to morbidity and mortality. This review comprehensively explores the pathophysiological mechanisms underlying these complications, protective strategies, and both existing and emerging secondary preventive measures. Furthermore, we delve into the applications of experimental models and methodologies in foundational research while also highlighting current research limitations and future directions. Specifically, we focus on the literature published post-2020 concerning the secondary prevention of macrovascular complications in patients with T2DM by conducting a targeted review of studies supported by robust evidence to offer a holistic perspective.

Double-blinded, randomized clinical trial of Gegen Qinlian decoction pinpoints Faecalibacterium as key gut bacteria in alleviating hyperglycemia.

Background: Accumulating evidence suggests that metabolic disorders, including type 2 diabetes mellitus (T2DM), can be treated with traditional Chinese medicine formulas, such as the Gegen Qinlian decoction (GQD). This study elucidates the mechanisms by which gut microbes mediate the anti-diabetic effects of GQD. Methods: We conducted a double-blind randomized clinical trial involving 120 untreated participants with T2DM. During the 12-week intervention, anthropometric measurements and diabetic traits were recorded every 4 weeks. Fecal microbiota and serum metabolites were measured before and after the intervention using 16S rDNA sequencing, liquid chromatography-mass spectrometry, and Bio-Plex panels. Results: Anti-diabetic effects were observed in the GQD group in the human trial. Specifically, glycated hemoglobin, fasting plasma glucose, and two-hour postprandial blood glucose levels were significantly lower in the GQD group than in the placebo group. Additionally, Faecalibacterium was significantly enriched in the GQD group, and the short-chain fatty acid levels were higher and the serum inflammation-associated marker levels were lower in the GQD group compared to the placebo group. Moreover, Faecalibacterium abundance negatively correlated with the levels of serum hemoglobin, fasting plasma glucose, and pro-inflammatory cytokines. Finally, the diabetes-alleviating effect of Faecalibacterium was confirmed by oral administration of Faecalibacterium prausnitzii (DSMZ 17677) in T2DM mouse model. Conclusions: GQD improved type 2 diabetes primarily by modulating the abundance of Faecalibacterium in the gut microbiota, alleviating metabolic disorders and the inflammatory state. Trial registration: Registry No. ChiCTR-IOR-15006626.

Early effective intervention can significantly reduce all-cause mortality in prediabetic patients: a systematic review and meta-analysis based on high-quality clinical studies.

Background: Reducing the occurrence of diabetes is considered a primary criterion for evaluating the effectiveness of interventions for prediabetes. There is existing evidence that early lifestyle-based interventions can significantly decrease the incidence of diabetes. However, whether effective interventions can reduce long-term outcomes in patients, including all-cause mortality, cardiovascular risks, and the occurrence of microvascular complications, which are the most concerning issues for both patients and clinicians, remains a subject of inconsistent research findings. And there is no direct evidence to answer whether effective intervention has long-term benefits for prediabetic patients. Therefore, we conducted a systematic review and meta-analysis to assess the relationship between early effective intervention and macrovascular and microvascular complications in prediabetic patients. Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for the randomized controlled trials of lifestyle or/and drugs intervention in prediabetes from inception to 2023.9.15. Two investigators independently reviewed the included studies and extracted relevant data. Random or fixed effects model meta-analysis to derive overall relative risk (RR) with 95% CI for all-cause mortality, cardiovascular events, and microvascular complications. Results: As of September 15, 2023, a total of 7 effective intervention studies were included, comprising 26 articles out of 25,671 articles. These studies involved 26,389 patients with a total follow-up duration of 178,038.6 person-years. The results indicate that effective intervention can significantly reduce all-cause mortality in prediabetic patients without a history of cardiovascular disease by 17% (RR 0.83, 95% CI 0.70-0.98). Additionally, effective intervention reduced the incidence of retinopathy by 38% (RR 0.62, 95% CI 0.70-0.98). Furthermore, the study results suggest that women and younger individuals have lower all-cause mortality and cardiovascular mortality. Subsequently, we conducted an in-depth analysis of patients without a history of cardiovascular disease. The results revealed that prediabetic patients with a 10-year cardiovascular risk >10% experienced more significant benefits in terms of all-cause mortality (P=0.01). When comparing the results of all-cause mortality and cardiovascular mortality from the Da Qing Diabetes Prevention Outcome Study longitudinally, it was evident that the duration of follow-up is a key factor influencing long-term benefits. In other words, the beneficial effects become more pronounced as the intervention duration reaches a certain threshold. Conclusion: Early effective intervention, which significantly reduces the incidence of diabetes, can effectively lower all-cause mortality in prediabetic patients without a history of cardiovascular disease (especially those with a 10-year cardiovascular risk >10%), with women and younger individuals benefiting more significantly. Additionally, the duration of follow-up is a key factor influencing outcomes. The conclusions of this study can provide evidence-based guidance for the clinical treatment of prediabetic patients to prevent cardiovascular and microvascular complications. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42020160985.

