Dahuang-Wumei decoction protects against hepatic encephalopathy in mice: Behavioural, biochemical, and molecular evidence.

BACKGROUND: Disturbance of the blood‒brain barrier (BBB) and associated inflammatory responses are observed in patients with hepatic encephalopathy (HE) and can cause long-term complications. Dahuang-Wumei decoction (DWD) is a renowned traditional Chinese herbal medicine with a long history of clinical use and has been widely employed as an effective treatment for hepatic encephalopathy (HE). Despite its established efficacy, the precise mechanisms underlying the therapeutic effects of DWD have not been fully elucidated. PURPOSE: The present study aimed to comprehensively explore the potential effects and underlying molecular mechanisms of DWD on HE through an integrated investigation that included both in vivo and in vitro experiments. METHODS: In the present study, carbon tetrachloride (CCl4) and thioacetamide (TAA) were used to establish an HE model in mice. The therapeutic effects of DWD on liver injury, fibrosis, brain injury, behaviour, and consciousness disorders were evaluated in vivo. C8-D1A and bEnd.3 cells were used to construct a BBB model in vitro. The effects of DWD on proinflammatory factor expression, BBB damage and the Wnt/ß-catenin pathway were detected in vivo and in vitro. RESULTS: Our results showed that DWD can improve liver injury and fibrosis and brain damage and inhibit neurofunctional and behavioural disorders in mice with HE. Afterwards, we found that DWD decreased the levels of proinflammatory factors and suppressed BBB disruption by increasing the levels of junction proteins in vivo and vitro. Further studies verified that the Wnt/ß-catenin pathway may play a pivotal role in mediating the inhibitory effect of DWD on HE. CONCLUSION: These results demonstrated that DWD can treat HE by preventing BBB disruption, and the underlying mechanisms involved were associated with the activation of the Wnt/ß-catenin pathway and the inhibition of inflammatory responses.

Mechanisms of NLRP3 inflammasome in rheumatoid arthritis and osteoarthritis and the effects of traditional Chinese medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: It has been widely reported that various anti-rheumatic traditional Chinese medicines (TCMs) ameliorate rheumatoid arthritis (RA) and osteoarthritis (OA) through regulating the abnormal production, assembly, and activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome. These TCMs include monomers isolated from Chinese herbs, extracts of Chinese herbs, and Chinese medical formulae with a lengthy application history. AIM OF THE STUDY: This review aimed to summarize and analyze the published articles about the NLRP3 inflammasome and its role in the pathogenesis of RA and OA. We also reviewed existing knowledge on the therapeutic mechanism of TCMs in RA and OA via the regulation of the NLRP3 inflammasome. MATERIALS AND METHODS: We searched for relevant articles with the keywords "NLRP3 inflammasome", "traditional Chinese medicine," "Chinese herbal drugs," "rheumatoid arthritis," and "osteoarthritis." The information retrieval was conducted in medical Chinese and English databases from the date of construction to April 19, 2023, including PubMed, MEDLINE, Web of Science, Scopus, Ovid, China National Knowledge Infrastructure (CNKI), Chinese Biomedicine Literature Database (CBM), Chinese Science and Technology Periodicals Database (VIP), and China Online Journals (COJ). RESULTS: According to retrieval results, 35 TCMs have been demonstrated to relieve RA by targeting the NLRP3 inflammasome, including six traditional Chinese prescriptions, seven extracts of Chinese herbs, and 22 monomers extracted from traditional Chinese herbs and formulae. Additionally, 23 TCMs have shown anti-OA effects with abilities to modulate the NLRP3 inflammasome, including five traditional Chinese prescriptions, one extract of Chinese herbs, and 17 monomers from Chinese herbs. CONCLUSIONS: We summarized mechanism research about the pivotal roles of the NLRP3 inflammasome in the pathogenesis of RA and OA. Moreover, a review of TCMs with targets of the NLRP3 inflammasome in RA and OA treatment was also conducted. Our work is conducive to a better application of TCMs in complementary and alternative therapies in RA and OA.

The mechanism and application of traditional Chinese medicine extracts in the treatment of lung cancer and other lung-related diseases.

