Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy.

Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.

Irbesartan ameliorates diabetic kidney injury in db/db mice by restoring circadian rhythm and cell cycle.

Background and Objectives: Irbesartan has been widely used in the clinical treatment of diabetic kidney disease (DKD). However, the molecular mechanism of its delay of DKD disease progression has not been fully elucidated. The aim of the present study was to investigate the mechanism of irbesartan in the treatment of DKD. Materials and Methods: C57BL/KsJ db/db mice were randomly divided into the model group and irbesartan-treated group. After treatment with irbesartan for 12 weeks, the effects on blood glucose, body weight, 24-h urinary albumin, and renal injuries were evaluated. Microarray was used to determine the differentially expressed genes (DEGs) in the renal cortex of mice. |Log FC| <0.5 and false discovery rate (FDR) <0.25 were set as the screening criteria. Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology (GO), protein-protein interaction (PPI) network and modules, and microRNA (miRNA)-DEGs network analysis were applied to analyze the DEGs. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of microarray. Results: The present study demonstrated irbesartan could significantly improve the renal function in db/db mice through decreasing 24-h urinary albumin and alleviating the pathological injury of kidney. Irbesartan may affect the expression of numerous kidney genes involved in circadian rhythm, cell cycle, micoRNAs in cancer, and PI3K-AKT signaling pathway. In the miRNA-DEGs network, miR-1970, miR-703, miR-466f, miR-5135, and miR-132-3p were the potential targets for irbesartan treatment. The validation test confirmed that key genes regulating circadian rhythm (Arntl, Per3, and Dbp) and cell cycle (Prc1, Ccna2, and Ccnb2) were restored in db/db mice on treatment with Irbesartan. Conclusion: Generally, irbesartan can effectively treat DKD by regulating the circadian rhythm and cell cycle. The DEGs and pathways identified in the study will provide new insights into the potential mechanisms of irbesartan in the treatment of DKD.

Irbesartan ameliorates diabetic kidney injury in db/db mice by restoring circadian rhythm and cell cycle.

Background and Objectives: Irbesartan has been widely used in the clinical treatment of diabetic kidney disease (DKD). However, the molecular mechanism of its delay of DKD disease progression has not been fully elucidated. The aim of the present study was to investigate the mechanism of irbesartan in the treatment of DKD. Materials and Methods: C57BL/KsJ db/db mice were randomly divided into the model group and irbesartan-treated group. After treatment with irbesartan for 12 weeks, the effects on blood glucose, body weight, 24-h urinary albumin, and renal injuries were evaluated. Microarray was used to determine the differentially expressed genes (DEGs) in the renal cortex of mice. |Log FC| <0.5 and false discovery rate (FDR) <0.25 were set as the screening criteria. Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology (GO), protein-protein interaction (PPI) network and modules, and microRNA (miRNA)-DEGs network analysis were applied to analyze the DEGs. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of microarray. Results: The present study demonstrated irbesartan could significantly improve the renal function in db/db mice through decreasing 24-h urinary albumin and alleviating the pathological injury of kidney. Irbesartan may affect the expression of numerous kidney genes involved in circadian rhythm, cell cycle, micoRNAs in cancer, and PI3K-AKT signaling pathway. In the miRNA-DEGs network, miR-1970, miR-703, miR-466f, miR-5135, and miR-132-3p were the potential targets for irbesartan treatment. The validation test confirmed that key genes regulating circadian rhythm (Arntl, Per3, and Dbp) and cell cycle (Prc1, Ccna2, and Ccnb2) were restored in db/db mice on treatment with Irbesartan. Conclusion: Generally, irbesartan can effectively treat DKD by regulating the circadian rhythm and cell cycle. The DEGs and pathways identified in the study will provide new insights into the potential mechanisms of irbesartan in the treatment of DKD.

Tangshen Formula alleviates inflammatory injury against aged diabetic kidney disease through modulating gut microbiota composition and related amino acid metabolism.

