The Scutellaria-Coptis herb couple and its active small-molecule ingredient wogonoside alleviate cytokine storm by regulating the CD39/NLRP3/GSDMD signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: A drug pair is a fundamental aspect of traditional Chinese medicine prescriptions. Scutellaria baicalensis Georgi and Coptis chinensis Franch, commonly used as an herb couple (SBCC), are representative heat-clearing and dampness-drying drugs. They possess functions such as clearing heat, drying dampness, purging fire, and detoxifying. These herbs are used in both traditional and modern medicine for treating inflammation. AIM OF THE STUDY: This study investigated the effects of SBCC on cytokine storm syndrome (CSS) and explored its potential regulatory mechanism. MATERIALS AND METHODS: We assessed the impact of SBCC in a sepsis-induced acute lung injury mouse model by administering an intraperitoneal injection of LPS (15 mg/kg). The cytokine levels in the serum and lungs, the wet-to-dry ratio of the lungs, and lung histopathological changes were evaluated. The macrophages in the lung tissue were examined through transmission electron microscopy. Western blot was used to measure the levels of the CD39/NLRP3/GSDMD pathway-related proteins. Immunofluorescence imaging was used to assess the activation of pro-caspase-1 and ASC and their interaction. AMP-Glo™ assay was used to screen for active ingredients in SBCC targeting CD39. One of the ingredients was selected, and its effect on cell viability was assessed. We induced inflammation in macrophages using LPS + ATP and detected the levels of proinflammatory factors. The images of cell membrane large pores were captured using scanning electron microscopy, the interaction between NLRP3 and ASC was detected using immunofluorescence imaging, and the levels of CD39/NLRP3/GSDMD pathway-related proteins were assessed using Western blot. RESULTS: SBCC administration effectively mitigated LPS-induced cytokine storm, pulmonary edema and lung injury. Furthermore, it repressed the programmed death of lung tissue macrophages by inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. Based on the results of the AMP-Glo™ assay, we selected wogonoside for further valuation. Wogonoside alleviated LPS + ATP-induced inflammatory damage by regulating the inhibiting the NLRP3/GSDMD pyroptosis pathway and regulating the CD39 purinergic pathway. However, its effect on NLRP3 is not mediated though CD39. CONCLUSION: SBCC and its active small-molecule ingredient, wogonoside, improved CSS by regulating the NLRP3/GSDMD pyroptosis pathway and its upstream CD39 purinergic pathway. It is essential to note that the regulatory effect of wogonoside on NLRP3 is not mediated by CD39.

Electroacupuncture improves peripheral neuropathy by up-regulating Sirt1/PGC-1α/TFAM pathway in type 2 diabetes rats with peripheral neuropathy. / 基于Sirt1/PGC-1α/TFAM通路探讨电针治疗2åž‹ç³–å°¿ç— å‘¨å›´ç¥žç»ç— å˜çš„æœºåˆ¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on activation of silent information regulator 1 (Sirt1)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/mitochondrial transcription factor A (TFAM) pathway in type 2 diabetes (T2DM) rats with peripheral neuropathy (DPN) , so as to explore its possible mechanisms underlying improvement of DPN. METHODS: Thirty male SD rats were randomly divided into blank control group (n=8) and DPN model group (n=22) which were further divided into model group (n=8) and EA group (n=8) after successful modeling. The model of T2DM was established by high-fat diet and low-dose intraperitoneal injection of streptozocin (35 mg/kg). For rats of the EA group (anesthetized with isoflurane), EA stimulation (2 Hz/15 Hz, 2 mA) was applied to "Tianshu"(ST25) for 20 min, once daily, 6 times a week for 6 weeks. The blood glucose level, body weight, area under curve (AUC) of glucose tolerance test, and hind-paw mechanical pain threshold and thermal pain threshold were observed. The intra-epidermal nerve fiber density (IENFD) of the hind-foot pad was observed by immunofluorescence staining. The motor nerve conduction velocity (MNCV) of the sciatic nerve was measured by using electrophysiological method. H.E. staining was used to observe the histopathological changes of the sciatic nerve after modeling. Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of the sciatic nerve. The protein expressions of energy-related Sirt1, PGC-1α and TFAM in the sciatic nerve was detected by Western blot. RESULTS: Compared with the blank control group, the model group had a higher blood glucose contents and AUC (P<0.001), a slower MNCV (P<0.01), and a decrease in the body weight and in the mechanical and thermal pain thresholds (P<0.001) and IENFD (P<0.001), and in the expression levels of Sirt1, PGC-1α and TFAM (P<0.05, P<0.01). In contrast to the model group, the EA group had a decrease in the blood glucose contents and AUC (P<0.05, P<0.01), and an increase in mechanical and thermal pain thresholds, MNCV, IENFD, and expression levels of Sirt1, PGC-1α and TFAM proteins (P<0.01, P<0.05). In addition, results of histopathological and ultrastructural changes of the sciatic nerve showed more fragmented and disordered distribution of axons on the transverse section, and extensive separation of myelin and axons, uneven myelin thickness, axonal degeneration and irregular shape in the model group, whereas in the EA group, the axons on the transverse section were relatively more dense and more complete, the myelin sheath of the sciatic nerve was relatively uniform, and the axonal shape was relatively regular with relatively milder lesions. CONCLUSIONS: EA up-regulates the expressions of Sirt1, PGC-1α, TFAM in T2DM rats with DPN, which may be associated with its functions in improving and repairing the injured peripheral nerves in rats with DPN.