Microbiome and metabolome dysbiosis analysis in impaired glucose tolerance for the prediction of progression to diabetes mellitus.

Gut microbiota and circulating metabolite dysbiosis predate important pathological changes in glucose metabolic disorders; however, comprehensive studies on impaired glucose tolerance (IGT), a diabetes mellitus (DM) precursor, are lacking. Here, we perform metagenomic sequencing and metabolomics on 47 pairs of individuals with IGT and newly diagnosed DM and 46 controls with normal glucose tolerance (NGT); patients with IGT are followed up after 4 years for progression to DM. Analysis of baseline data reveals significant differences in gut microbiota and serum metabolites among the IGT, DM, and NGT groups. In addition, 13 types of gut microbiota and 17 types of circulating metabolites showed significant differences at baseline before IGT progressed to DM, including higher levels of Eggerthella unclassified, Coprobacillus unclassified, Clostridium ramosum, L-valine, L-norleucine, and L-isoleucine, and lower levels of Eubacterium eligens, Bacteroides faecis, Lachnospiraceae bacterium 3_1_46FAA, Alistipes senegalensis, Megaspaera elsdenii, Clostridium perfringens, α-linolenic acid, 10E,12Z-octadecadienoic acid, and dodecanoic acid. A random forest model based on differential intestinal microbiota and circulating metabolites can predict the progression from IGT to DM (AUC = 0.87). These results suggest that microbiome and metabolome dysbiosis occur in individuals with IGT and have important predictive values and potential for intervention in preventing IGT from progressing to DM.

Multiomics Analyses With Stool-Type Stratification in Patient Cohorts and Blautia Identification as a Potential Bacterial Modulator in Type 2 Diabetes Mellitus.

Heterogeneity in host and gut microbiota hampers microbial precision intervention of type 2 diabetes mellitus (T2DM). Here, we investigated novel features for patient stratification and bacterial modulators for intervention, using cross-sectional patient cohorts and animal experiments. We collected stool, blood, and urine samples from 103 patients with recent-onset T2DM and 25 healthy control subjects (HCs), performed gut microbial composition and metabolite profiling, and combined it with host transcriptome, metabolome, cytokine, and clinical data. Stool type (dry or loose stool), a feature of the stool microenvironment recently explored in microbiome studies, was used for stratification of patients with T2DM as it explained most of the variation in the multiomics data set among all clinical parameters in our covariate analysis. T2DM with dry stool (DM-DS) and loose stool (DM-LS) were clearly differentiated from HC and each other by LightGBM models, optimal among multiple machine learning models. Compared with DM-DS, DM-LS exhibited discordant gut microbial taxonomic and functional profiles, severe host metabolic disorder, and excessive insulin secretion. Further cross-measurement association analysis linked the differential microbial profiles, in particular Blautia abundances, to T2DM phenotypes in our stratified multiomics data set. Notably, oral supplementation of Blautia to T2DM mice induced inhibitory effects on lipid accumulation, weight gain, and blood glucose elevation with simultaneous modulation of gut bacterial composition, revealing the therapeutic potential of Blautia. Our study highlights the clinical implications of stool microenvironment stratification and Blautia supplementation in T2DM, offering promising prospects for microbial precision treatment of metabolic diseases.

