Metabolomic analysis reveals Ligilactobacillus salivarius CCFM 1266 fermentation improves dairy product quality.

Previous studies have demonstrated that Ligilactobacillus salivarius CCFM 1266 exhibits anti-inflammatory properties and the capability to synthesize niacin. This study aimed to investigate the fermentative abilities of L. salivarius CCFM 1266 in fermented milk. Metabonomic analysis revealed that fermentation by L. salivarius CCFM 1266 altered volatile flavor compounds and metabolite profiles, including heptanal, nonanal, and increased niacin production. Genomic investigations confirmed that L. salivarius CCFM 1266 possess essential genes for the metabolism of fructose and mannose, affirming its proficiency in utilizing fructooligosaccharides and mannan oligosaccharides. The addition of fructooligosaccharides and mannan oligosaccharides during the fermentation process significantly facilitated the proliferation of L. salivarius CCFM 1266 in fermented milk, with growth exceeding 107 colony-forming units (CFU)/mL. This intervention not only augmented the microbial density but also modified the metabolite composition of fermented milk, resulting in an elevated presence of advantageous flavor compounds such as nonanal, 2,3-pentanedione, and 3-methyl-2-butanone. However, its influence on improving the texture of fermented milk was observed to be minimal. Co-fermentation of L. salivarius CCFM 1266 with commercial fermentation starters indicated that L. salivarius CCFM 1266 was compatible, similarly altering metabolite composition and increasing niacin content in fermented milk. In summary, the findings suggest that L. salivarius CCFM 1266 holds substantial promise as an adjunctive fermentation starter, capable of enhancing the nutritional diversity of fermented milk products.

Neuroprotective effects of Anshen Bunao Syrup on cognitive dysfunction in Alzheimer's disease rat models.

Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup, a traditional Chinese medicine known for its neuroprotective properties, shows promise in addressing this need. However, understanding its precise mechanisms in AD remains elusive. This study aimed to investigate Anshen Bunao Syrup's therapeutic potential in AD treatment using a scopolamine-induced AD rat model. Assessments included novel-object recognition and Morris water maze tasks to evaluate spatial learning and memory, alongside Nissl staining and ELISA analyses for neuronal damage and biomarker levels. Results demonstrated that Anshen Bunao Syrup effectively mitigated cognitive dysfunction by inhibiting amyloid-ß and phosphorylation Tau aggregation, thereby reducing neuronal damage. Metabolomics profiling of rats cortex revealed alterations in key metabolites implicated in tryptophan and fatty acid metabolism pathways, suggesting a role in the therapeutic effects of Anshen Bunao Syrup. Additionally, ELISA and correlation analyses indicated attenuation of oxidative stress and immune response through metabolic remodeling. In conclusion, this study provides compelling evidence for the neuroprotective effects of Anshen Bunao Syrup in AD models, shedding light on its potential as a therapeutic agent for AD prevention and treatment.

[Research progress in preparations of Panax ginseng].

Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits, among which the roots are the most commonly used. The main active components of this medicinal plant include triterpenoid saponins, polysaccharides, peptides, and volatile oils. The chemical components and active metabolites endow this herb with a variety of pharmacological effects, and thus this herb is used to treat various diseases and play healthcare roles. Currently, a wide range of preparations of P. ginseng have been officially registered and marketed, including tablets, oral liquids, and injections, which demonstrate good clinical efficacy in regulating immunity, adjuvant treatment of tumors, alleviating fatigue, delaying the aging process, improving glucose and lipid metabolism, treating cardiovascular diseases, and relieving inflammation and pain. The production process and quality standards of these drugs are of great significance to ensure their efficacy. According to the theory that Ginseng Radix et Rhizoma can greatly replenish original Qi, tonify the spleen and lung, promote fluid production to quench thirst, tranquilize mind and enrich the intelligence, this paper systematically summarized the clinical application progress of P. ginseng and rela-ted preparations on the market and prospected the further development of preparations from P. ginseng, providing a reference for further exploring the medicinal value and healthcare function of this herb. The above contents, as an important basis for the in-depth development of P. ginseng and related drugs, increase the possibilities for the application of P. ginseng.