Chinese medicine Phragmites communis (Lu Gen) for acute respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials.

Background: Acute respiratory tract infections (ARTIs) are the most common cause of morbidity and mortality worldwide, with most people experiencing at least one episode per year. Current treatment options are mainly symptomatic therapy. Antivirals, antibiotics, and glucocorticoids are of limited benefit for most infections. Traditional Chinese medicine has shown potential benefits in the treatment of ARTIs. Objective: The objective of this study was to determine the efficacy, effectiveness, and safety of Phragmites communis Trin. (P. communis, a synonym of Phragmites australis (Cav.) Trin. ex Steud) as monotherapy or as part of an herb mixture for ARTIs. Method: Eight databases and two clinical trial registries were searched from inception to 8 February 2023 for randomized controlled trials (RCTs) evaluating any preparation involving P. communis without language restrictions. The Risk of Bias Tool 2.0 was used to assess the risk of bias of the included trials. RevMan 5.3 software was used for data analyses with effects estimated as risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% confidence intervals (CIs). The online GRADEpro tool was used to assess the certainty of the evidence, if available. Results: Forty-two RCTs involving 6,879 patients with ARTIs were included, with all trials investigating P. communis as part of an herbal mixture. Of the included trials, the majority (38/42) were considered high risk. Compared to the placebo, P. communis preparations improved the cure rate [RR = 1.60, 95% CI (1.13, 2.26)] and fever clearance time [MD = -2.73 h, 95% CI (-4.85, -0.61)]. Compared to usual care alone, P. communis preparations also significantly improved the cure rate [RR = 1.57, 95% CI (1.36, 1.81)] and fever clearance time [SMD = -1.24, 95% CI (-2.37, -0.11)]. P. communis preparations plus usual care compared to usual care alone increased the cure rate [RR = 1.55, 95% CI (1.35, 1.78)], shortened the fever clearance time [MD = -19.31 h, 95% CI (-33.35, -5.27)], and improved FEV1 [ MD = 0.19 L, 95% CI (0.13, 0.26)] and FVC [ MD = 0.16 L, 95% CI (0.03, 0.28)]. Conclusion: Low- or very low-certainty evidence suggests that P. communis preparations may improve the cure rate of ARTIs, shorten the fever clearance time in febrile patients, and improve the pulmonary function of patients with acute exacerbation of chronic obstructive pulmonary disease or chronic bronchitis. However, these findings are inconclusive and need to be confirmed in rigorously designed trials. Systematic review registration: PROSPERO, identifier CRD42021239936.

Mechanism of the Effect of Scopolamine on Breast Cancer: Determination by Network Pharmacology and Bioinformatics.