The rational dose for MaXingShiGan decoction is crucial for its clinical effectiveness in treating bronchial pneumonia: three randomized, double-blind, dose-parallel controlled clinical studies.

Objective: Evaluate the impact of adjusting the overall dose, Gypsum Fibrosum [Mineral; Gypsum] (ShiGao, SG) dose, and Prunus armeniaca L. [Rosaceae; Semen Armeniacae Amarum] (KuXingRen, KXR) dose on the efficacy of MaXingShiGan Decoction (MXSG) in treating children with bronchial pneumonia (Wind-heat Blocking the Lung), in order to provide strategy supported by high-quality evidence for the selection of rational clinical doses of MXSG. Methods: Based on the basic dose of MXSG, we conducted three randomized, double-blind, dose parallel controlled, multicenter clinical trials, involving adjustments to the overall dose, SG dose, and KXR dose, and included 120 children with bronchial pneumonia (Wind-heat Blocking the Lung) respectively. And the patients were divided into low, medium, and high dose groups in a 1:1:1 ratio, with 40 cases in each group. The intervention period lasted for 10 days. The primary outcome was the clinical cured rate, while the secondary outcomes included the effectiveness in alleviating major symptoms of bronchial pneumonia (including fever, cough, dyspnea, and phlegm congestion). And the occurrence of adverse events was recorded. Results: We first recorded and analyzed the baseline characteristics of the three studies, including age, gender, height, and so on. The results indicated that there were no significant differences among the dose groups within each study. For the study adjusting the overall dose of MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher clinical cured rates compared to the low-dose group (Chi-square value 9.01, p = 0.0111). However, there was no significant benefit between the high-dose group and the medium-dose group (81.58% vs. 81.08%). Regarding phlegm congestion, excluding fever, cough, and dyspnea, both the medium-dose group and high-dose group had significantly higher clinical cured rates than the low-dose group (Chi-square value 6.31, p = 0.0426), and there was no significant benefit between the high-dose group and the medium-dose group (69.23% vs. 75.00%). A total of 5 adverse events were observed, of which only 1 case in the medium-dose group was possibly related to the experimental medication. For the study adjusted the SG dose in MXSG, the results showed that the high-dose group had the highest clinical cured rate, but the inter-group difference was not statistically significant (Chi-square value 3.36, p = 0.1864). The area under the curve (AUC) for cough in the medium-dose group was significantly lower than in the low-dose group and high-dose group (F-test value 3.14, p = 0.0471). Although no significant differences were observed in fever and dyspnea among the groups, the AUC in the high-dose group was lower than in the medium-dose and low-dose groups. In comparing the complete defervescence time, both the high-dose group (p < 0.0001) and the medium-dose group (p = 0.0015) achieved faster than the low-dose group. The high-dose group slightly outperformed the medium-dose group (0.50 (0.50, 0.80) vs. 0.80 (0.40, 1.40)), although the difference was not significant. In the medium-dose group, 1 adverse event was observed, but it was not related to the experimental medication. For the study adjusted the KXR dose in MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher cured rates compared to the low-dose group (Chi-square value 47.05, p < 0.0001). However, there was no significant benefit comparing the high-dose group to the medium-dose group (90.00% vs. 92.50%). Regarding clinical symptoms, the results indicated that for cough (F-test value 3.16, p = 0.0460) and phlegm congestion (F-test value 3.84, p = 0.0243), the AUC for both the medium-dose group and high-dose group were significantly lower than in the low-dose group. Although there was benefit in the high-dose group compared to the medium-dose group, it was not statistically significant. No adverse events were observed during the study period. Conclusion: The synthesis of the three conducted clinical studies collectively indicates that for children with bronchial pneumonia (Wind-heat Blocking the Lung), the basic clinical dose of MXSG may represents an optimal intervention dose based on the accumulated clinical experience of doctors. If the dose is insufficient, the clinical effects might be compromised, but using a higher dose does not significantly enhance benefits. Concerning different symptoms, increasing the overall formula's dose has a favorable impact on improving phlegm congestion, increasing the SG is effective in improving symptoms such as fever, cough, and dyspnea, while higher dose of KXR is effective in alleviating cough and phlegm congestion. These findings suggest that for MXSG, achieving the optimal intervention dose is crucial to achieve better clinical efficacy. For the SG and KXR, if certain symptoms are more severe, increasing the dose can be considered within safe limits, can lead to significant clinical benefits in symptom improvement. This also explains why the dose of MXSG might vary among clinical doctors, while maintaining a balance between safety and effectiveness. Of course, our study is still exploratory clinical trials, and further studies are needed to confirm our findings. Clinical Trial Registration: https://www.chictr.org.cn/index.html; Identifier: ChiCTR-TRC-13003093, ChiCTR-TRC-13003099.

