Integrative analysis of network pharmacology and proteomics reveal the protective effect of Xiaoqinglong Decotion on neutrophilic asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoqinglong Decotion (XQLD) is a commonly used Chinese herbal formula in clinical practice, especially for allergic diseases such as asthma. However, its intrinsic mechanism for the treatment of neutrophilic asthma (NA) remains unclear. AIM OF THE STUDY: The aim of this study was to evaluate the efficacy and potential mechanisms of XQLD on NA using network pharmacology and in vivo experiments. MATERIALS AND METHODS: First, the active compounds, potential targets and mechanisms of XQLD against NA were initially elucidated by network pharmacology. Then, OVA/CFA-induced NA mice were treated with XQLD to assess its efficacy. Proteins were then analyzed and quantified using a Tandem Mass Tags approach for differentially expressed proteins (DEPs) to further reveal the mechanisms of NA treatment by XQLD. Finally, the hub genes, critical DEPs and potential pathways were validated. RESULTS: 176 active compounds and 180 targets against NA were identified in XQLD. Protein-protein interaction (PPI) network revealed CXCL10, CX3CR1, TLR7, NCF1 and FABP4 as hub genes. In vivo experiments showed that XQLD attenuated inflammatory infiltrates, airway mucus secretion and remodeling in the lungs of NA mice. Moreover, XQLD significantly alleviated airway neutrophil inflammation in NA mice by decreasing the expression of IL-8, MPO and NE. XQLD also reduced the levels of CXCL10, CX3CR1, TLR7, NCF1 and FABP4, which are closely associated with neutrophil inflammation. Proteomics analysis identified 28 overlapping DEPs in the control, NA and XQLD groups, and we found that XQLD inhibited ferroptosis signal pathway (elevated GPX4 and decreased ASCL3) as well as the expression of ARG1, MMP12 and SPP1, while activating the Rap1 signaling pathway. CONCLUSION: This study revealed that inhibition of ARG1, MMP12 and SPP1 expression as well as ferroptosis pathways, and activation of the Rap1 signaling pathway contribute to the therapeutic effect of XQLD on NA.

Effects of Aloe Gel on Lactating Women with Nipple Trauma.

Background: To investigate the efficacy of aloe gel in reducing pain and promoting wound healing in postpartum women with nipple trauma. Method: There were 80 postpartum women who took part in this study having developed nipple trauma during breastfeeding in the obstetrics department of a tertiary grade A hospital in Suzhou from January to December 2021. Postpartum women with nipple trauma whose hospital bed numbers ranged between 15 and 33 were included in the test group, whereas those whose hospital bed numbers ranged between 35 and 53 were included in the control group. Both groups received health education and breastfeeding guidance. The control group applied lanolin cream to their nipple trauma, whereas the test group used aloe gel. We used a nipple trauma severity assessment table to determine the severity of nipple trauma in lactating women and a Visual Analogue Scale (VAS) to determine the level of nipple pain and referred to the Traditional Chinese Medicine Standard for Diagnosis and Therapeutic Efficacy for Diseases and Syndromes to determine the healing time of their wounds. Results: The test group scored 3.70 ± 1.24 and 1.65 ± 0.74 points on the VAS on the first and third days following the intervention, whereas the control group scored 4.30 ± 0.94 and 2.23 ± 1.07 points, respectively. It took 3.75 ± 1.08 days and 4.45 ± 1.15 days for the nipple pain to completely disappear in the test group and the control group, respectively. The healing period for nipple trauma was 5.28 ± 1.26 days for the test group and 6.03 ± 1.61 days for the control group. All of the aforementioned distinctions were statistically significant (p < 0.05). Conclusions: Aloe gel can significantly alleviate the pain associated with nipple trauma in lactating women, accelerate wound healing, and reduce the duration of nipple trauma.

Berberine promotes lacteal junction zippering and ameliorates diet-induced obesity through the RhoA/ROCK signaling pathway.