BACKGROUND: To a certain extent, traditional Chinese medicine (TCM)-based anesthesia has replaced opiate administration in recent years. Preliminary drug screening has revealed that scopolamine may affect breast cancer (BC) metastasis by an unknown mechanism. METHODS: Network pharmacology, bioinformatics, and protein-protein interaction (PPI) topological analysis were implemented to identify the core genes linking scopolamine and BC. The core genes were then subjected to gene expression profiling interactive analysis (GEPIA). The top ten pathways were detected by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The impact of immune infiltration on the core gene difference and survival analyses was then determined. Molecular docking was then performed on the core genes and the main active components. RESULTS: Protein kinase 1 (AKT1), epidermal growth factor receptor (EGFR), heat shock protein 90 alpha class A (HSP90AA1), caspase 3 (CASP3), and estrogen receptor 1 (ESR1) were the key genes in the interaction between scopolamine and BC cells. The KEGG enrichment analysis disclosed that the top ten pathways significantly associated with the scopolamine response in BC included "protein glycosylation," "phosphoinositide 3-kinase (PI3K)-Akt signaling," "mitogen- activated protein kinase (MAPK) signaling" and others. The AKT1, EGFR, and especially the HSP90AA1 expression levels were correlated with survival in patients with BC. Immune infiltration also influenced the survival outcome. Molecular docking demonstrated that scopolamine bound and formed stable complexes with the protein products of all five aforementioned genes. CONCLUSION: Scopolamine has multiple targets regulating BC cell function and may increase the risk of metastasis during treatment. Therefore, it should be preoperatively administered with caution to patients with BC.

A role for the cerebellum in motor-triggered alleviation of anxiety.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.

Biocontrol potential of endophytic bacterium Bacillus altitudinis GS-16 against tea anthracnose caused by Colletotrichum gloeosporioides.

Background: As one of the main pathogens causing tea anthracnose disease, Colletotrichum gloeosporioides has brought immeasurable impact on the sustainable development of agriculture. Given the adverse effects of chemical pesticides to the environment and human health, biological control has been a focus of the research on this pathogen. Bacillus altitudinis GS-16, which was isolated from healthy tea leaves, had exhibited strong antagonistic activity against tea anthracnose disease. Methods: The antifungal mechanism of the endophytic bacterium GS-16 against C. gloeosporioides 1-F was determined by dual-culture assays, pot experiments, cell membrane permeability, cellular contents, cell metabolism, and the activities of the key defense enzymes. Results: We investigated the possible mechanism of strain GS-16 inhibiting 1-F. In vitro, the dual-culture assays revealed that strain GS-16 had significant antagonistic activity (92.03%) against 1-F and broad-spectrum antifungal activity in all tested plant pathogens. In pot experiments, the disease index decreased to 6.12 after treatment with GS-16, indicating that strain GS-16 had a good biocontrol effect against tea anthracnose disease (89.06%). When the PE extract of GS-16 treated mycelial of 1-F, the mycelial appeared deformities, distortions, and swelling by SEM observations. Besides that, compared with the negative control, the contents of nucleic acids, protein, and total soluble sugar of GS-16 group were increased significantly, indicating that the PE extract of GS-16 could cause damage to integrity of 1-F. We also found that GS-16 obviously destroyed cellular metabolism and the normal synthesis of cellular contents. Additionally, treatment with GS-16 induced plant resistance by increasing the activities of the key defense enzymes PPO, SOD, CAT, PAL, and POD. Conclusions: We concluded that GS-16 could damage cell permeability and integrity, destroy the normal synthesis of cellular contents, and induce plant resistance, which contributed to its antagonistic activity. These findings indicated that strain GS-16 could be used as an efficient microorganism for tea anthracnose disease caused by C. gloeosporioides.

Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways.

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FJHQ), a traditional Chinese medicinal formula outlined in Zhang Zhongjing's "Jin Gui Yao Lue" during the Han Dynasty, is often used to treat conditions characterized by symptoms like edema and dysuria, including membranous nephropathy (MN). Despite its proven clinical effectiveness, the exact mechanisms through which FJHQ acts on MN remain elusive. AIM OF THE STUDY: This study aimed to investigate whether FJHQ enhances BNIP3-mediated mitophagy in podocytes by promoting BNIP3 expression and whether this improvement leads to the amelioration of MN. MATERIALS AND METHODS: In this study, by establishing passive Heymann nephritis (PHN) rats, an experimental rat model of MN induced by sheep anti-rat Fx1A serum, we evaluated the effects of FJHQ in vivo. In vitro experiments were carried out by treating primary podocytes with experimental rat serum. Furthermore, the potential mechanism by which FJHQ acts through BNIP3 was further examined by transfecting primary podocytes with the siRNA of BNIP3 or the corresponding control vector. RESULTS: After 4 weeks, significant kidney damage was observed in the rats in the model group, comparatively, FJHQ markedly decreased urine volume, 24-h urinary protein, blood urea nitrogen (BUN), creatinine (Scr), and increased serum total albumin (ALB). Histology showed that FJHQ caused significant improvements in glomerular hyperplasia, and IgG immune complex deposition in MN rats. JC-1 fluorescence labelling and flow cytometry analysis showed that FJHQ could significantly increase mitochondrial membrane potential in vivo. In the mitochondria of MN model rats, FJHQ was able to down-regulate the expression of P62 and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I, according to Western blot and immunofluorescence studies. Furthermore, FJHQ has been shown to significantly up-regulate mitochondrial membrane potential, down-regulate P62 expression in mitochondria, and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I in mitochondria at the cellular level. After the administration of the autophagy inhibitor chloroquine, the serum of rats treated with FJHQ further increased the expression of LC3 II/LC3 I in primary podocytes, showing higher autophagy flow. After the interference of BNIP3 in podocytes, the effect of FJHQ on mitochondrial membrane potential and autophagy-related proteins almost disappeared. CONCLUSION: FJHQ enhanced mitophagy in podocytes by promoting the expression of BNIP3, thereby contributing to the amelioration of MN. This work reveals the possible underlying mechanism by which FJHQ improves MN and provides a new avenue for MN treatment.