Diabetic kidney disease (DKD) is leading causes and one of the fastest growing causes of chronic kidney disease worldwide, and leads to high morbidity and mortality. Emerging evidences have revealed gut microbiota dysbiosis and related metabolism dysfunction play a dominant role in DKD progression and treatment through modulating inflammation. Our previous studies showed that Tangshen Formula (TSF), a Chinese herbal prescription, exhibited anti-inflammatory effect on DKD, but underlying mechanism that involved gut microbiota and related metabolism in aged model remained obscure. Here, BTBR ob/ob mice were used to establish aged DKD model, and 16S rRNA sequence and untargeted metabolomic analyses were employed to investigate the correlation between colonic microbiota and serum metabolism. The aged ob/ob mice exhibited obvious glomerular and renal tubule injury and kidney function decline in kidney, while TSF treatment significantly attenuated these abnormalities. TSF also exhibited potent anti-inflammatory effect in aged ob/ob mice indicating by reduced proinflammatory factor IL-6 and TNF-α, MCP-1 and COX-2 in serum, kidney and intestine, which suggested the involvement of gut microbiota with TSF effect. The 16S rDNA sequencing of the colonic microbiome and untargeted serum metabolomics analysis revealed significant differences in gut microbiota structure and serum metabolomic profiles between WT and ob/ob mice. Notably, TSF treatment reshaped the structure of gut microbiota and corrected the disorder of metabolism especially tryptophan metabolism and arginine biosynthesis. TSF increased Anaeroplasma and Barnesiella genera and decreased Romboutsia, Akkermansia, and Collinsella genera, and further elevated tryptophan, 5-hydroxyindoleacetate, glutamic acid, aspartate and reduced 4-hydroxy-2-quinolinecarboxylic acid, indole-3-acetic acid, xanthurenic acid, glutamine. Further correlation analysis indicated that disturbed gut microbiota was linked to tryptophan metabolism and arginine biosynthesis to regulate inflammation in aged DKD. Our data revealed that TSF attenuated renal inflammation by modulating gut microbiota and related amino acid metabolism in aged DKD model, highlighting gut microbiota and related metabolism functioned as potential therapeutic target for DKD in elderly patients.

Serum high mobility group box 1 as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes.

Background: As a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression. Methods: We recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison. Results: Serum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R 2 = 0.567, p<0.001) and urine KIM-1 levels (R 2 = 0.440, p<0.001), and urine HMGB1 has a similar correlation. In the population with T2DM, the risk of DKD progression increased with an increase in serum HMGB1 levels. Multivariate logistic regression analysis showed that elevated serum HMGB1 level was an independent risk factor for renal function progression in patients with DKD, and regression analysis did not change in the model corrected for multiple variables. The restricted cubic spline depicted a nonlinear relationship between serum HMGB1 and renal function progression in patients with DKD (p-nonlinear=0.007, p<0.001), and this positive effect remained consistent across subgroups. Conclusion: Serum HMGB1 was significantly correlated with DKD and disease severity. When the HMGB1 level was ≥27 ng/ml, the risk of renal progression increased sharply, indicating that serum HMGB1 can be used as a potential biomarker for the diagnosis of DKD progression.

The neural mechanisms of identifiable victim effect in prosocial decision-making.

The phenomenon known as the "identifiable victim effect" describes how individuals tend to offer more assistance to victims they can identify with than to those who are vague or abstract. The neural underpinnings of this effect, however, remain elusive. Our study utilized functional magnetic resonance imaging to delve into how the "identifiable victim effect" influences prosocial decision-making, considering different types of helping costs, across two distinct tasks. Participants were instructed to decide whether to help a victim with personal information shown (i.e., the identifiable victim) and an unidentifiable one by costing their money (task 1) or physical effort (task 2). Behaviorally, we observed a pronounced preference in both tasks for aiding identifiable victims over anonymous ones, highlighting a robust "identifiable victim effect." On a neural level, this effect was associated with heightened activity in brain areas like the bilateral temporoparietal junction (TPJ) when participants confronted anonymous victims, potentially indicating a more intensive mentalizing process for less concrete victims. Additionally, we noted that the TPJ's influence on value judgment processes is mediated through its functional connectivity with the medial prefrontal cortex. These insights contribute significantly to our understanding of the psychological and neural dynamics underlying the identifiable victim effect.

Tangshen formula improves diabetic nephropathy in STZ-induced diabetes rats fed with hyper-methionine by regulating the methylation status of kidney.