BACKGROUND: Obesity has emerged as a global epidemic. Recent research has indicated that diet-induced obesity can be prevented by promoting lacteal junction zippering. Berberine, which is derived from natural plants, is found to be promising in weight reduction, but the underlying mechanism remains unspecified. PURPOSE: To determine whether berberine protects against obesity by regulating the lacteal junction and to explore potential molecular mechanisms. METHODS: Following the induction of the diet-induced obese (DIO) model, mice were administered low and high doses of berberine for 4 weeks. Indicators associated with insulin resistance and lipid metabolism were examined. Various methods, such as Oil Red O staining, transmission electron microscopy imaging, confocal imaging and others were used to observe the effects of berberine on lipid absorption and the lacteal junction. In vitro, human dermal lymphatic endothelial cells (HDLECs) were used to investigate the effect of berberine on LEC junctions. Western Blot and immunostaining were applied to determine the expression levels of relevant molecules. RESULTS: Both low and high doses of berberine reduced body weight in DIO mice without appetite suppression and ameliorated glucolipid metabolism disorders. We also found that the weight loss effect of berberine might contribute to the inhibition of small intestinal lipid absorption. The possible mechanism was related to the promotion of lacteal junction zippering via suppressing the ras homolog gene family member A (RhoA)/Rho-associated kinase (ROCK) signaling pathway. In vitro, berberine also promoted the formation of stable mature junctions in HDLECs, involving the same signaling pathway. CONCLUSION: Berberine could promote lacteal junction zippering and ameliorate diet-induced obesity through the RhoA/ROCK signaling pathway.

Integrating serum pharmacochemistry and network pharmacology to reveal the mechanism of chickpea in improving insulin resistance.

Although chickpea have great potential in the treatment of obesity and diabetes, the bioactive components and therapeutic targets of chickpea to prevent insulin resistance (IR) are still unclear. The purpose of this study was to investigate the chemical and pharmacological characteristics of chickpea on IR through serum pharmacochemistry and network pharmacology. The results revealed that compared with other polar fractions, the ethyl acetate extract of chickpea (CE) had the definitive performance on enhancing the capacities of glucose consumption and glycogen synthesis. In addition, we analyzed the components of CE in vivo and in vitro based on UPLC-Q-Orbitrap HRMS technology. There were 28 kinds of in vitro chemical components, among which the isoflavones included biochanin A, formononetin, ononin, sissotrin, and astragalin, etc. Concerningly, the chief prototype components of CE absorbed into the blood were biochanin A, formononetin, loliolide, and lenticin, etc. Furthermore, a total of 209 common targets between IR and active components of CE were screened out by network pharmacology, among which the key targets involved PI3K p85, NF-κB p65 and estrogen receptor 1, etc. Specifically, KEGG pathway analysis indicated that PI3K-AKT signaling pathway, HIF-1 signaling pathway, and AGE-RAGE signaling pathway may play critical roles in the IR remission by CE. Finally, the in vitro validation experiments disclosed that CE significantly balanced the oxidative stress state of IR-HepG2 cells and inhibited expressions of inflammatory cytokines. In conclusion, the present study will be an important reference for clarifying the pharmacodynamic substance basis and underlying mechanism of chickpea to alleviate IR.

Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis.

BACKGROUND: Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored. PURPOSE: This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms. METHODS: The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the molecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification. RESULTS: Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1α/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis. CONCLUSION: Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.

Oxygen vacancy engineering of TiO2 nanosheets for enhanced photothermal therapy against cervical cancer in the second near-infrared window.

Cervical cancer is the most common and deadly female cancer on the worldwide scale. Considering that the conventional surgery treatment and chemotherapy would cause certain side effects, photothermal therapy (PTT) possesses desired therapeutic efficiency and insignificant side effects against cervical cancer. However, the lack of efficient and safe photothermal agents that operate in the second near-infrared (NIR-II) window is a main obstacle hindering the clinical transformation of PTT. Titanium dioxide (TiO2)-based nanomaterials are commonly applied in the biomedicine field, but the weak absorption and low photothermal conversion efficiency (PCE) of TiO2 in the NIR region limit their applications in PTT. Herein, we report the oxygen vacancy engineering that is a robust strategy to regulate the electronic structures of TiO2 for photothermal conversion properties optimizing. The obtained oxygen vacancy-doped TiO2-x nanosheets exhibit strong NIR-II absorption and high PCE owing to their decreased bandgap. Specifically, the PCE of TiO2-x nanosheets is determined to be 69.5 % in the efficient NIR-II window, which is much higher than that of widely reported PTT agents. Complete tumor recession without recurrence or pulmonary metastasis is realized by enhanced NIR-II PTT via TiO2-x nanosheets at an ultralow and safe laser exposure (0.6 W/cm2). Our findings suggest that oxygen vacancy engineering of nanomaterials could regulate their photothermal conversion performances, promoting the further application of TiO2-based nanomaterials in the biomedical.