Lung cancer stands as one of the most prevalent malignancies worldwide, bearing the highest morbidity and mortality rates among all malignant tumors. The treatment of lung cancer primarily encompasses surgical procedures, radiotherapy, and chemotherapy, which are fraught with significant side effects, unfavorable prognoses, and a heightened risk of metastasis and relapse. Although targeted therapy and immunotherapy have gradually gained prominence in lung cancer treatment, diversifying the array of available methods, the overall recovery and survival rates for lung cancer patients remain suboptimal. Presently, with a holistic approach and a focus on syndrome differentiation and treatment, Traditional Chinese Medicine (TCM) has emerged as a pivotal player in the prognosis of cancer patients. TCM possesses characteristics such as targeting multiple aspects, addressing a wide range of concerns, and minimizing toxic side effects. Research demonstrates that Traditional Chinese Medicine can significantly contribute to the treatment or serve as an adjunct to chemotherapy for lung cancer and other lung-related diseases. This is achieved through mechanisms like inhibiting tumor cell proliferation, inducing tumor cell apoptosis, suppressing tumor angiogenesis, influencing the cellular microenvironment, regulating immune system function, impacting signal transduction pathways, and reversing multidrug resistance in tumor cells. In this article, we offer an overview of the advancements in research concerning Traditional Chinese Medicine extracts for the treatment or adjunctive chemotherapy of lung cancer and other lung-related conditions. Furthermore, we delve into the challenges that Traditional Chinese Medicine extracts face in lung cancer treatment, laying the foundation for the development of diagnostic, prognostic, and therapeutic targets.

Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). FINDINGS: Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. INTERPRETATION: This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. FUNDING: National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Molecular Mechanism of the Therapeutic Effect of Peach Blossom against Constipation: An Exploratory Study Based on Network Pharmacology Analysis and Molecular Docking Verification.

Objective: The aim of the study is to verify the active ingredients of peach blossom and to explore the molecular mechanisms of their therapeutic effects against constipation through network pharmacology and molecular docking analysis. Methods: The potential active ingredients of peach blossom were identified from published literature and the BAT-TCM database, and their potential targets were predicted using the SwissTargetPrediction and PharmMapper platforms. In addition, targets related to constipation were retrieved using OMIM, DrugBank, GeneCards, TTD, and DisGeNET databases. The intersection of drug targets and disease targets was considered as the potential targets of peach blossom in the treatment of constipation. The STRING platform was used to construct a protein interaction network. Gene ontology (GO) functional analysis and KEGG pathway enrichment analysis were performed on key targets using the DAVID database. Molecular docking verification between the active ingredients of peach blossom and the targets was conducted using AutoDock software. Results: A total of 33 active ingredients of peach blossom and 185 corresponding targets were identified, and 88 intersection targets were obtained after Venny mapping. These 33 active ingredients (including naringenin, aromadendrin, and cordycepin) in peach blossom may play a role in the treatment of constipation by regulating signaling pathways through targets such as EGFR, VEGFA, ESR1, GSTP1, and PTGS2. Conclusion: A variety of active ingredients of peach blossom regulate multiple signaling pathways by acting on targets, which reflects the characteristic of "multiple ingredients-multiple targets-multiple pathways," thereby playing a role in the treatment of constipation.

Interaction of gut microbiota with the tumor microenvironment: A new strategy for antitumor treatment and traditional Chinese medicine in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the second leading cause of cancer-related death. In recent years, the relationship between gut microbiota and CRC has attracted increasing attention from researchers. Studies reported that changes in the composition of gut microbiota, such as increase in the number of Fusobacterium nucleatum and Helicobacter hepaticus, impair the immune surveillance by affecting the intestinal mucosal immunity and increase the risk of tumor initiation and progression. The tumor microenvironment is the soil for tumor survival. Close contacts between gut microbiota and the tumor microenvironment may directly affect the progression of tumors and efficacy of antitumor drugs, thus influencing the prognosis of patients with CRC. Recently, many studies have shown that traditional Chinese medicine can safely and effectively improve the efficacy of antitumor drugs, potentially through remodeling of the tumor microenvironment by regulated gut microbiota. This article describes the effect of gut microbiota on the tumor microenvironment and possible mechanisms concerning the initiation and progression of CRC, and summarizes the potential role of traditional Chinese medicine.