Ginsenoside Rb2 inhibits p300-mediated SF3A2 acetylation at lysine 10 to promote Fscn1 alternative splicing against myocardial ischemic/reperfusion injury.

INTRODUCTION: Ginsenosides (GS) derived from Panax ginseng can regulate protein acetylation to promote mitochondrial function for protecting cardiomyocytes. However, the potential mechanisms of GS for regulating acetylation modification are not yet clear. OBJECTIVES: This study aimed to explore the potential mechanisms of GS in regulating protein acetylation and identify ginsenoside monomer for fighting myocardial ischemia-related diseases. METHODS: The 4D-lable free acetylomic analysis was employed to gain the acetylated proteins regulated by GS pretreatment. The co-immunoprecipitation assay, immunofluorescent staining, and mitochondrial respiration measurement were performed to detect the effect of GS or ginsenoside monomer on acetylated protein level and mitochondrial function. RNA sequencing, site-specific mutation, and shRNA interference were used to explore the downstream targets of acetylation modificationby GS. Cellular thermal shift assay and surface plasmon resonance were used for identifying the binding of ginsenoside with target protein. RESULTS: In the cardiomyocytes of normal, oxygen glucose deprivation and/or reperfusion conditions, the acetylomic analysis identified that the acetylated levels of spliceosome proteins were inhibited by GS pretreatment and SF3A2 acetylation at lysine 10 (K10) was significantly decreased as a potential target of GS. Ginsenoside Rb2 was identified as one of the active ginsenoside monomers for reducing the acetylation of SF3A2 (K10), which enhanced mitochondrial respiration against myocardial ischemic injury in in vivo and in vitro experiments. RNA-seq analysis showed that ginsenoside Rb2 promoted alternative splicing of mitochondrial function-related genes and the level of fascin actin-bundling protein 1 (Fscn1) was obviously upregulated, which was dependent on SF3A2 acetylation. Critically, thermodynamic, kinetic and enzymatic experiments demonstrated that ginsenoside Rb2 directly interacted with p300 for inhibiting its activity. CONCLUSION: These findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 by inhibiting p300-mediated SF3A2 acteylation for promoting Fscn1 expression, which might be a promising approach for the prevention and treatment of myocardial ischemic diseases.

Practice and principle of traditional Chinese medicine for the prevention and treatment of COVID-19.

Traditional Chinese medicine (TCM) has played an important role in the prevention and treatment of Coronavirus disease 2019 (COVID-19) epidemic in China. The integration of Chinese and Western medicine is an important feature of Chinese COVID-19 prevention and treatment. According to a series of evidence-based studies, TCM can reduce the infection rate of severe acute respiratory syndrome coronavirus 2 in high-risk groups. For patients with mild and moderate forms of COVID-19, TCM can relieve the related signs and symptoms, shorten the period of nucleic-acid negative conversion, and reduce conversion rate to the severe form of the disease. For COVID-19 patients with severe and critical illnesses, TCM can improve inflammatory indicators and blood oxygen saturation, shorten the hospital stay, and reduce the mortality rate. During recovery, TCM can improve patients' symptoms, promote organ function recovery, boost the quality of patients' life, and reduce the nucleic-acid repositive conversion rate. A series of mechanism research studies revealed that capability of TCM to treat COVID-19 through antiviral and anti-inflammatory effects, immune regulation, and protection of organ function via a multicomponent, multitarget, and multipathway approach.