Pharmacists' perspectives on recommending herbal medicines for acute infections: a qualitative study.

BACKGROUND: Community pharmacists have an essential role in antimicrobial stewardship by providing self-care advice for self-limiting infections. AIM: To explore community pharmacists' perceptions and experiences of advising patients on management of acute respiratory tract infections (RTIs) and urinary tract infections (UTIs), and to explore issues regarding use of over-the-counter (OTC) medicines, including herbal medicines. DESIGN & SETTING: A qualitative study using semi-structured interviews with community pharmacists in England. METHOD: Qualitative interviews with community pharmacists were carried out face to face and by telephone between November 2019 and March 2020. Data were collected through in-depth, semi-structured interviews, recorded and transcribed. A reflexive thematic analysis was undertaken. RESULTS: In total, 18 community pharmacists were interviewed. Three main themes were identified. Theme 1 was self-management recommendations. Community pharmacists considered patients' preferences when recommending self-management strategies. Some believed that conventional OTC medications had quicker and stronger effects, while others preferred herbal OTCs as a more natural approach, particularly for less severe symptoms. Theme 2 was factors influencing pharmacists' recommendations for acute infections. This included pharmacists' perceptions of patient preferences, nature or severity of illness, research evidence, training, commercial pressures, and patient concerns about medication cost. Theme 3 was pharmacist-patient communication. Pharmacists sometimes experienced challenges with language barriers and patients' expectations of receiving antibiotics. Pharmacists emphasised the importance of being trusted by their patients. There was widespread acceptance of their role in self-management advice for acute illness and interest in the role of herbal medicines, but pharmacists did not feel confident in recommending these. CONCLUSION: Pharmacists are central to the management of self-limiting infections. There is a need to educate the public about appropriate use of antibiotics and provide training and support for pharmacists on self-management strategies including herbal medicine.

Chemical Composition, Antibacterial Activity and Mechanism of Action of Fermentation Products from Aspergillus Niger xj.

Six compounds were isolated and purified from the crude acetone extract of Aspergillus niger xj. Characterization of all compounds was done by NMR and MS. On the basis of chemical and spectral analysis structure, six compounds were elucidated as metazachlor (1), nonacosane (2), palmitic acid (3), 5,5'-oxybis(5-methylene-2-furaldehyde) (4), dimethyl 5-nitroisophthalate (5) and cholesta-3,5-dien-7-one (6), respectively, and compounds 1, 4, 5 and 6 were isolated for the first time from A. niger. To evaluate the antibacterial activity of compounds 1-6 against three plant pathogenic bacteria (Agrobacterium tumefaciens T-37, Erwinia carotovora EC-1 and Ralstonia solanacearum RS-2), and the minimum inhibitory concentrations (MICs) were determined by broth microdilution method in 96-well microtiter plates. Results of the evaluation of the antibacterial activity showed that T-37 strain was more susceptible to metazachlor with the lowest MIC of 31.25 µg/mL. The antibacterial activity of metazachlor has rarely been reported, thus the antibacterial mechanism of metazachlor against T-37 strain were investigated. The permeability of cell membrane demonstrated that cells membranes were broken by metazachlor, which caused leakage of ions in cells. SDS-PAGE of T-37 proteins indicated that metazachlor could damage bacterial cells through the destruction of cellular proteins. Scanning electron microscopy results showed obvious morphological and ultrastructural changes in the T-37 cells, further confirming the cell membrane damages caused by metazachlor. Overall, our findings demonstrated that the ability of metazachlor to suppress the growth of T-37 pathogenic bacteria makes it potential biocontrol agents.

Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Huang-Lian-Jie-Du decoction drug-containing serum inhibits IL-1ß secretion from D-glucose and PA induced BV2 cells via autophagy/NLRP3 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD), a famous traditional Chinese medicine prescription with heat-clearing and detoxifying effects, has been widely used to treat diabetes, dementia, stroke, and other diseases. However, the detailed mechanisms of HLJDD against type 2 diabetes associated cognitive dysfunction (DACD) through inhibiting interleukin-1ß (IL-1ß) mediated neuroinflammation remain to be further elucidated. AIM OF THE STUDY: The aim of this study was to investigate the effect and potential mechanism of HLJDD on IL-1ß secretion in a DACD model of BV2 cells induced by D-glucose and palmitic acid (PA). MATERIALS AND METHOD: sUltra-performance liquid chromatography-quadrupole/electrostatic field orbital well high-resolution mass spectrometry technology was used to analyze the compounds in HLJDD drug-containing serum. The cytotoxicity was detected by cell counting kit-8. Enzyme-linked immunosorbent assay was used to measure the secretion of IL-1ß in BV2 cells. Reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde kits were used to detect the intracellular oxidative stress levels. The autophagy level was determined by autophagy staining kit and transmission electron microscope. The expression levels of autophagy-related 7 (Atg7), P62, LC3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3(NLRP3), Caspase1, and IL-1ß were detected by real-time PCR, immunofluorescence, and western blotting. The Atg7siRNA was transfected into BV2 cells to produce autophagy inhibitory effect. Then the effect of HLJDD drug-containing serum on IL-1ß secretion in D-glucose and PA induced BV2 cells and the potential mechanism of autophagy-NLRP3 inflammasome activation were further observed. RESULTS: Eighty-eight compounds were preliminarily identified in HLJDD drug-containing serum, among which geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid were identified as the main prototype components of HLJDD into the blood. In this study, the DACD model of BV2 cells induced by high concentrations of glucose and PA was successfully constructed. HLJDD drug-containing serum significantly reduced the secretion of IL-1ß and the activity of NLRP3 inflammasome with improving the oxidative stress level. Interestingly, the enhanced autophagy level was also found. After transfection of Atg7siRNA into BV2 cells, the effect of HLJDD drug-containing serum on autophagy promotion was reversed, but the inhibitory effects on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were reduced. CONCLUSIONS: These results indicated that the inhibition of HLJDD drug-containing serum on the IL-1ß secretion in D-glucose and PA induced BV2 cells was related to autophagy promotion, the decreased NLRP3 inflammasome activation, and the improved oxidative stress. Moreover, the improvement of HLJDD drug-containing serum on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were all closely associated with Atg7 mediated autophagy promotion. Geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid may be the potential active ingredients of HLJDD drug-containing serum.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Effect of Buzhong Yiqitang on Th17/Treg Immune Imbalance and Notch1 Signaling Pathway in AIT Mice / 中国实验方剂学杂志

ObjectiveTo explore the effect of Buzhong Yiqitang on the immune imbalance of helper T cell 17 （Th17）/regulatory T cell （Treg） and Notch1 signaling pathway in mice with autoimmune thyroiditis （AIT）. MethodA total of 60 8-week-old NOD.H-2h4 mice were randomly divided into the normal group， model group， western medicine group （selenium yeast tablet， 32.5 mg·kg-1）， and low-dose （4.78 g·kg-1·d-1）， middle-dose （9.56 g·kg-1·d-1）， and high-dose （19 g·kg-1·d-1） Buzhong Yiqitang groups， with 10 mice in each group. The normal group was fed with distilled water， and the other groups were fed with water containing 0.05% sodium iodide for eight weeks. After the animal model of AIT was formed spontaneously， the mice were killed under anesthesia after intragastric administration for eight weeks. Serum anti-thyroglobulin antibodies （TGAb）， thyroid-stimulating hormone （TSH）， free triiodothyronine （FT3）， and free thyroid hormone （FT4） were detected by enzyme-linked immunosorbent assay （ELISA）， and thyroid tissue changes were observed by hematoxylin-eosin （HE） staining. The mRNA and protein expressions of retinoid-related orphan receptor-γt （RORγt）， interleukin （IL）-17， forkhead box P3 （FoxP3）， IL-10， Notch1， and hair division-related enhancer 1 （Hes1） in thyroid tissue were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the normal group， the thyroid structure of the model group was severely damaged， and lymphocytes were infiltrated obviously. The levels of serum TGAb， FT3， and FT4 contents were significantly increased， and TSH content was significantly decreased （P<0.01）. The mRNA and protein expression levels of RORγt， IL-17， Notch1， and Hes1 were significantly increased， while those of FoxP3 and IL10 were significantly decreased in the model group （P<0.01）. Compared with the model group， thyroid structural damage and lymphocyte infiltration were improved in the treatment groups， and serum TGAb， FT3， and FT4 contents were significantly decreased. TSH content was increased， and mRNA and protein expression levels of RORγt， IL-17， Notch1， and Hes1 were decreased. mRNA and protein expression levels of FoxP3 and IL-10 were increased to different degrees （P<0.05， P<0.01）， and the middle-dose Buzhong Yiqitang group had the most significant intervention effect. ConclusionBuzhong Yiqitang can alleviate the thyroid structural damage in AIT mice， and its mechanism may be related to improving the abnormal differentiation of Th17/Treg immune cells and inhibiting the activation of the Notch1 signaling pathway.