Exploring the relationship between intestinal flora and the pathological mechanism of myopia in adolescents from the perspective of Chinese and Western medicine: A review.

The etiology of adolescent myopia involves genetic and environmental factors. The pathological mechanism of modern medicine includes blood perfusion, changes in blood molecules, neurotransmitters, and sclera remodeling. Chinese medicine believes that myopia is mainly related to the deficiency of liver blood and spleen and stomach disorders. The prevention and treatment of myopia in adolescents are very important, but in terms of the current incidence of myopia in adolescents and the level of clinical diagnosis and treatment, its prevention and treatment are insufficient. Modern medicine and traditional Chinese medicine both pay attention to integrity, so adolescent myopia should not only pay attention to eye changes but also pay attention to other body systems and other aspects of change. Intestinal flora has become a research hotspot in recent years, and it has been found that it is closely associated with multi-system and multi-type diseases. No studies have directly investigated the link between Intestinal flora and myopia in adolescents. Therefore, by summarizing the pathological mechanism of adolescent myopia and the connection between intestinal flora and the pathological mechanism of adolescent myopia, this paper analyzes the possible pathological mechanism of the influence of intestinal flora on adolescent myopia, providing a theoretical basis for future studies on the correlation between changes of intestinal flora and its metabolites and the incidence of adolescent myopia, which is of great significance for the study on the risk prediction of adolescent myopia.

Simiao pill attenuates collagen-induced arthritis and bleomycin-induced pulmonary fibrosis in mice by suppressing the JAK2/STAT3 and TGF-ß/Smad2/3 signalling pathway.

ETHNOPHAMACOLOGICAL RELEVANCE: Simiao Pill (SM) as a classic prescription of traditional Chinese medicine treatment of damp-heat arthralgia, the earliest from 'Cheng Fan Bian Du ', written by the Qing Dynasty doctor Zhang Bingcheng. Previous studies have shown that SM has obvious curative effect on rheumatoid arthritis, which provides a basis for the application of SM in rheumatoid arthritis related complications. AIM OF THE STUDY: Interstitial lung disease (ILD), as the most severe complication of rheumatoid arthritis (RA), lacks effective clinical treatments and a corresponding animal model. Simiao pill (SM) is a traditional Chinese medicine prescription extensively used as a complementary and alternative treatment for RA. However, the effect and mechanism of SM on RA-ILD have not yet been reported. This study aimed to investigate an appropriate animal model that can simulate RA-ILD, and the efficacy, safety, and mechanism of SM on RA-ILD. METHODS: Collagen-induced arthritis (CIA) and bleomycin-induced pulmonary fibrosis model were combined to construct the CIA-BLM model. After the intervention of SM, the protective effects of SM on RA-ILD were determined by detecting the CIA mouse arthritis index (AI), Spleen index, and the extent of pulmonary fibrosis. The joint inflammation and pulmonary fibrosis were detected by immunohistochemistry, H&E staining, safranin- O fast green Sirius red staining, trap staining, and Masson staining. Finally, the mechanism was verified by Western blot and immunohistochemistry. RESULTS: Our work showed that SM significantly reduced joint swelling, arthritis index, pulmonary fibrosis score, and spleen index in CIA mice. The pathological examination results indicated Si-Miao Pill suppressed inflammation, pulmonary fibrosis, bone erosion, and cartilage degradation of the ankle joint. Besides, SM up-regulated expressions of E-cadherin, whereas down-regulated expressions of α-SMA. Further studies confirmed that SM regulated JAK2/STAT3 and TGF-ß/SMAD2/3. CONCLUSION: SM can not only effectively improve joint inflammation by JAK2/STAT3 Pathway but also inhibit pulmonary fibrosis by TGF-ß/SMAD2/3. The fibrosis induced by CIA-BLM model was more stable and obvious than that induced by CIA model alone.

Advances of berberine against metabolic syndrome-associated kidney disease: Regarding effect and mechanism.