A literature review on Epimedium, a medicinal plant with promising slow aging properties.

Ethnopharmacological relevance: Aging is related to many factors, such as genes, oxidative damage, metabolic abnormalities, immune regulation and sex hormones. This article reviews the pharmacological mechanism of Epimedium on slow aging from six aspects: gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, the regulation of sex hormone, and clinical efficacy.Aim of the studyThrough literature review, to discover the potential pharmacological mechanism of Epimedium for slow aging. Materials and methods: We reviewed the literature on the applications of Epimedium in multiple systems and the potential underlying mechanisms with systematic and comprehensive illustrations. The review includes the following aspects: gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, the regulation of sex hormone, clinical efficacy and safety. Results: The slow aging active components of Epimedium may be flavonoids, such as Epimedins A, B, C and icariin The slow aging effect of Epimedium may be related to gene regulation, antioxidant, the regulation of metabolism, the modulation of the immune system, and the regulation of sex hormone. No severe adverse reaction has been reported. Conclusions: Epimedium has potential slow aging effect and been widely used in the clinic for aging-related diseases in the real world in China; however, large-scale studies are still needed.

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.

Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction.

Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial and role step for the pathogenesis of DVCs. Hyperglycemia and lipid metabolism disorders contribute to endothelial dysfunction via direct injury of metabolism products, crosstalk between immunity and inflammation, as well as related interaction network. Although physiological and phenotypic differences support their specified changes in different targeted organs, there are still several common mechanisms underlying DVCs. Also, inhibitors of these common mechanisms may decrease the incidence of DVCs effectively. Thus, this review may provide new insights into the possible measures for the secondary prevention of DM. And we discussed the current limitations of those present preventive measures in DVCs research. Video Abstract.

Natural compounds efficacy in complicated diabetes: A new twist impacting ferroptosis.

Ferroptosis, as a way of cell death, participates in the body's normal physiological and pathological regulation. Recent studies have shown that ferroptosis may damage glucose-stimulated islets ß Insulin secretion and programmed cell death of T2DM target organs are involved in the pathogenesis of T2DM and its complications. Targeting suppression of ferroptosis with specific inhibitors may provide new therapeutic opportunities for previously untreated T2DM and its target organs. Current studies suggest that natural bioactive compounds, which are abundantly available in drugs, foods, and medicinal plants for the treatment of T2DM and its target organs, have recently received significant attention for their various biological activities and minimal toxicity, and that many natural compounds appear to have a significant role in the regulation of ferroptosis in T2DM and its target organs. Therefore, this review summarized the potential treatment strategies of natural compounds as ferroptosis inhibitors to treat T2DM and its complications, providing potential lead compounds and natural phytochemical molecular nuclei for future drug research and development to intervene in ferroptosis in T2DM.

Probiotic Fermentation of Herbal Medicine: Progress, Challenges, and Opportunities.

Fermentation is a processing method used in traditional Chinese medicine (TCM). However, traditional fermentation methods suffer from poor production control. In contrast, probiotic fermented herbal medicine (PFHM) offers advantages such as the use of pure strains, a controllable process, and the ability to produce a variety of active enzymes during fermentation. As a result, PFHM has become a research hotspot. This review focuses on the progress, challenges, and opportunities in the research of PFHM. The use of probiotic enzymes during fermentation alters the active ingredients of TCM, resulting in positive pharmacological effects such as increased active ingredients, reduced toxicity, new pharmacological effects, and the reuse of herbal residues. PFHM has the potential to transfer the metabolic transformation of the effective components of TCM by intestinal flora outside the body during production and preparation, which has a broad application prospect. However, due to the complexity of the chemical composition of TCM, the mechanism of PFHM requires further investigation. Finally, we discuss the prospects of industrializing PFHM, which is essential for promoting the innovation and modernization of TCM.

Jinlida granules combined with metformin improved the standard-reaching rate of blood glucose and clinical symptoms of patients with type 2 diabetes: secondary analysis of a randomized controlled trial.