Three new Furano-lactones from the endophytic fungus Aspergillus nidulans.

Three new furano-lactones, asperilactones A-C (1-3), and two known compounds silvaticol (4) and violaceic acid (5) were isolated from an ethanol extract of Aspergillus nidulans, a fungus isolated from the Annelida Whitmania pigra Whitman (Haemopidae). Their structures were elucidated by a combination of spectroscopy, ECD calculations, comparing optical rotation values, and single-crystal X-ray diffraction analyses. Asperilactone A (1) represented the first example of furano-lactone with an unusual 2-thia-6-oxabicyclo[3.3.0]octane ring system. Asperilactones A and B showed weak toxicity against the HL-60 and RKO.

Treating acute exacerbations of COPD with Chinese herbal medicine to aid antibiotic use reduction (Excalibur): a randomised double-blind, placebo-controlled feasibility trial.

Background: Although many acute exacerbations of COPD (AECOPD) are triggered by non-bacterial causes, they are often treated with antibiotics. Preliminary research suggests that the Chinese herbal medicine "Shufeng Jiedu" (SFJD), may improve recovery and therefore reduce antibiotic use in patients with AECOPD. Aims: To assess the feasibility of conducting a randomised placebo-controlled clinical trial of SFJD for AECOPD in UK primary care. Methods: GPs opportunistically recruited patients experiencing an AECOPD. Participants were randomised 1:1 to usual care plus SFJD or placebo for 14 days. Participants, GPs and research nurses were blinded to treatment allocation. GPs could prescribe immediate, delayed or no antibiotics, with delayed prescribing encouraged where appropriate. Participants were asked to complete a participant diary, including EXACT-PRO and CAT™ questionnaires for up to 4 weeks. Outcomes included recruitment rate and other measures of study feasibility described using only descriptive statistics and with no formal comparisons between groups. We also conducted qualitative interviews with recruited and non-recruited COPD patients and clinicians, analysed using framework analysis. Results: Over 6 months, 19 participants (6 SFJD, 13 placebo) were recruited. Sixteen (84%) participants returned diaries or provided a diary by recall. Overall, 1.3 participants were recruited per 1,000 patients on the COPD register per month open. Median duration of treatment was 9.8 days in the intervention group vs 13.3 days in the placebo group. The main reason for discontinuation in both groups was perceived side-effects. in both groups. Point estimates for both the EXACT-PRO and CAT™ outcomes suggested possible small benefits of SFJD. Most patients and clinicians were happy to try SFJD as an alternative to antibiotics for AECOPD. Recruitment was lower than expected because of the short recruitment period, the lower incidence of AECOPD during the COVID-19 pandemic, patients starting antibiotics from "rescue packs" before seeing their GP, and workforce challenges in primary care. Conclusion: Recruitment was impaired by the COVID-19 pandemic. Nevertheless, we were able to demonstrate the feasibility of recruiting and randomising participants and identified approaches to address recruitment challenges such as including the trial medication in COPD patients' "rescue packs" and delegating recruitment to a central trials team. Clinical Trial Registration: Identifier, ISRCTN26614726.

The efficacy and safety of Niaoduqing granules in the treatment of diabetic kidney disease: a systematic review and meta-analysis.