BACKGROUND: The objective of this study was to examine and analyze differential methylation profiles in order to investigate the influence of hyper-methioninemia (HM) on the development of diabetic nephropathy (DN). Male Wistar rats, aged eight weeks and weighing 250-300 g, were randomly assigned into four groups: a control group (Healthy, n = 8), streptozocin-induced rats (STZ group, n = 8), HM + STZ group (n = 8), and the Tangshen Formula (TSF) treatment group (TSF group, n = 8). Blood glucose levels and other metabolic indicators were monitored before treatment and at four-week intervals until 12 weeks. Total DNA was extracted from the aforementioned groups, and DNA methylation landscapes were analyzed via reduced representative bisulfite sequencing. RESULTS: Both the STZ group and HM + STZ group exhibited increased blood glucose levels and urinary albumin/creatinine ratios in comparison with the control group. Notably, the HM + STZ group exhibited a markedly elevated urinary albumin/creatinine ratio (411.90 ± 88.86 mg/g) compared to the STZ group (238.41 ± 62.52 mg/g). TSF-treated rats demonstrated substantial reductions in both blood glucose levels and urinary albumin/creatinine ratios in comparison with the HM + STZ group. In-depth analysis of DNA methylation profiles revealed 797 genes with potential therapeutic effects related to TSF, among which approximately 2.3% had been previously reported as homologous genes. CONCLUSION: While HM exacerbates DN through altered methylation patterns at specific CpG sites, TSF holds promise as a viable treatment for DN by restoring abnormal methylation levels. The identification of specific genes provides valuable insights into the underlying mechanisms of DN pathogenesis and offers potential therapeutic targets for further investigation.

Tangshen formula protects against podocyte apoptosis via enhancing the TFEB-mediated autophagy-lysosome pathway in diabetic nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and currently there are no specific and effective drugs for its treatment. Podocyte injury is a detrimental feature and the major cause of albuminuria in DN. We previously reported Tangshen Formula (TSF), a Chinese herbal medicine, has shown therapeutic effects on DN. However, the underlying mechanisms remain obscure. AIM OF THE STUDY: This study aimed to explore the protective effect of TSF on podocyte apoptosis in DN and elucidate the potential mechanism. MATERIALS AND METHODS: The effects of TSF were assessed in a murine model using male KKAy diabetic mice, as well as in advanced glycation end products-stimulated primary mice podocytes. Transcription factor EB (TFEB) knockdown primary podocytes were employed for mechanistic studies. In vivo and in vitro studies were performed and results assessed using transmission electron microscopy, immunofluorescence staining, and western blotting. RESULTS: TSF treatment alleviated podocyte apoptosis and structural impairment, decreased albuminuria, and mitigated renal dysfunction in KKAy mice. Notably, TSF extracted twice showed a more significant reduction in proteinuria than TSF extracted three times. Accumulation of autophagic biomarkers p62 and LC3, and aberrant autophagic flux in podocytes of DN mice were significantly altered by TSF therapy. Consistent with the in vivo results, TSF prevented the apoptosis of primary podocytes exposed to AGEs and activated autophagy. However, the anti-apoptosis capacity of TSF was countered by the autophagy-lysosome inhibitor chloroquine. We found that TSF increased the nuclear translocation of TFEB in diabetic podocytes, and thus upregulated transcription of its several autophagic target genes. Pharmacological activation of TFEB by TSF accelerated the conversion of autophagosome to autolysosome and lysosomal biogenesis, further augmented autophagic flux. Conversely, TFEB knockdown negated the favorable effects of TSF on autophagy in AGEs-stimulated primary podocytes. CONCLUSIONS: These findings indicate TSF appears to attenuate podocyte apoptosis and promote autophagy in DN via the TFEB-mediated autophagy-lysosome system. Thus, TSF may be a therapeutic candidate for DN.

Triazine herbicide reduced the toxicity of the harmful dinoflagellate Karenia mikimotoi by impairing its photosynthetic systems.