The prevalence of metabolic syndrome (MetS) is drastically growing worldwide, resulting in MetS-associated kidney disease. According to traditional theories, preventing blood pressure, lipid, glycose, and obesity and improving insulin resistance (IR), a couple of medications are required for MetS. It not only lowers patients' compliance but also elevates adverse reactions. Accordingly, we attempted to seek answers from complementary and alternative medicine. Ultimately, berberine (BBR) was chosen due to its efficacy and safety on MetS through multi-pathways and multi-targets. The effects and mechanisms of BBR on obesity, IR, diabetic nephropathy, hypertension, hyperlipidemia, and hyperuricemia were elaborated. In addition, the overall properties of BBR and interventions for various kidney diseases were also collected. However, more clinical trials are expected to further identify the beneficial effects of BBR.

Wutou decoction attenuates the synovial inflammation of collagen-induced arthritis rats via regulating macrophage M1/M2 type polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: Thousands of years of clinical practice in the treatment of joint-related diseases support the efficacy and safety of Wutou decoction (WTD). Nevertheless, the lack of pharmacological evidence and unclear mechanisms make it difficult for WTD to become a recognized complementary therapy for the treatment of rheumatoid arthritis (RA). AIM OF THE STUDY: This study aimed to investigate the effect of WTD against synovial inflammation in RA and whether this effect depends on the regulation of macrophage polarization. MATERIALS AND METHODS: Sprague-Dawley rats were used to establish the collagen-induced arthritis (CIA) model. WTD with low and high doses was administered for 45 days. RAW264.7 cells were stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4 to polarize M1 and M2 macrophages, which were pre-treated with WTD extract for 4 h. The anti-arthritic and anti-inflammatory effects of WTD were studied using arthritis score, histopathological staining, immunostaining, and enzyme-linked immunosorbent assay (ELISA). The polarization state of RAW264.7 cells and related pro/anti-inflammatory cytokines was detected by ELISA, reverse transcription quantitative polymerase chain reaction and western blotting. Western blotting and immunofluorescence were used to investigate the effect of WTD on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptors γ (PPARγ) activation both in vivo and in vitro. RESULTS: WTD significantly reduced the arthritis score and the pathological damage of the knee joint and decreased the expression of tumor necrosis factor alpha (TNF-α), IL-6 in serum, TNF-α, IL-1ß, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-3 (MMP3) in the knee synovium. WTD inhibited M1 type polarization and promoted M2 type polarization, both in vitro and in vivo, and reduced the expression of pro-inflammatory cytokines while increasing the expression of anti-inflammatory cytokines. Experiments showed that WTD inhibited the phosphorylation of NF-κB and downstream p38 in the synovium of CIA rats and LPS-induced M1 type polarized RAW264.7 cells. In addition, PPARγ expression in the synovium of CIA rats was mainly located in the cytoplasm, and WTD treatment increased the nuclear translocation of PPARγ, which was further verified in RAW264.7 cells. CONCLUSIONS: NF-κB and PPARγ regulating M1 and M2 macrophage polarization and subsequent secretion of pro-inflammatory and anti-inflammatory cytokines are the underlying mechanisms of WTD that ameliorate RA synovial inflammation.

Potential molecular mechanisms of Ermiao san in the treatment of hyperuricemia and gout based on network pharmacology with molecular docking.

A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of Ermiao san in the treatment of hyperuricemia and gout. Traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform were used to screen out the active compounds and their targets of Ermiao san. The disease target genes related to hyperuricemia (HUA) and gout were obtained by searching CTD, DisGeNET, DrugBank, GeneCards, OMIM, TTD, and PharmGKB databases with "Hyperuricemia" and "Gout" as keywords, respectively. The potential targets of Ermiao san in the treatment of HUA and gout were screened through a Venn diagram. The protein-protein interaction network was constructed using Cytoscape software. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were then conducted. Finally, some compounds and core targets were selected for molecular docking verification by Autodock Vina and Pymol software. Forty-six active compounds, such as quercetin, wogonin and beta-sitosterol, etc were identified. Ermiao san plays a therapeutic role in HUA and gout regulating various biological processes, cellular compounds, and molecular functions. The core targets of Ermiao san for treating HUA and gout are AT1 (namely Protein Kinase Bα), interleukin-1 beta, prostaglandin-endoperoxide synthase 2, JUN, etc. And the key pathways are nuclear factor-κB, interleukin-17 and tumor necrosis factor. The results of molecular docking analyses suggested that active compounds of Ermiao san could bind well to the core protein receptors. Ermiao san has a synergistic mechanism of multiple compounds, multiple targets, and multiple pathways in the treatment of HUA and gout, which provides a good theoretical basis for the clinical application.

Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: VEGF inhibitors can enhance the efficacy of immunotherapy. However, despite high initial response rates, almost all patients eventually develop treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of patients with locally advanced or metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase inhibitor therapy. METHODS: This randomised, double-blind, multicentre, phase 3 trial was conducted at 52 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC and EGFRmut who progressed after receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology Group performance status of 0 or 1 with at least one measurable lesion, and an estimated life expectancy of at least 3 months. Participants were randomly assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block randomisation with stratification according to sex and presence or absence of brain metastases. All study drugs were administered intravenously on day 1 of each cycle, once every 3 weeks. Except for cisplatin, which was only given in the first four cycles, treatment was given for 24 months or until disease progression, intolerable toxic effects, withdrawal of consent, death, or other protocol-specified conditions, whichever occurred first. The primary endpoint was progression-free survival in the intention-to-treat population. We herein report the first planned interim analysis, with progression-free survival results for the comparison between sintilimab plus IBI305 plus chemotherapy versus chemotherapy alone. The progression-free survival results for the sintilimab plus pemetrexed and cisplatin group are immature and not reported here. This study is registered with ClinicalTrials.gov, NCT03802240 (recruiting). FINDINGS: Between July 11, 2019, and July 31, 2021, 936 patients were screened and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to the chemotherapy alone group). Data cutoff for this interim analysis was July 31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3), progression-free survival was significantly longer in the sintilimab plus IBI305 plus chemotherapy group versus the chemotherapy alone group (median 6·9 months [95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64]; p<0·0001). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27 [18%] in the chemotherapy alone group), decreased white blood cell count (17 [11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]). Potentially treatment-related deaths occurred in six patients (intestinal obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus chemotherapy group, and in one patient in the chemotherapy alone group (unknown cause). INTERPRETATION: In this interim analysis, sintilimab plus IBI305 plus cisplatin and pemetrexed was generally efficacious and well tolerated in patients with EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor therapy. FUNDING: Innovent Biologics and the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Acquired coagulation dysfunction resulting from vitamin K-dependent coagulation factor deficiency associated with rheumatoid arthritis: A case report.

BACKGROUND: Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease with the main clinical feature of progressive joint synovial inflammation, which can lead to joint deformities as well as disability. RA often causes damage to multiple organs and systems within the body, including the blood hemostasis system. Few reports have focused on acquired coagulation dysfunction resulting from vitamin K-dependent coagulation factor deficiency associated with RA. CASE SUMMARY: A 64-year-old woman with a history of RA presented to our hospital, complaining of painless gross hematuria for 2 wk. Blood coagulation function tests showed increased prothrombin time, international normalized ratio, and activated partial thromboplastin time. Abnormal blood coagulation factor (F) activity was detected (FII, 7.0%; FV, 122.0%; and FX, 6.0%), indicating vitamin K-dependent coagulation factor deficiency. Thromboelastography and an activated partial thromboplastin time mixed correction experiment also suggested decreased coagulation factor activity. Clinically, the patient was initially diagnosed with hematuria, RA, and vitamin K-dependent coagulation factor deficiency. The patient received daily intravenous administration of vitamin K1 20 mg, etamsylate 3 g, and vitamin C 3000 mg for 10 d. Concurrently, oral leflunomide tablets and prednisone were administered for treatment of RA. After the treatment, the patient's symptoms improved markedly and she was discharged on day 12. There were no hemorrhagic events during 18 mo of follow- up. CONCLUSION: RA can result in vitamin K-dependent coagulation factor deficiency, which leads to acquired coagulation dysfunction. Vitamin K1 supplementation has an obvious effect on coagulation dysfunction under these circumstances.