Background: Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and end-stage renal failure (ESRF), and the control of disease progression and adverse events during treatment needs to be improved. Objective: This study aimed to systematically evaluate the clinical efficacy and safety of Niaoduqing granules (NDQG) in the treatment of diabetic kidney disease (DKD). Method: Randomized controlled trials (RCTs) of NDQG for DKD from Chinese and English databases up to 31 August 2022 were included. The quality of the literature was assessed using the risk of bias tool of the Cochrane Handbook. At a 95% confidence interval (CI), relative risk (RR) and Cohen's d were used for the categorical and continuous variables, respectively, and Stata 16.0 software was used for statistical analysis. A funnel plot and Egger's tests were used to assess publication bias. Result: A total of 4,006 patients were included in 52 RCTs, including 1,987 cases in the control group and 2,019 cases in the treatment group. Compared with conventional treatment (CT), combined NDQG therapy is more effective in improving clinical efficiency [RR = 1.23, 95% confidence interval (1.17, 1.29), p < 0.001, I 2 = 53.17%], kidney function (urinary albumin excretion rate [SMD = -0.90, 95% CI (-1.14, -0.66), p < 0.001, I 2 = 78.19%], 24hUTP levels [SMD = -0.81, 95% CI (-1.08, -0.55), p < 0.001, I 2 = 87.08%], blood urea nitrogen [SMD = -0.54, 95% CI (-0.69, -0.39), p < 0.01, I 2 = 77.01%], SCr [SMD = -0.68, 95% CI (-0.90, -0.45), p < 0.001, I 2 = 89.97%], CCr [SMD = 0.76, 95% CI (0.10,1.42), p = 0.02, I 2 = 95.97%], and Cys-C [SMD = -1.32, 95% CI (-2.25, -0.40), p = 0.01, I 2 = 93.44%]), the level of glucose metabolism (fasting blood glucose [SMD = -0.18, 95% CI (-0.38, 0.03), p = 0.10, I 2 = 71.18%] and HbA1c [SMD = -0.42, 95% CI (-0.86, -0.02), p = 0.06, I 2 = 81.64%]), the level of lipid metabolism (total cholesterol [SMD = -0.70, 95% CI (-1.01, -0.39), p < 0.001, I 2 = 86.74%] and triglyceride [SMD = -0.61, 95% CI (-0.87,-0.36), p < 0.001, I 2 = 80.64%]), inflammatory factors (Hs-CRP [SMD = -1.00, 95% CI (-1.54, -0.46), p < 0.001, I 2 = 86.81%], IL-18 [SMD = -1.25, 95% CI (-1.58, -0.92), p < 0.001, I 2 = 0], and TNF-α [SMD = -1.28, 95% CI (-1.64, -0.91), p < 0.001, I 2 = 75.73%]), and indicators of oxidative stress (malondialdehyde [SMD = -0.88, 95% CI (-1.22, -0.54), p < 0.001, I 2 = 66.01%] and advanced oxidation protein products [SMD = -0.92, 95% CI (-1.85, 0.00), p < 0.001, I 2 = 90.68%]). In terms of improving uric acid [SMD = -1.59, 95% CI (-3.45, 0.27), p = 0.09, I 2 = 94.67%], 2hPG [SMD = -0.04, 95% CI (-0.61, 0.53), p = 0.89, I 2 = 84.33%], HDL-C [SMD = 0.71, 95% CI (0.02, 1.40), p = 0.04, I 2 = 87.43%], Hb [SMD = 0.11, 95% CI (-0.10, 0.32), p = 0.32, I 2 = 0.00]), and superoxide dismutase [SMD = 1.32, 95% CI (0.44, 2.20), p < 0.001, I 2 = 93.48%], the effect is not obvious. Adjuvant treatment with NDQG did not increase the incidence of adverse reactions in the control group [SMD = 0.98, 95% CI (0.71, 1.34), p = 0.89, I 2 = 1.59%]. Obvious publication bias was detected by funnel plot and Egger's test. Conclusion: Our meta-analysis showed that adjuvant treatment with NDQG has more advantages than conventional treatment alone in the DKD treatment, which could improve clinical efficiency, kidney function, the level of glucose metabolism, the level of lipid metabolism, inflammatory factors, and oxidative stress indicators. At the same time, it also showed that NDQG are relatively safe. However, more high-quality studies are needed to provide more reliable evidence for clinical use. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022373726, identifier CRD42022373726.

Echinocystic acid prevents obesity and fatty liver via interacting with FABP1.