Triazine herbicides are common contaminants in coastal waters, and they are recognized as inhibitors of photosystem II, causing significant hinderance to the growth and reproduction of phytoplankton. However, the influence of these herbicides on microalgal toxin production remains unclear. This study aimed to examine this relationship by conducting a comprehensive physiological and 4D label-free quantitative proteomic analysis on the harmful dinoflagellate Karenia mikimotoi in the presence of the triazine herbicide dipropetryn. The findings demonstrated a significant decrease in photosynthetic activity and pigment content, as well as reduced levels of unsaturated fatty acids, reactive oxygen species (ROS), and hemolytic toxins in K. mikimotoi when exposed to dipropetryn. The proteomic analysis revealed a down-regulation in proteins associated with photosynthesis, ROS response, and energy metabolism, such as fatty acid biosynthesis, chlorophyll metabolism, and nitrogen metabolism. In contrast, an up-regulation of proteins related to energy-producing processes, such as fatty acid ß-oxidation, glycolysis, and the tricarboxylic acid cycle, was observed. This study demonstrated that dipropetryn disrupts the photosynthetic systems of K. mikimotoi, resulting in a notable decrease in algal toxin production. These findings provide valuable insights into the underlying mechanisms of toxin production in toxigenic microalgae and explore the potential effect of herbicide pollution on harmful algal blooms in coastal environments.

Prosocial decision-making under time pressure: Behavioral and neural mechanisms.

The present study employed a novel paradigm and functional magnetic resonance imaging (fMRI) to uncover the specific regulatory mechanism of time pressure and empathy trait in prosocial decision-making, compared to self-decision making. Participants were instructed to decide whether to spend their own monetary interest to alleviate themselves (or another person) from unpleasant noise threats under high and low time pressures. On the behavioral level, results showed that high time pressure had a significant effect on reducing participants' willingness to spend money on relieving themselves from the noise, while there is a similar but not significant trend in prosocial decision-making. On the neural level, for self-concerned decision-making, low time pressure activated the bilateral insula more strongly than high time pressure. For prosocial decision-making, high time pressure suppressed activations in multiple brain regions related to empathy (temporal pole, middle temporal gyrus, and inferior frontal gyrus), valuation (medial orbitofrontal cortex), and emotion (putamen). The functional connectivity strength among these regions, especially the connectivity between the medial orbitofrontal cortex and putamen, significantly predicted the effect of time pressure on prosocial decision-making at the behavioral level. Additionally, we discovered the activation of the medial orbitofrontal cortex partially mediated the effect of empathy trait scores on prosocial decision-making. These findings suggest that (1) there are different neural underpinnings for the modulation of time pressure for self and prosocial decision-making, and (2) the empathy trait plays a crucial role in the latter.

In-depth insights into Fe(III)-doped g-C3N4 activated peracetic acid: Intrinsic reactive species, catalytic mechanism and environmental application.

In this study, we demonstrate that Fe(III)-doped g-C3N4 can efficiently activate peracetic acid (PAA) to degrade electron-rich pollutants (e.g., sulfamethoxazole, SMX) over a wide pH range (3-7). Almost ∼100% high-valent iron-oxo species (Fe(V)) was generated and acted as the dominant reactive species responsible for the micropollutants oxidation based on the analysis result of quenching experiments, 18O isotope-labeling examination and methyl phenyl sulfoxide (PMSO) probe method. Electrochemical testing (e.g., amperometric i-t and linear sweep voltammetry (LSV)) and density functional theory (DFT) calculations illustrated that the main active site Fe atom and PAA underwent electron transfer to form Fe(V) for attacking SMX. Linear free energy relationship (LFER) between the pseudo-first-order rates of different substituted phenols (SPs) and the Hammett constant σ+ depicted the electrophilic oxidation properties. The selective oxidation of Fe(V) endows the established system remarkable anti-interference capacity against water matrices, while the Fe(V) lead to the formation of iodinated disinfection by-products (I-DBPs) in the presence of I-. Fe(III)-doped g-C3N4/PAA system showed excellent degradation efficiency of aquaculture antibiotics. This study enriches the knowledge and research of high-valent iron-oxo species and provides a novel perspective for the activation of PAA via heterogeneous iron-based catalysts and practical environmental applications.

Research progress on Cornus officinalis and its active compounds in the treatment of diabetic nephropathy.