Side-Chain-Tuned Molecular Packing Allows Concurrently Boosted Photoacoustic Imaging and NIR-II Fluorescence.

It is generally considered that photoacoustic imaging (PAI) and fluorescence imaging (FLI) cannot be enhanced concurrently, as they are dependent on competitive photophysical processes at the single-molecule level. Herein, we reveal that BDTR9-OC8 and BDTR9-C8, which have identical π-conjugated backbones but are substituted by side chains of different rigidity, show distinct phototheranostic properties in the aggregated state. The NIR-II FLI and PAI brightness of BDTR9-C8 nanoparticles are enhanced by 4.6 and 1.4 times compared with BDTR9-OC8 nanoparticles. Theoretical calculations and GIWAXS analysis revealed that BDTR9-C8 with rigid side chains shows a relative amorphous condensed state, which will benefit the efficient transportation of photo-generated excitons and phonons, subsequently enhancing the FLI and PAI signals. Besides, both nanoparticles exhibit excellent photothermal conversion efficiency due to their strong light-harvesting capability and are considered effective photothermal therapy materials. This work provides an illuminating strategy for material design in the future.

Potential Implications of Quercetin in Autoimmune Diseases.

Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.

Quercetin-mediated SIRT1 activation attenuates collagen-induced mice arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Herba taxilli (HT, Sangjisheng in Chinese), which is composed of the dried stems and leaves of Taxillus chinensis (DC.) Danser, has been commonly used to treat inflammation and arthritis in traditional Chinese medicine (TCM). Quercetin (Que) is a major active flavonoid component isolated from HT and is one of the quality control indexes of HT. In the clinical practice of TCM, formulas containing HT are commonly used to treat rheumatoid arthritis (RA). Recent studies have shown that Que exerts antiarthritic effects. However, the mechanism by which Que treatment affects RA is not fully understood. AIM OF THE STUDY: This study aimed to explore the antiarthritic activity of Que in a collagen-induced arthritis (CIA) mouse model and investigate the underlying mechanisms. MATERIALS AND METHODS: The antiarthritic activity of Que was evaluated in a CIA mouse model by determining the paw clinical arthritis scores and left ankle thicknesses and by conducting micro-PET imaging and histopathological analysis of ankle joint tissues. The proinflammatory cytokine (IL-6, TNF-α, IL-1ß, IL-8, IL-13, IL-17) levels in the serum and ankle joint tissues were measured by ELISA. Mitochondrial oxidative stress was assessed by biochemical methods. Mitochondrial biogenesis was analysed by RT-qPCR. The protein levels of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), p38, phospho-p38, extracellular signal-regulated kinases (ERK)-1/2, phospho-ERK1/2, p65, and phospho-p65 in ankle joint tissues were detected by Western blot analysis. A total of 30 RA patients were recruited to investigate the relationship between the disease activity score (DAS28) and the SIRT1, PGC-1α, NRF1, and HMGB1 plasma levels. RESULTS: Que treatment decreased the clinical score and left ankle thickness of CIA mice, attenuated the synovial inflammation and hyperplasia and bone/cartilage destruction in ankle joints, and decreased the secretion of IL-6, TNF-α, IL-1ß, IL-8, IL-13, and IL-17. Mechanistically, Que treatment improved impaired mitochondrial biogenesis and mitochondrial function by regulating the SIRT1/PGC-1α/NRF1/TFAM pathway and inhibited inflammation via the HMGB1/TLR4/p38/ERK1/2/NF-κB p65 pathway. Notably, epidemiological data revealed correlations between abnormal circulating levels of SIRT1, PGC-1α, NRF1, HMGB1 and RA disease activity in patients. CONCLUSIONS: Our data suggested a potential role of Que as a dietary therapeutic drug for RA treatment that may act through SIRT1 to target mitochondrial biogenesis. Additionally, the role of impaired mitochondrial biogenesis in RA was evaluated.

Effect of manipulative reduction combined with air enema on intestinal mucosal immune function in children with intussusception.