Two new phenolic amides from Allium chinense.

Objective: To isolate the phenolic amides from the dried bulbs of Allium chinense and investigate their myocardium protective activities. Methods: The chemical constituents were isolated and purified by combining with silica gel column, Sephadex LH-20 column, HPLC and other chromatography techniques. Their structures were elucidated by NMR techniques and mass spectrometry. The isolated compounds were evaluated to determine their protective effect for myocardium cells in vitro. Results: Two new phenolic amides, namely, alichinemide I (1) and alichinemide II (2), and six konwn amides were isolated from the dried bulbs of A. chinense. The structures of compounds 3-8 were identified as 3-indolcarbaldehyde (3), 1-(2-aminophenyl)urea (4), 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (5), N-trans-feruloyltyramine (6), N-trans-p-coumaroyltyramine (7), and N-(3,4-dimethoxyphenethyl) acetamide (8). Compound 3 (50 µmol/L) showed significant inhibitory effect on the damage of H9c2 myocardial cells induced by H2O2in vitro. Conclusion: Compounds 1 and 2 were new phenolic amides. Compound 3 could be one of the potential myocardium protective constituents of A. chinense.

Ligilactobacillus salivarius CCFM 1266 modulates gut microbiota and GPR109a-mediated immune suppression to attenuate immune checkpoint blockade-induced colitis.

The wide application of immune checkpoint blockade (ICB) therapy is impeded by the development of ICB-induced colitis, a condition intricately linked to alterations in the gut microbiota. In our previous study, Ligilactobacillus salivarius CCFM 1266 and Bacteroides fragilis HCK-B3 exhibited anti-inflammatory properties. In this research, treatment with both L. salivarius CCFM 1266 and B. fragilis HCK-B3 significantly ameliorated body weight loss and colonic inflammation in murine colitis models induced by intravenous ipilimumab injection, with L. salivarius CCFM 1266 demonstrating superior effectiveness. This amelioration was characterized by an augmented ratio of Treg cells and M2 macrophages, a diminishment in pro-inflammatory cytokines (IL-1ß, TNF-α, IFN-γ, IL-23), and an elevation in the anti-inflammatory cytokine IL-10. The ingestion of L. salivarius CCFM 1266 exerted a discernible influence on the composition of the gut microbiota. Untargeted metabolomics revealed an increase in colonic nicotinic acid levels following the administration of L. salivarius CCFM 1266, potentially initiating the activation of the colonic GPR109a pathway. This mechanism likely serves as the fundamental basis for the protective capacity of L. salivarius CCFM 1266 against ICB-induced colitis. Importantly, L. salivarius CCFM 1266 did not interfere with the anti-tumor immune response elicited by ipilimumab. Probiotic intervention thus emerges as a promising approach for alleviating ICB-induced colitis.

An extensive pharmacological evaluation of novel anti-nociceptive and IL-6 targeted anti-inflammatory guaiane-type sesquiterpenoids from Cinnamomum migao H. W. Li through in-depth in-vitro, ADMET, and molecular docking studies.

Guaiane-type sesquiterpenoids are most prevalent in the genus Cinnamomum. Hence this study investigates the structures, anti-nociceptive and IL-6 targeted anti-inflammatory potential of three novels C-14 guaiane-type sesquiterpenoids and two new monoterpenoids, isolated from Cinnamomum migao. The structures were precisely confirmed and characterized through the modern chromatographic and spectroscopic techniques of HRESIMS, 1D NMR, 2D NMR, experimental circular dichroism (ECD), and calculated (ECD). Novel sesquiterpenoids 1 and 2 exhibited significant anti-inflammatory activities against the NO production and pro-inflammatory cytokines. Their IC50 values were determined as 9.52 and 13.42 µΜ against IL-6 mRNA, respectively. Similarly, subcutaneous injection of n-BuT and EA extracts showed a dose-dependent suppression of formalin-induced tonic biting/licking responses during the tonic antinociceptive phase. Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of guaiane-type sesquiterpenoids 1 and 2 displayed that both compounds have a high level of GIT absorption, with a high zone of safety for cardiac and hepatotoxicity and no inhibition of cytochromes. In addition, molecular docking and simulation studies strengthen the anti-inflammatory potential of sesquiterpene 2 which showed a good binding affinity with IL-6 protein. Overall the inclusive results showed that the extracts and newly isolated guaiane-type sesquiterpenoids from C. migao will provide new evidence for the traditional use of this species to treat inflammation and nociception.