Diabetic nephropathy (DN) is a kidney disorder secondary to diabetes and is one of the main diabetic microvascular complications. As the number of diabetic patients grows, DN has become the leading cause of chronic kidney disease in China. Unfortunately, no definitive cure currently exists for DN. Cornus officinalis (CO), frequently utilized in clinical settings for diabetes mellitus treatment, has proven vital in both preventing and treating DN. This article explores the pathogenesis of DN and how CO and its active compounds regulate glucose and lipid metabolism, exhibit anti-inflammatory properties, inhibit oxidative stress, regulate podocytes, and manage autophagy. The mechanism and role of and its active compounds in the treatment of DN are discussed.

Effect of different iodide intake during pregnancy and lactation on thyroid and cardiovascular function in maternal and offspring rats.

OBJECTIVE: We aimed to investigate the impact of different iodide intake during pregnancy and lactation on iodine concentration in urine and serum, fatty acid metabolism, thyroid and cardiovascular function in maternal and offspring rats. METHODS: Pregnant rats were randomly assigned to four groups: normal adult iodide intake (NAI, 7.5 µg/d), normal pregnant iodide intake (NPI, 12.5 µg/d), 5 times (5 HI, 62.5 µg/d) and 10 times higher-than-normal pregnant iodide intake (10 HI, 125 µg/d). The maternal rats were continuously administered potassium iodide until postnatal day 16 (PN16). Thyroid function was measured by enzyme-linked immunosorbent assay (ELISA). The iodine concentration in urine and serum were detected by inductively coupled plasma mass spectrometry (ICP-MS). The messenger ribonucleic acid (mRNA) expressions of Krüppel-like factor 9 (KLF9) and thioredoxin reductase 2 (Txnrd2) were measured using quantitative real-time polymerase chain reaction (RT-qPCR). Characteristic distribution of KLF9 expression and its interaction with TRß was assessed by immunohistochemical and immunofluorescence staining. Serum fatty acids were analyzed by Liquid Chromatography-Mass Spectrometry (LC-MS). Cardiac function and blood pressure were measured by echocardiography and a non-invasive tail-cuff system. RESULTS: High iodide intake (5 HI and 10 HI) during pregnancy and lactation results in increased urinary iodine concentration (UIC), serum total iodine concentration (STIC) and serum non-protein-bound iodine concentration (SNBIC) in both maternal and offspring rats, along with significantly increased FT3 and its target gene expression of KLF9. In maternal rats of both 5 HI and 10 HI groups, systolic blood pressure (SBP) was significantly higher, the increased SBP was significantly correlated with the increased UIC (r = 0.968, p = 0.002; r = 0.844, p = 0.035), KLF9 (r = 0.935, p = 0.006; r = 0.954, p = 0.003) and the decreased Txnrd2 (r = -0.909, p = 0.012; r = -0.912, p = 0.011). In maternal rats of 10 HI group, cardiac hyperfunction with increased LVEF, LVFS and decreased LVESD were observed. The increased LVEF and decreased LVESD were significantly correlated with UIC, STIC and SNBIC (r = 0.976, p = 0.001; r = 0.945, p = 0.005; r = 0.953, p = 0.003; r = -0.917, p = 0.01; r = -0.859, p = 0.028; r = -0.847, p = 0.033), LVEF, LVFS and LVESD were significant correlated with KLF9 (r = 0.950, p = 0.004; r = 0.963, p = 0.002; r = -0.990, p = 0.0002) and Txnrd2 expression (r = -0.979, p = 0.001; r = -0.915, p = 0.01; r = 0.933, p = 0.007), and the decreased LVESD was correlated with decreased epoxyeicosatrienoic acid (EET) metabolites: 5,6-EET, 8,9-DHET and 11,12-DHET (r = 0.999, p = 0.034; r = 1.000, p = 0.017; r = 1.000, p = 0.017). While in offspring rats, no significant change in SBP and cardiac function was found. STIC and SNBIC were much lower than those in maternal rats, and eicosapentaenoic acid (EPA) metabolites (9-HEPE, 15-HEPE and 14,15 DiHETE) were significantly increased. CONCLUSION: In addition to thyroid hormones, STIC, SNBIC, KLF9, Txnrd2, EET and EPA metabolites might be promising biomarkers in high iodide intake-induced thyroid and cardiovascular function.