[Rapid identification and differential markers of Curcumae Radix decoction pieces of different sources based on Heracles Neo ultra-fast gas phase electronic nose].

Since Curcumae Radix decoction pieces have multiple sources, it is difficult to distinguish depending on traditional cha-racters, and the mixed use of multi-source Curcumae Radix will affect its clinical efficacy. Heracles Neo ultra-fast gas phase electronic nose was used in this study to quickly identify and analyze the odor components of 40 batches of Curcumae Radix samples from Sichuan, Zhejiang, and Guangxi. Based on the odor fingerprints established for Curcumae Radix decoction pieces of multiple sources, the odor components was identified and analyzed, and the chromatographic peaks were processed and analyzed to establish a rapid identification method. Principal component analysis(PCA), discriminant factor analysis(DFA), and soft independent modeling cluster analysis(SIMCA) were constructed for verification. At the same time, one-way analysis of variance(ANOVA) combined with variable importance in projection(VIP) was employed to screen out the odor components with P<0.05 and VIP>1, and 13 odor components such as ß-caryophyllene and limonene were hypothesized as the odor differential markers of Curcumae Radix decoction pieces of diffe-rent sources. The results showed that Heracles Neo ultra-fast gas phase electronic nose can well analyze the odor characteristics and rapidly and accurately discriminate Curcumae Radix decoction pieces of different sources. It can be applied to the quality control(e.g., online detection) in the production of Curcumae Radix decoction pieces. This study provides a new method and idea for the rapid identification and quality control of Curcumae Radix decoction pieces.

WMNN: Wearables-Based Multi-Column Neural Network for Human Activity Recognition.

In recent years, human activity recognition (HAR) technologies in e-health have triggered broad interest. In literature, mainstream works focus on the body's spatial information (i.e. postures) which lacks the interpretation of key bioinformatics associated with movements, limiting the use in applications requiring comprehensively evaluating motion tasks' correctness. To address the issue, in this article, a Wearables-based Multi-column Neural Network (WMNN) for HAR based on multi-sensor fusion and deep learning is presented. Here, the Tai Chi Eight Methods were utilized as an example as in which both postures and muscle activity strengths are significant. The research work was validated by recruiting 14 subjects in total, and we experimentally show 96.9% and 92.5% accuracy for training and testing, for a total of 144 postures and corresponding muscle activities. The method is then provided with a human-machine interface (HMI), which returns users with motion suggestions (i.e. postures and muscle strength). The report demonstrates that the proposed HAR technique can enhance users' self-training efficiency, potentially promoting the development of the HAR area.

Ban-xia-xie-xin-tang ameliorates hepatic steatosis by regulating Cidea and Cidec expression in HFD-fed mice.

BACKGROUND: Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown. PURPOSE: To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice. METHODS: After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy. RESULTS: First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs ß-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT. CONCLUSION: BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.

Diosgenin protects against podocyte injury in early phase of diabetic nephropathy through regulating SIRT6.

BACKGROUND: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. DN is the main cause of end-stage renal disease (ESRD). SIRT6 becomes the important target of DN. Diosgenin (a monomer from Chinese herbs) is probable to bind to SIRT6. PURPOSE: Based on studies presented in the literature on kidney injuries plus screening for the binding effects of the drug to Sirt6, we aimed to carry out the study to assess the effects of diosgenin involved in improving podocyte damage in the early phase of DN.. METHODS: DN model was established in spontaneous diabetic db/db mice. Animal experiment was in two parts. The first part includes four groups consisting of control (Con) group, model (Mod) group, low dose of diosgenin (DL) group and high dose of diosgenin (DH) group. The second part includes four groups consisting of control group, model group, DH+OSS_128167 (OSS, inhibitor of SIRT6) group, MDL800 (agonist of SIRT6) group. MPC5 cell line was selected in cell experiment, which was mainly composed of six groups including Con group, palmitic acid (PA) group, PA+DL group, PA+DH group, PA+DH+OSS group, PA+MDL800 group. Some procedures such as transcriptomics, RT-qPCR and so on were used in the study to explore and verify the mechanism. RESULTS: The abnormal changes of mesangial matrix expansion, glomerular basement membrane (GBM) thickness, foot process (FP) width, urine albumin/creatinine (UACR), DESMIN, ADRP, NEPHRIN, PODOCIN, SIRT6 in Mod group were alleviated in DH group rather than DL group in the first part of animal experiment. The effect in DH group could be reversed in DH+OSS group and the same effect was observed in MDL800 group in the second part of animal experiment. The same results were also found in cell experiment. Protein level and mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and Angiopoietin-like-4 (ANGPTL4) were increased in PA group, which could be alleviated in DH group, MDL800 group rather than DH+OSS group. CONCLUSIONS: Diosgenin could protect against podocyte injury in early phase of diabetic nephropathy by regulating SIRT6.