Investigation on the mechanism of Ginkgo Folium in the treatment of Non-alcoholic Fatty Liver Disease by strategy of network pharmacology and molecular docking.

BACKGROUND: Ginkgo Folium has a favorable effect on non-alcoholic fatty live disease (NAFLD), but its mechanism remains unclear. OBJECTIVE: The aim of this study is to reveal the underlying mechanism of Ginkgo Folium in the treatment of NAFLD. METHODS: Ingredients of Ginkgo Folium and ingredients-related genes were collected from TCMSP database and SwissTargetPrediction website, respectively. Genecards database was used to obtain NAFLD-related genes. Next, the protein-protein interaction network and key ingredients-genes network were constructed via Cytoscape3.7.0. Based on the Metascape website, gene ontology function analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were carried out for key genes. Finally, molecular docking was performed to present the interaction between components and genes using AutoDock Vina 1.1.2. RESULTS: Eighteen active ingredients and 10 target genes were screened from Ginkgo Folium. AKT1, TNF, EGFR, PTGS2, MAPK8, PPAγ, APP, ESR1, HIFα and PPAα were considered as potential therapeutic targets. These target genes were mainly enriched in insulin resistance, HIF-1, adipocytokine and AMPK signaling pathways. Molecular docking results suggested that Ginkgo Folium active ingredients including luteolin-4'-glucoside, sesamin, luteolin, chryseriol, isorhamnetin and laricitrin showed strong binding capacities with AKT1. CONCLUSION: The study showed that multi-components in Ginkgo Folium interacted with AKT1 and regulated AKT-AMPK/HIF pathway to alleviate NAFLD. Our findings provided an essential role and basis for new anti-NAFLD drug discovery and further research on Ginkgo Folium.

Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) remains a critical issue and a hindrance to clinical application of Tripterygium Glycosides Tablet (TGT) despite its favorable therapeutic efficacy in rheumatoid arthritis. Herein, we aimed to elucidate the molecular mechanisms underlying TGT-induced hepatotoxicity. METHODS: Chemical profiling of TGT was identified by UPLC-Q/TOF-MS/MS and its putative targets were predicted based on chemical structure similarity calculation. Following "DILI-related gene-TGT putative target" interaction network construction, a list of key network targets was screened according to nodes' topological importance and functional relevance. Both in vivo and in vitro experiments were performed to determine drug hepatotoxicity and the underlying mechanisms. RESULT: A total of 49 chemical components and 914 putative targets of TGTs were identified. Network calculation and functional modularization screened RAS-ERK and mTOR signalings-associated autophagy to be one of the candidate targets of TGT-induced hepatotoxicity. Experimentally, TGT significantly activated RAS-ERK axis, elevated the number of autophagosomes and the expression of LC3II protein, but reduced the expression of p62 protein and suppressed mTOR phosphorylation in the liver tissues of TGT-induced acute liver injury mice and chronic liver injury mice in vivo and AML12 cells in vitro. Moreover, TGT and mL-098 (an activator of RAS) co-treatment reduced AML12 cell viability via regulating autophagy and TGT-induced liver injury-related indicators more dramatically than TGT treatment alone, whereas Salirasib (an inhibitor of RAS) had an opposite effect. CONCLUSION: RAS-ERK-mTOR cross-talk may play a crucial role in TGT-induced hepatocyte autophagy, offering a promising target for developing novel therapeutics to combat TGT-induced hepatotoxicity.

Emerging Biopharmaceuticals from Pimpinella Genus.