[Retracted] MicroRNA­599 targets high­mobility group AT­hook 2 to inhibit cell proliferation and invasion in clear cell renal carcinoma.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that cell migration and invasion assay data shown in Fig. 5C were strikingly similar to data appearing in different form in other articles by different authors, which have been retracted. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere when it was submitted to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 7451­7459, 2018; DOI: 10.3892/mmr.2018.8755].

Potential use of seaweed polysaccharides as prebiotics for management of metabolic syndrome: a review.

Seaweed polysaccharides (SPs) obtained from seaweeds are a class of functional prebiotics. SPs can regulate glucose and lipid anomalies, affect appetite, reduce inflammation and oxidative stress, and therefore have great potential for managing metabolic syndrome (MetS). SPs are poorly digested by the human gastrointestinal tract but are available to the gut microbiota to produce metabolites and exert a series of positive effects, which may be the mechanism by which SPs render their anti-MetS effects. This article reviews the potential of SPs as prebiotics in the management of MetS-related metabolic disturbances. The structure of SPs and studies related to the process of their degradation by gut bacteria and their therapeutic effects on MetS are highlighted. In summary, this review provides new perspectives on SPs as prebiotics to prevent and treat MetS.

Chinese herbal medicine and its active compounds in attenuating renal injury via regulating autophagy in diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease worldwide, and there is a lack of effective treatment strategies. Autophagy is a highly conserved lysosomal degradation process that maintains homeostasis and energy balance by removing protein aggregates and damaged organelles. Increasing evidence suggests that dysregulated autophagy may contribute to glomerular and tubulointerstitial lesions in the kidney under diabetic conditions. Emerging studies have shown that Chinese herbal medicine and its active compounds may ameliorate diabetic kidney injury by regulating autophagy. In this review, we summarize that dysregulation or insufficiency of autophagy in renal cells, including podocytes, glomerular mesangial cells, and proximal tubular epithelial cells, is a key mechanism for the development of DKD, and focus on the protective effects of Chinese herbal medicine and its active compounds. Moreover, we systematically reviewed the mechanism of autophagy in DKD regulated by Chinese herb compound preparations, single herb and active compounds, so as to provide new drug candidates for clinical treatment of DKD. Finally, we also reviewed the candidate targets of Chinese herbal medicine regulating autophagy for DKD. Therefore, further research on Chinese herbal medicine with autophagy regulation and their targets is of great significance for the realization of new targeted therapies for DKD.

Iodide intake during pregnancy and lactation stimulates KLF9, BDNF expression in offspring brain with elevated DHA, EPA metabolites.

To investigate the effect of different iodide intake during pregnancy and lactation on thyroid function, docosahexaenoic acid (DHA), Eicosapentaenoic acid (EPA) metabolites, the expression of Krüppel-like factor KLF9 (KLF9), brain-derived neurotrophic factor (BDNF) in brain in offspring rats. In both male and female offspring rats, serum FT3, FT4 levels and the expression of KLF9, thyroid hormone receptors (TR)α, TRß and BDNF in the hippocampal region and cerebellum were significantly increased in 5 times higher-than-normal pregnant iodide intake (5 HI) and 10 times higher-than-normal pregnant iodide intake (10 HI) group. The median levels of DHA metabolite (17-HDoHE) and EPA metabolites (15-HEPE, 17,18-EEQ, 9-HEPE and 14,15-DiHETE) were significantly increased in 5 HI and 10 HI group of offspring rats. Serum DHA, EPA metabolites and KLF9 as well as BDNF expression in brain might be potential iodine status biomarkers to reflect brain development in offspring.

Poricoic acid A suppresses renal fibroblast activation and interstitial fibrosis in UUO rats via upregulating Sirt3 and promoting ß-catenin K49 deacetylation.