New Therapeutic Horizon of Graves' Hyperthyroidism: Treatment Regimens Based on Immunology and Ingredients From Traditional Chinese Medicine.

Graves' disease is an autoimmune disease characterized by goiter and hyperthyroidism, and 25% patients develop GO. Traditional treatment options, such as antithyroid drugs, radioiodine or thyroidectomy, have remained largely unchanged over the past 70 years. For many patients, there is a high rate of recurrence after antithyroid drugs and lifelong hypothyroidism after ablation and thyroidectomy. The symptoms and quality of life of some patients have not been effectively improved. The clinical demand for new therapeutic regimens, coupled with a deeper understanding of the pathophysiology and immunobiology of Graves' disease, has led to the emergence of several new therapeutic ideas, including biologics, small molecule peptides, immunomodulators and teprotumumab, a specific antibody targeting IGF-1R. Besides, the elements of TCM have attracted more and more interests in modern medicine, because some effective components have been successfully used in the treatment of autoimmune diseases. Based on the pathophysiology and efficacy of clinical management and treatment in Graves' hyperthyroidism, here we review the new strategies under investigation and summarize the effective components of traditional Chinese medicine used for Graves' hyperthyroidism, and explore their mechanisms. These therapies have opened a new window for the treatment of Graves' disease, but the exact mechanism and the research direction still need to be further explored.

Potato tillage method is associated with soil microbial communities, soil chemical properties, and potato yield.

Intensive potato continuous cropping (IPCC) results in low potato yields compared with non-intensive potato continuous cropping (PCC) and potato-maize rotation (PMRC). However, it is still unclear whether the degree of potato continuous cropping obstacle is related to the soil environment formed by the previous crop. To investigate the effect of planting potatoes and planting maize after harvesting the spring potatoes on soil chemical properties and soil microbial community structure, an experiment was carried out in the same origin soil environment over a period of seven years: (a) PCC, i.e., spring planting; (b) IPCC, i.e., autumn and spring planting (IPCC); (c) PMRC, i.e., spring potatoes and summer maize (PMRC), and (d) fallow (CK). We confirmed that the potato yield under PMRC was significantly higher than that under PCC and IPCC. Under IPCC, soil total phosphorus content was significantly higher than other treatments, whereas ammonium nitrogen content was the lowest. Compared with PCC and IPCC, PMRC had a higher ammonium nitrogen content and lower total phosphorus content. The significantly different fungal taxa in IPCC (Glomerellales, Plectosphaerella, Thelebolales) may threaten the health of the plant and positive correlated with soil total phosphorus, while other microbial taxa in PMRC (Bacillales, Polythrincium, Helotiales) can mainly promotes plant nitrogen uptake and protects plants against diseases. The PMRC-promoting taxa were positively correlated with the ammonium nitrogen content and negative correlated with soil total phosphorus content. In summary, the cropping systems might have affected potato yields by changed soil microorganism community structures - especially fungal community structures - and by the chemical properties of the soils that also depends on microbes.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Chickpea Extract Ameliorates Metabolic Syndrome Symptoms via Restoring Intestinal Ecology and Metabolic Profile in Type 2 Diabetic Rats.

SCOPE: Chickpeas have been recognized as a natural Uyghur medicine in Xinjiang (China) for 2500 years. Although the phenotypic effect on obesity or diabetes was authenticated, the mechanism was unclear. This work aims to study the effect of chickpea extract (CE) on metabolic syndrome induced by type 2 diabetes and to reveal its related mechanisms, focusing on intestinal flora and metabolomics. METHODS AND RESULTS: Diabetic rats are induced by a high-fat diet and intraperitoneal injection of streptozotocin. CE supplementation (3 g kg-1 ) for 4 weeks improved the hyperglycemia, inflammatory state, and organ functions of diabetic rats. The metabolic profile trajectories of urine and faeces obtained by NMR have good separations among all groups, and CE significantly increases the contents of SCFAs in the cecum. Moreover, CE relieves intestinal dysbiosis by increasing the abundance of SCFAs-producing bacteria (e.g., Enterococcaceae) but reduces conditional pathogenic bacteria (e.g., Corynebacterium). PICRUSt predicts the functions of gut microbiome from the 16S rRNA gene sequences and metagenome, and finds that CE restored amino acids degradation, bile acids metabolism, and carbohydrate metabolism. CONCLUSION: This study elucidates the role of CE from the perspective of metabolomics and the microbiota, which provides evidence for chickpea as a prebiotic to prevent diabetes.