Evolved over eons to encode biological assays, plants-derived natural products are still the first dawn of drugs. Most researchers have focused on natural compounds derived from commonly used Pimpinella species, such as P. anisum, P. thellungiana, P. saxifrage, and P. brachycarpa, to investigate their antioxidant, antibacterial, and anti-inflammatory properties. Ethnopharmacological studies demonstrated that the genus Pimpinella has the homology characteristics of medicine and food and mainly in the therapy of gastrointestinal dysfunction, respiratory diseases, deworming, and diuresis. The natural product investigation of Pimpinella spp. revealed numerous natural products containing phenylpropanoids, terpenoids, flavonoids, coumarins, sterols, and organic acids. These natural products have the potential to provide future drugs against crucial diseases, such as cancer, hypertension, microbial and insectile infections, and severe inflammations. It is an upcoming field of research to probe a novel and pharmaceutically clinical value on compounds from the genus Pimpinella. In this review, we attempt to summarize the present knowledge on the traditional applications, phytochemistry, and pharmacology of more than twenty-five species of the genus Pimpinella.

Metals-triggered compound CDPDP exhibits anti-arthritic behavior by downregulating the inflammatory cytokines, and modulating the oxidative storm in mice models with extensive ADMET, docking and simulation studies.

Triggering through abiotic stress, including chemical triggers like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metal Nickel on actinobacteria Streptomyces sp. SH-1327 to obtain a stress-derived compound was firstly investigated. A new compound cyclo-(D)-Pro-(D)-Phe (CDPDP) was triggered from the actinobacteria strain SH-1327 with the addition of nickel ions 1 mM. The stress compound was further evaluated for its anti-oxidant, analgesic, and anti-inflammatory activity against rheumatoid arthritis through in-vitro and in-vivo assays in albino mice. A remarkable in-vitro anti-oxidant potential of CDPDP was recorded with the IC50 value of 30.06 ± 5.11 µg/ml in DPPH, IC50 of 18.98 ± 2.91 against NO free radicals, the IC50 value of 27.15 ± 3.12 against scavenging ability and IC50 value of 28.40 ± 3.14 µg/ml for iron chelation capacity. Downregulation of pro-inflammatory mediators (NO and MDA), suppressed levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-Iß) and upregulation of expressions of anti-oxidant enzymes (GSH, catalase, and GST) unveiled its anti-inflammatory potential. CDPDP was analyzed in human chondrocyte cell line CHON-001 and the results demonstrated that CDPDP significantly increased cell survival, and inhibited apoptosis of IL-1ß treated chondrocytes and IL-1ß induced matrix degrading markers. In addition, to evaluate the mitochondrial fitness of CHON-001 cells, CDPDP significantly upregulated pgc1-α, the master regulator of mitochondrial biogenesis, indicating that CDPDP provides protective effects in CHON-001 cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the CDPDP showed that CDPDP is safe in cases of hepatotoxicity, cardiotoxicity, and cytochrome inhibition. Furthermore, docking results showed good binding of CDPDP with IL-6-17.4 kcal/mol, and the simulation studies proved the stability between ligand and protein. Therefore, the findings of the current study prospect CDPDP as a potent anti-oxidant and a plausible anti-arthritic agent with a strong pharmacokinetic and pharmacological profile.

Camganoids A and B, two new sesquiterpenes with different carbon skeletons isolated from fruits of Cinnamomum migao.

Objective: To isolate and identify the undescribed compounds from the fruits of Cinnamomum migao and evaluate its nitric oxide inhibition potential. Methods: The chromatographic techniques of silica gel, Sephadex, and HPLC were used for isolation and purification of the compounds, while HR-ESI-MS, 1D NMR, 2D NMR, ECD, and X-ray diffraction techniques were used to characterize and confirm the isolated compounds. Moreover, the anti-inflammatory activity of the isolated compounds was carried out to check inhibitory potential against the production of nitric oxide with RAW264.7 cells stimulated by LPS. Results: Camganoid A (1), a novel sesquiterpene possessing an unprecedented skeleton, and camganoid B (2), containing a unique eight-membered sesquiterpene moiety with a new carbon skeleton, were isolated and identified from the fruits of C. migao. The absolute configurations of 1 and 2 were confirmed by single crystal X-ray diffraction and electronic circular dichroism (ECD) calculations. Among these compounds, compound 1 exhibited potent inhibitory activity against the production of nitric oxide with IC50 value of 4.59 µmol/L in RAW264.7 cells stimulated by LPS. Conclusion: The isolation of two new skeletons from the fruits part of C. migao possessed unique skeletons which have not been reported before.