Renal interstitial fibrosis is the common pathological process of various chronic kidney diseases to end-stage renal disease. Inhibition of fibroblast activation attenuates renal interstitial fibrosis. Our previous studies show that poricoic acid A (PAA) isolated from Poria cocos is a potent anti-fibrotic agent. In the present study we investigated the effects of PAA on renal fibroblast activation and interstitial fibrosis and the underlying mechanisms. Renal interstitial fibrosis was induced in rats or mice by unilateral ureteral obstruction (UUO). UUO rats were administered PAA (10 mg·kg-1·d-1, i.g.) for 1 or 2 weeks. An in vitro model of renal fibrosis was established in normal renal kidney fibroblasts (NRK-49F cells) treated with TGF-ß1. We showed that PAA treatment rescued Sirt3 expression, and significantly attenuated renal fibroblast activation and interstitial fibrosis in both the in vivo and in vitro models. In TGF-ß1-treated NRK-49F cells, we demonstrated that Sirt3 deacetylated ß-catenin (a key transcription factor of fibroblast activation) and then accelerated its ubiquitin-dependent degradation, thus suppressing the protein expression and promoter activity of pro-fibrotic downstream target genes (twist, snail1, MMP-7 and PAI-1) to alleviate fibroblast activation; the lysine-49 (K49) of ß-catenin was responsible for Sirt3-mediated ß-catenin deacetylation. In molecular docking analysis, we found the potential interaction of Sirt3 and PAA. In both in vivo and in vitro models, pharmacological activation of Sirt3 by PAA significantly suppressed renal fibroblast activation via facilitating ß-catenin K49 deacetylation. In UUO mice and NRK-49F cells, Sirt3 overexpression enhanced the anti-fibrotic effect of PAA, whereas Sirt3 knockdown weakened the effect. Taken together, PAA attenuates renal fibroblast activation and interstitial fibrosis by upregulating Sirt3 and inducing ß-catenin K49 deacetylation, highlighting Sirt3 functions as a promising therapeutic target of renal fibroblast activation and interstitial fibrosis.

ß-1,6-Glucan From Pleurotus eryngii Modulates the Immunity and Gut Microbiota.

Polysaccharides from Pleurotus eryngii exhibit a variety of biological activities. Here, we obtained a homogeneous branched ß-1,6-glucan (APEP-A-b) from the fruiting bodies of P. eryngii and investigated its effect on immunity and gut microbiota. Our results showed that APEP-A-b significantly increases splenic lymphocyte proliferation, NK cell activity and phagocytic capacity of peritoneal cavity phagocytes. Furthermore, we found that the proportion of CD4+ and CD8+ T cells in lamina propria are significantly increased upon APEP-A-b treatment. Additionally, APEP-A-b supplementation demonstrated pronounced changes in microbiota reflected in promotion of relative abundances of species in the Lachnospiraceae and Rikenellaceae families. Consistently, APEP-A-b significantly increased the concentration of acetic and butyric acid in cecum contents. Overall, our results suggest that ß-1,6-glucan from P. eryngii might enhance immunity by modulating microbiota. These results are important for the processing and product development of P. eryngii derived polysaccharides.

Characteristics of Serum Metabolites and Gut Microbiota in Diabetic Kidney Disease.

Disturbance of circulating metabolites and disorders of the gut microbiota are involved in the progression of diabetic kidney disease (DKD). However, there is limited research on the relationship between serum metabolites and gut microbiota, and their involvement in DKD. In this study, using an experimental DKD rat model induced by combining streptozotocin injection and unilateral nephrectomy, we employed untargeted metabolomics and 16S rRNA gene sequencing to explore the relationship between the metabolic profile and the structure and function of gut microbiota. Striking alterations took place in 140 serum metabolites, as well as in the composition and function of rat gut microbiota. These changes were mainly associated with carbohydrate, lipid, and amino acid metabolism. In these pathways, isomaltose, D-mannose, galactonic acid, citramalic acid, and prostaglandin B2 were significantly upregulated. 3-(2-Hydroxyethyl)indole, 3-methylindole, and indoleacrylic acid were downregulated and were the critical metabolites in the DKD model. Furthermore, the levels of these three indoles were restored after treatment with the traditional Chinese herbal medicine Tangshen Formula. At the genera level, g_Eubacterium_nodatum_group, g_Lactobacillus, and g_Faecalibaculum were most involved in metabolic disorders in the progression of DKD. Notably, the circulating lipid metabolites had a strong relationship with DKD-related parameters and were especially negatively related to the mesangial matrix area. Serum lipid indices (TG and TC) and UACR were directly associated with certain microbial genera. In conclusion, the present research verified the anomalous circulating metabolites and gut microbiota in DKD progression. We also identified the potential metabolic and microbial targets for the treatment of DKD.