The Effect of Momordica charantia in the Treatment of Diabetes Mellitus: A Review.

In recent years, many studies of Momordica charantia (MC) in the treatment of diabetes mellitus (DM) and its complications have been reported. This article reviewed the effect and mechanism of MC against diabetes, including the results from in vitro and in vivo experiments and clinical trials. The common side effects of MC were also summarized. We hope that it might open up new ideas for further mechanism exploration and clinical application as well as provide a scientific theoretical basis for the development of drugs or foods derived from MC.

Simultaneous determination of gallic acid, methyl gallate, and 1,3,6-tri-O-galloyl-ß-d-glucose from Turkish galls in rat plasma using liquid chromatography-tandem mass spectrometry and its application to pharmacokinetics study.

Turkish galls (TG) is a traditional Uygur medicine typically used in clinics for dental disease and chronic ulcerative colitis. In this study, a novel liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of gallic acid, methyl gallate, and 1,3,6-tri-O-galloyl-ß-d-glucose in rat plasma, which are the major bioactive compounds of TG. After a feasible protein precipitation using acetonitrile for sample preparation, chromatographic separation was performed with a BDS Hypersil C18 column (2.1 × 100 mm, 5 µm) at 30°C, and water containing 10 mmol of ammonium acetate and acetonitrile was used as the mobile phase with a flow rate of 0.3 mL/min. The MS detector was operated in the selective reaction monitoring with negative-ionization mode. The results of the method validation, including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of the compounds in the biosamples, were all within the current acceptance criteria. The established method was successfully applied to the pharmacokinetics study of three analytes in rats after an oral administration of TG extract and laid the foundation for studying the active components and mechanism of TG in vivo.

Berberine protects against diabetic kidney disease via promoting PGC-1α-regulated mitochondrial energy homeostasis.

BACKGROUND AND PURPOSE: Disordered lipid metabolism and disturbed mitochondrial bioenergetics play pivotal roles in the initiation and development of diabetic kidney disease (DKD). Berberine is a plant alkaloid, used in Chinese herbal medicine. It has multiple therapeutic actions on diabetes mellitus and its complications, including regulation of glucose and lipid metabolism, improvement of insulin sensitivity, and alleviation of oxidative damage. Here, we investigated the reno-protective effects of berberine. EXPERIMENTAL APPROACH: We used samples from DKD patients and experiments with models of DKD (db/db mice) and cultured podocytes, to characterize energy metabolism profiles using metabolomics. Molecular targets and mechanisms involved in the regulation of mitochondrial function and bioenergetics by berberine were investigated, along with its effects on metabolic alterations in DKD mice. KEY RESULTS: Metabolomic analysis suggested altered mitochondrial fuel usage and generalized mitochondrial dysfunction in patients with DKD. In db/db mice, berberine treatment reversed the disordered metabolism, podocyte damage and glomerulosclerosis. Lipid accumulation, excessive generation of mitochondrial ROS, mitochondrial dysfunction, and deficient fatty acid oxidation in DKD mouse models and in cultured podocytes were suppressed by berberine. These protective effects of berberine were accompanied by activation of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling pathway, which promoted mitochondrial energy homeostasis and fatty acid oxidation in podocytes. CONCLUSION AND IMPLICATIONS: PGC-1α-mediated mitochondrial bioenergetics could play a key role in lipid disorder-induced podocyte damage and development of DKD in mice. Restoration of PGC-1α activity and the energy homeostasis by berberine might be a potential therapeutic strategy against DKD.

Inhibitory effects of berberine on proinflammatory M1 macrophage polarization through interfering with the interaction between TLR4 and MyD88.