The Antifatigue Mechanism of Buyang-huanwu Decoction as Revealed by Serum Metabolomics in an Endurance Swimming Rat Model.

Buyang-huanwu decoction (BHD) is a classic prescription that has great potential to be developed into antifatigue functional food. It may activate blood circulation to relieve fatigue in some clinical cases by unclear mechanisms. In this study, a metabolomics approach was conducted to investigate the antifatigue mechanism of BHD. The murine fatigue model was established in rats by endurance swimming, and hemorheology, blood biochemistry, and ultraperformance liquid chromatography-mass spectrometry-based metabolomics were conducted on serum samples. The rate of weight gain, hemorheological parameters, and serum creatine kinase activities were significantly altered in model rats and they returned to a normal level after BHD administration. Pattern recognition screened 18 potential biomarkers, which are mainly involved in glycerophospholipid, arachidonic acid, and cholesterol metabolisms. The results demonstrate that the antifatigue mechanism of BHD is mainly related to the function of enhancing nerve conduction, relieving inflammation and regulating cholesterol metabolism and energy metabolism.

Chuanzhitongluo capsule ameliorates microcirculatory dysfunction in rats: Efficacy evaluation and metabolic profiles.

Background: Ischemic stroke is a leading cause of mortality and disability worldwide. Microcirculatory dysfunction is the foremost hindrance for a good clinical prognosis in ischemic stroke patients. Clinical researches show that Chuanzhitongluo capsule (CZTL) has a curative effect during the recovery period of ischemic stroke, which contributes to a good prognosis. However, it is not known whether CZTL treats ischemic stroke by ameliorating microcirculation dysfunction. Objective: In this study, we investigated the influence of CZTL on microcirculation and its underlying mechanism. Methods: A rat model of acute microcirculatory dysfunction was established by stimuli of adrenaline and ice water. The microcirculatory damage in model rats and the efficacy of CZTL were assessed by detecting laser speckle contrast imaging, coagulation function, hemorheology, vasomotor factor and microcirculation function. The potential mechanism of CZTL action was explored by the untargeted metabolomic analysis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry. Results: Laser speckle contrast imaging showed that model rats suffered low perfusion in ears, feet and tails, and CZTL treatment increased microcirculatory blood flow. Coagulation function detection results showed that CZTL diminished the reduction of thrombin time, prothrombin time, activated partial thromboplastin time and the elevated fibrinogen level caused by acute microcirculatory dysfunction. Furthermore, CZTL could recover the increased blood viscosity as well as the abnormal vasomotor and microcirculation function in rats with acute microcirculatory dysfunction. Metabolomics analysis indicated that CZTL might regulate sphingolipid metabolism and arachidonic acid metabolism to exert protective effects on microcirculation. Conclusion: These results elucidated that CZTL was highly effective against microcirculatory dysfunction and its potential mechanisms related with the modulation of sphingolipid and arachidonic acid metabolic pathways. The present study provided a new perspective on the clinical application of CZTL, and it contribute to explore novel therapeutic drug against microcirculatory dysfunction.

The effect of chronic exposure to a low concentration of perfluorooctanoic acid on cognitive function and intestinal health of obese mice induced by a high-fat diet.

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant associated with many adverse health risks. Evidence suggests that obese individuals may be more susceptible to environmental substances. In the present work, we explored the effects of PFOA exposure on the cognitive function and intestinal health of obese mice. Obese mice induced by a high-fat diet were exposed to PFOA (0.5 mg/kg (bw)/day) via drinking water for 100 days. After exposure to PFOA, decreased body weight, enlarged liver, abnormal behavior, impaired synapse structure, neuroinflammation, activated glial cell, decreased nerve growth factor, altered gut microbiota, and disturbed serum metabolites were observed, while the gut inflammation and intestinal barrier were not significantly influenced. These results suggest that exposure to PFOA is associated with cognitive impairment in obese mice.

[A new isoflavone from Dalbergia odorifera and inhibitory activity of its tyrosinase].