Long-term high-fat diet (HFD) will lead to obesity and their complications. Echinocystic acid (EA), a triterpene, shows anti-inflammatory and antioxidant effects. We predict that EA supplementation can prevent obesity, diabetes, and nonalcoholic steatohepatitis. To test our hypothesis, we investigated the effects of EA supplementation on mice with HFD-induced obesity in vivo and in vitro by adding EA to the diet of mice and the medium of HepG2 cells, the protein target of EA was analyzed by molecular docking. The results showed that EA ameliorated obesity and inhibited blood triglyceride and liver triglyceride concentrations than those in the HFD groups. The data on molecular docking indicated that FABP1 was a potential target of EA. Further experimental results confirmed that EA affected the triglyceride level by regulating the function of FABP1. This study may provide a new potential inhibitor for FABP1 and a new strategy for the treatment of obesity.

Mechanism of lead adsorption by a Bacillus cereus strain with indole-3-acetic acid secretion and inorganic phosphorus dissolution functions.

BACKGROUND: Heavy metal pollution has become a major source of environmental pollution because of increasing industrialization. Microbial remediation is a promising approach to remediate lead-contaminated environments owing to its cost-effective, environment-friendly, ecologically sustainable, and highly efficient properties. In this study, the growth-promoting functions and lead-adsorption ability of Bacillus cereus SEM-15 were examined, and the functional mechanism of the strain was preliminarily identified using scanning electron microscopy, energy spectrum, infrared spectrum, and genome analyses, providing theoretical support for utilization of B. cereus SEM-15 in heavy metals remediation. RESULTS: B. cereus SEM-15 showed strong ability to dissolve inorganic phosphorus and secrete indole-3-acetic acid. The lead adsorption efficiency of the strain at lead ion concentration of 150 mg/L was more than 93%. Single factor analysis revealed the optimal conditions for heavy metal adsorption by B. cereus SEM-15 (adsorption time, initial lead ion concentration, pH, and inoculum amount were 10 min, 50-150 mg/L, 6-7, and 5 g/L, respectively) in nutrient-free environment, with the lead adsorption rate reaching 96.58%. Scanning electron microscopy of B. cereus SEM-15 cells before and after lead adsorption showed adherence of a large number of granular precipitates to the cell surface after lead adsorption. X-Ray photoelectron spectroscopy and Fourier transform infrared spectroscopy results indicated the characteristic peaks of Pb-O, Pb-O-R (R = functional group), and Pb-S bonds after lead adsorption, and a shift in the characteristic peaks of bonds and groups related to C, N, and O. Genome annotation results showed the presence of genes related to heavy metals tolerance and plant growth promotion in B. cereus SEM-15, providing a molecular basis for the strain's heavy metals tolerance and plant growth promotion functions. CONCLUSIONS: This study analyzed the lead adsorption characteristics of B. cereus SEM-15 and the associated influencing factors, and discussed the adsorption mechanism and related functional genes, providing a basis for clarifying the underlying molecular mechanism and offering a reference for further research on plant-microorganisms combined remediation of heavy metals polluted environments.

Use of antibiotics and other treatments in Chinese adults with acute cough: An online survey.

Background: This study aimed to identify use of various treatments and their association with the use of antibiotics and patient reported clinical recovery in Chinese adults with acute cough. Methods: An online survey recruiting people who had recently experienced cough was conducted. Their sociodemographic, clinical characteristics, treatments received and their perceived changes in symptoms were collected. Factors influencing avoidance of antibiotics and improvement in symptoms were explored. Results: A total of 22,787 adults with recent acute cough completed the questionnaire, covering all 34 province-level administrative units in China. Most respondents were male (68.0%), young (89.4%, aged 18-45), educated to university/degree or postgraduate level (44.6%), with a median cough severity of 6/10 on a numerical rating scale. Nearly half of the participants (46.4%) reported using antibiotics, among which 93.1% were for presumed upper respiratory tract infections (URTIs). Pharmacies (48.8%) were the most common source of antibiotics. Fewer patients took antibiotics after taking CHM (14.9%), compared to those who started with home remedies (18.0%), or allopathic non-antibiotic medication (25.0%). Antibiotics, allopathic non-antibiotic medications, CHM and home remedies were all perceived beneficial in relieving cough. Conclusions: Chinese adult responders report use of a considerable variety of treatments alone or in combination for acute cough. Patient-reported clinical recovery was similar regardless of treatment. There is likely a high proportion of inappropriate use of antibiotics for treatment of simple acute cough. As the majority of respondents did not use antibiotics as a first-line, and use of CHM was associated with relief of cough symptoms and reduction in the use of antibiotics, this presents an important opportunity for prudent antibiotic stewardship in China.