Background: Previous studies found that Jinlida granules could significantly reduce blood glucose levels and enhance the low-glucose action of metformin. However, the role of Jinlida in the standard-reaching rate of blood glucose and improving clinical symptoms has yet to be studied. We aimed to elaborate on the efficacy of Jinlida in type 2 diabetes (T2D) patients who experience clinical symptoms based on secondary analysis of a randomized controlled trial. Methods: Data were analyzed from a 12-week, randomized, placebo-controlled study of Jinlida. The standard-reaching rate of blood glucose, the symptom disappearance rate, the symptom improvement rate, the efficacy of single symptoms, and the total symptom score were evaluated. The correlation between HbA1c and the improvement of clinical symptoms was analyzed. Results: For 12 weeks straight, 192 T2D patients were randomly assigned to receive either Jinlida or a placebo. The treatment group showed statistically significant differences in the standard-reaching rate of HbA1c < 6.5% (p = 0.046) and 2hPG (< 10 mmol/L, 11.1 mmol/L) (p < 0.001), compared with the control group. The standard-reaching rate of HbA1c < 7% (p = 0.06) and FBG < 7.0 mmol/L (p = 0.079) were not significantly different between the treatment and control groups. Five symptoms exhibited a statistical difference in symptom disappearance rate (p < 0.05). All the symptoms exhibited a significant difference in symptom improvement rate (p < 0.05). The mean change in total symptom score from baseline to week 12 was -5.45 ± 3.98 in the treatment group and -2.38 ± 3.11 in the control group, with statistically significant differences (p < 0.001). No significant correlations were noted between symptom improvement and HbA1c after 12 weeks of continuous intervention with Jinlida granules or placebo. Conclusion: Jinlida granules can effectively improve the standard-reaching rate of blood glucose and clinical symptoms of T2D patients, including thirst, fatigue, increased eating with rapid hungering, polyuria, dry mouth, spontaneous sweating, night sweat, vexing heat in the chest, palms, and soles, and constipation. Jinlida granules can be used as an effective adjuvant treatment for T2D patients who experience those symptoms.

Qimai Feiluoping decoction inhibits mitochondrial complex I-mediated oxidative stress to ameliorate bleomycin-induced pulmonary fibrosis.

BACKGROUND: Qimai Feiluoping decoction (QM), a Traditional Chinese Medicine formula, has been included in rehabilitation program for functional disorders of discharged COVID-19 patients. QM has been proved to effectively improve the clinical symptoms and imaging signs of PF in COVID-19 convalescent patients. PURPOSE: This study to explore the pharmacological effect of QM against PF from the perspectives of imaging, pathological staining, and molecular mechanisms, and identify possible active components. METHODS: Micro-CT imaging and immunohistochemical staining were investigated to verify the therapeutic effect of QM in the bleomycin (BLM)-induced PF mouse model. The 4D-label-free proteomics analysis of lung tissues was then conducted to explore the novel mechanisms of QM against PF, which were further validated by a series of experiments. The possible components of QM in plasma and lung tissues were identified with UHPLC/IM-QTOF-MS analysis. RESULTS: The results from micro-CT imaging and pathological staining revealed that QM treatment can inhibit BLM-induced lung injury, extracellular matrix accumulation and TGF-ß expression in the mouse model with PF. The 4D-label-free proteomics analysis demonstrated that the partial subunit proteins of mitochondrial complex I and complex II might be potential targets of QM against PF. Furthermore, QM treatment can inhibit BLM-induced mitochondrial ROS content to promote ATP production and decrease oxidative stress injury in the mouse and cell models of PF, which was mediated by the inhibition of mitochondrial complex I. Finally, a total of 13 protype compounds and 15 metabolites from QM in plasma and lung tissues were identified by UHPLC/IM-QTOF-MS, and liquiritin and isoliquiritigenin from Glycyrrhizae radix et rhizoma could be possible active compounds against PF. CONCLUSION: It concludes that QM treatment could treat PF by inhibiting mitochondrial complex I-mediated mitochondrial oxidated stress injury, which could offer new insights into the pharmacological mechanisms of QM in the clinical application of PF patients.