Twelve flavonoids were isolated and purified from the ethyl acetate fraction of 95% ethanol extract of Dalbergia odorifera by heat reflux extraction, solvent extraction, recrystallization, normal phase silica gel, Sephadex LH-20, MCI gel and HPLC methods. The structures were identified with multiple spectroscopic methods, including 1 D-NMR, 2 D-NMR and MS. The compounds were identified as 6,7,8-trimethoxy-5,4'-dihydroxy isoflavone(1), medicarpin(2), 7,2'-dihydroxy-4'-methoxy-isoflavanol(3), biochanin A(4), prunetin(5), genistein(6), pratensein(7), 3-(4-hydroxyphenyl)-6-isopentenyl-7-methoxy-4H-chromen-4-one(8), tectorigenin(9), irisolidone(10), vestitol(11), and formononetin(12). Compound 1 was a new isoflavone, and compound 8 was isolated from D. odorifera for the first time. The results showed that compounds 1-3 had inhibitory effects on tyrosinase, with inhibition rates of 35.58%, 38.63% and 51.34% at the concentration of 1.0 mmol·L~(-1), respectively.

Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression.

Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism remains unclear. The network pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms of action in the treatment of depression. Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone, and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. KEGG pathway analysis highlighted the most significant pathways associated with depression treatment, including neuroactive ligand-receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological process of GPCR signal transduction, hormone metabolism and nerve cell apoptosis. Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed greater binding ability with key antidepressant target 5-HTR. In conclusion, this study preliminarily revealed key active components in KXS, including Gomisin B, Asarone, Ginsenoside Rg1, Polygalaxanthone III and Pachymic acid, could interact with multiple targets (5-HTR, DR, ADRA, AR, ESR, NR3C1) and modulate the activation of multiple pathways (Neuroactive ligand -receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway).

Mechanisms of Zhenwu decoction for the treatment of renal fibrosis at various stages: What is the role of Corynebacterium?

Many studies demonstrated that Zhenwu decoction (ZWD) is effective in the treatment of kidney fibrosis, whereas the mechanism remains unclear. In this work, a microbiomics-based strategy was used to investigate the mechanism of protective effects of ZWD on kidney fibrosis. Unilateral ureteral obstruction was used to replicate a rat model of renal fibrosis, and rats were divided into prophylactic, early, and progression stages according to the timing of administration. Feces was collected to perform microbiota evaluation by high-throughput 16S DNA sequencing. The results indicated that Corynebacterium, Alistipes, Dorea, and Lactonifactor were highlighted as key targeted flora of ZWD in the treatment of renal fibrosis, and their biological functions were related to inflammation, immunity, and renal excretion. Especially, Corynebacterium presented a significant positive correlation with the concentration of Cys-C, Scr, and BUN. The studies on the changes in inflammatory cytokines (INF-γ, IL-1ß, IL-4, and TNF-α) and immunoglobulin (IgA, IgM, and IgG) confirmed the beneficial effects of ZWD on kidney fibrosis. Therefore, this study confirmed the protective effect of ZWD against renal fibrosis at various disease stages, and its mechanism was associated with re-establishing dysbiosis of the intestinal microbiota, reducing inflammation, as well as regulating immune functions. In particular, Corynebacterium may be a key flora in the treatment of renal fibrosis.

A Novel Drug Combination of Mangiferin and Cinnamic Acid Alleviates Rheumatoid Arthritis by Inhibiting TLR4/NFκB/NLRP3 Activation-Induced Pyroptosis.