BACKGROUNDS: Inflammation is recognized as the key pathological mechanism of type 2 diabetes. The hypoglyceamic effects of berberine (BBR) are related to the inhibition of the inflammatory response, but the mechanism is not completely clear. METHODS: The inflammatory polarization of Raw264.7 cells and primary peritoneal macrophages were induced by LPS, and then effects and underlying mechanisms of BBR were explored. An inflammatory model was established by LPS treatment at different concentrations for different treatment time. An ELISA assay was used to detect the secretions of TNF-α. RT-PCR was applied to detect M1 inflammatory factors. The F4/80+ ratio and CD11c+ ratio of primary peritoneal macrophages were determined by flow cytometry. The expressions of p-AMPK and TLR4 were detected by Western blot. The cytoplasmic and nuclear distributions of NFκB p65 were observed by confocal microscopy. The binding of TLR4 to MyD88 was tested by CoIP, and the affinity of BBR for TLR4 was assessed by molecular docking. RESULTS: Upon exposure to LPS, the secretion of TNF-α and transcription of inflammatory factors in macrophages increased, cell morphology changed and protrusions appeared gradually, the proportion of F4/80+CD11c+ M1 macrophages increased, and the nuclear distribution of NFκB p65 increased. BBR pretreatment partially inhibited the changes mentioned above. However, the expression of TLR4 and p-AMPK did not change significantly after LPS intervention for 3 h. Meanwhile, CoIP showed that the interaction between TLR4 and MyD88 increased, and BBR inhibited the binding. Molecular docking suggested that BBR might interact with TLR4. CONCLUSIONS: Inflammatory changes were induced in macrophages after LPS stimulation for 3 h, and BBR pretreatment inhibited inflammatory polarization. BBR might interact with TLR4 and disturb TLR4/MyD88/NFκB signalling pathway, and it might be the mechanism by which BBR attenuated inflammation in the early phase.

Anemia following zinc treatment for Wilson's disease: a case report and literature review.

BACKGROUND: Zinc therapy is considered an effective and safe treatment for Wilson's disease. Hypocupremia-related anemia is rarely reported after long-term zinc administration or combination therapy with copper-chelating agent. CASE PRESENTATION: We herein report a 12-year-old girl with pre-symptomatic Wilson's disease diagnosed 5 years ago who presented with severe anemia after high-dose oral zinc for 4 years and 4 months. Her hemoglobin was gradually restored to the normal range after the adjustment of zinc dose and diet therapy for 4 months. A review of the literature revealed eight patients with hypocupremia-associated anemia following zinc therapy for Wilson's disease, including 7 adults and 1 child. The only child patient was a 16-year-old boy, in whom the zinc therapy was succession to penicillamine administration. CONCLUSIONS: This is the first report worldwide that a child developed severe anemia following high-dose single zinc administration for Wilson's disease. It highlights the importance of regular follow-up during zinc treatment and the involvement of specialists in the long-term management of Wilson's disease. We hope that this will alert pediatricians the issue of zinc over-treatment.

Alpha 1-antitrypsin for treating ventilator-associated lung injury in acute respiratory distress syndrome rats.

Purpose: Mechanical ventilation (MV) is an essential life support tool for patients with acute respiratory distress syndrome (ARDS). However, MV for ARDS can result in ventilator-induced lung injury (VILI). This study aimed to assess whether alpha 1-antitrypsin (AAT) can reduce VILI in ARDS rats. Materials and Methods: Rats were randomly divided into five groups: the sham (S) group, MV (V) group, lipopolysaccharide (LPS) (L) group, MV/LPS (VL) group and MV/AAT (VA) group. Rats in the S group were anesthetized. The rats in the L group received LPS but not ventilation, the rats in the V group received only MV, and the rats in the VL and VA groups received LPS and MV. Additionally, the rats in the VA group were treated with AAT, and the other rats were injected with saline. The PaO2/FiO2 ratio and the wet/dry weight were assessed. The total protein and neutrophil elastase concentrations and the neutrophil and macrophage counts in bronchoalveolar lavage fluid (BALF) were evaluated. Proinflammatory factors in BALF and ICAM-1 and MIP-2 in serum were also tested. Furthermore, the oxidative stress response was detected, and histological injury and apoptosis were evaluated. Results: All the rats in the V, L and VL groups had significant lung injury, with the VL group exhibiting the most severe injury. Compared with the findings in the VL group, AAT significantly upregulated the PaO2/FiO2 ratio but decreased the wet/dry weight ratio and protein levels in BALF. AAT also reduced proinflammatory cytokine levels and inflammatory cell counts in BALF. Lung tissue injury and cell apoptosis were mitigated by AAT. Conclusions: AAT ameliorated VILI in ARDS rats. The protection conferred by AAT may be associated with the anti-inflammatory, antioxidative stress response and anti-apoptotic effects of AAT.