Growing evidence shows that Baihu-Guizhi decoction (BHGZD), a traditional Chinese medicine (TCM)-originated disease-modifying anti-rheumatic prescription, may exert a satisfying clinical efficacy for rheumatoid arthritis (RA) therapy. In our previous studies, we verified its immunomodulatory and anti-inflammatory activities. However, bioactive compounds (BACs) of BHGZD and the underlying mechanisms remain unclear. Herein, an integrative research strategy combining UFLC-Q-TOF-MS/MS, gene expression profiling, network calculation, pharmacokinetic profiling, surface plasmon resonance, microscale thermophoresis, and pharmacological experiments was carried out to identify the putative targets of BHGZD and underlying BACs. After that, both in vitro and in vivo experiments were performed to determine the drug effects and pharmacological mechanisms. As a result, the calculation and functional modularization based on the interaction network of the "RA-related gene-BHGZD effective gene" screened the TLR4/PI3K/AKT/NFκB/NLRP3 signaling-mediated pyroptosis to be one of the candidate effective targets of BHGZD for reversing the imbalance network of "immune-inflammation" during RA progression. In addition, both mangiferin (MG) and cinnamic acid (CA) were identified as representative BACs acting on that target, for the strong binding affinities between compounds and target proteins, good pharmacokinetic features, and similar pharmacological effects to BHGZD. Notably, both BHGZD and the two-BAC combination of MG and CA effectively alleviated the disease severity of the adjuvant-induced arthritis-modified rat model, including elevating pain thresholds, relieving joint inflammation and bone erosion via inhibiting NF-κB via TLR4/PI3K/AKT signaling to suppress the activation of the NLRP3 inflammasome, leading to the downregulation of downstream caspase-1, the reduced release of IL-1ß and IL-18, and the modulation of GSDMD-mediated pyroptosis. Consistent data were obtained based on the in vitro pyroptosis cellular models of RAW264.7 and MH7A cells induced by LPS/ATP. In conclusion, these findings offer an evidence that the MG and CA combination identified from BHGZD may interact with TLR4/PI3K/AKT/NFκB signaling to inhibit NLRP3 inflammasome activation and modulate pyroptosis, which provides the novel representative BACs and pharmacological mechanisms of BHGZD against active RA. Our data may shed new light on the mechanisms of the TCM formulas and promote the modernization development of TCM and drug discovery.

Metabolomic and Microbial Remodeling by Shanmei Capsule Improves Hyperlipidemia in High Fat Food-Induced Mice.

Hyperlipidemia refers to a chronic disease caused by systemic metabolic disorder, and its pathophysiology is very complex. Shanmei capsule (SM) is a famous preparation with a long tradition of use for anti-hyperlipidemia treatment in China. However, the regulation mechanism of SM on hyperlipidemia has not been elucidated so far. In this study, a combination of UPLC-Q-TOF/MS techniques and 16S rDNA gene sequencing was performed to investigate the effects of SM treatment on plasma metabolism-mediated change and intestinal homeostasis. The results indicated that SM potently ameliorated high-fat diet-induced glucose and lipid metabolic disorders and reduced the histopathological injury. Pathway analysis indicated that alterations of differential metabolites were mainly involved in glycerophospholipid metabolism, linolenic acid metabolism, α-linoleic acid metabolism, and arachidonic acid metabolism. These changes were accompanied by a significant perturbation of intestinal microbiota characterized by marked increased microbial richness and changed microbiota composition. There were many genera illustrating strong correlations with hyperlipidemia-related markers (e.g., weight gains, GLU, and total cholesterol), including the Lachnospiraceae NK4A136 group and the Lachnospiraceae NK4B4 group. Overall, this study initially confirmed that hyperlipidemia is associated with metabolic disturbance and intestinal microbiota disorders, and SM can be employed to help decrease hyperlipidemia risk, including improving the abnormal metabolic profile and maintaining the gut microbial environment.

Three new guaiane-type sesquiterpenoids and a monoterpenoid from Litsea lancilimba Merr.

Three undescribed guaiane-type sesquiterpenes (1-3), and a monoterpenoid (4) along with eleven known compounds (5 - 15) were isolated from the crude extract of Litsea lancilimba Merr. The structures of all the isolated compounds were extensively elucidated on the basis of comprehensive spectroscopic techniques (HRESIMS, 1 D NMR, and 2 D NMR). Their relative and absolute configurations were comprehensively established by NOESY spectroscopy, circular dichroism (ECD) and the calculated ECD analysis. All the isolates were tested for anti-inflammatory activity by measuring the amount of nitric oxide production. Amongst tested compounds, compounds 1 - 3 exhibited moderate inhibitory activities against the production of nitric oxide with IC50 value of 35.5, 32.1, 46.7 µM in RAW264.7 cells stimulated by LPS, respectively.