OBJECTIVE: To explore the effect of manipulative reduction combined with air enema on intestinal mucosal immune function in children with intussusception. METHODS: This is a prospective randomized controlled study in which 60 children with primary intussusception admitted to Hebei Children's Hospital from October 2018 to October 2019 were selected for this study. They were randomly divided into two groups. The 30 patients in the experimental group underwent manipulative reduction and air enema reduction, and 30 patients in the control group underwent only air enema reduction. Pain scores and pressure during enema were recorded and analyzed. Fasting blood of children in the experimental group were drawn to test the serum T lymphocyte subsets CD3+, CD4+, CD8+ levels, B lymphocyte subsets CD19+ level, and NK cell subsets CD56+ levels before reduction. Among them, fasting blood of 28 children with successful reduction were drawn again in the morning after reduction, and the indicators of each immune cell subgroup before and after reduction were analyzed. Two children with unsuccessful reduction were no longer tested for these indicators. RESULTS: Twenty-Eight children in the experimental group had successful reduction, and two children with unsuccessful reduction were changed to open surgery (28/30). Twenty five Children in the control group had successful reduction, and five were changed to open surgery (25/30). There was no significant difference in the success rate of reduction between two groups (p>0.05). Close observation for 12~24h after reduction found that none of the children had signs of peritonitis. The pain score and reduction pressure of the observation group were lower than those of the control group, and the difference was statistically significant (p<0.05). The levels of serum CD3+, CD4+, and CD8+ after reduction in the experimental group were significantly higher than before reduction, and the difference was statistically significant (p<0.05). CD19+ level was significantly lower than before reduction, and the difference was statistically significant (p<0.05). There was no significant difference in changes of other indicators. CONCLUSIONS: Manipulative reduction combined with air enema reduction can relieve pain and air injection pressure during enema, reduce reperfusion injury caused by intestinal ischemia, and protect intestinal mucosal immune function, which is a favored treatment.

Effectiveness comparisons of Chinese patent medicine on treating premature ejaculation: A systematic review and meta-analysis.

BACKGROUND: Premature ejaculation (PE) is a form of male sexual dysfunction. As people's lifestyle changes and the population ages, the incidence of PE continues to increase. Chinese patent medicines have been widely used in clinical practice as derivatives of traditional Chinese medicine (TCM). Many clinical trials have proven that Chinese patent medicine has a significant effect in the treatment of PE. In this systematic review, we aim to evaluate the effectiveness and safety of Chinese patent medicine for PE. METHODS: We will search for PubMed, Cochrane Library, AMED, Embase, WorldSciNet, Nature, Science online and China Journal Full-text Database, China Biomedical Literature CD-ROM Database, and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to September 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the RevMan 5.3 and Stata 13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of PE. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of TCM for treating PE. Because all of the data used in this systematic review and meta-analysis have been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial. TRIAL REGISTRATION NUMBER: PROSPERO CRD42017065316.

Curcumin Suppresses Hepatic Stellate Cell-Induced Hepatocarcinoma Angiogenesis and Invasion through Downregulating CTGF.

Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1α (HIF-1α) expression to promote angiogenesis, epithelial to mesenchymal transition (EMT) process and invasion. And HSCs could secrete soluble factors, such as interleukin-6 (IL-6), vascular endothelial cell growth factor (VEGF), and stromal-derived factor-1 (SDF-1) to facilitate HCC progression. Curcumin could significantly suppress the above HSC-induced effects in HCC and could abrogate ROS and HIF-1α expression in HCC. HIF-1α or connective tissue growth factor (CTGF) knockdown could abolish the aforementioned curcumin affection. Moreover, CTGF is a downstream gene of HIF-1α. In addition, nuclear factor E2-related factor 2 (Nrf2) and glutathione (GSH) are involved in curcumin protection of HCC. These data indicate that curcumin may induce ROS scavenging by upregulating Nrf2 and GSH, thus inhibiting HIF-1α stabilization to suppress CTGF expression to exhibit its protection on HCC. Curcumin has a promising therapeutic effect on HCC. CTGF is responsible for curcumin-induced protection in HCC.

The safety and efficacy of acupuncture for epididymitis protocol for a systematic review.

BACKGROUND: Epididymitis is a common disease in non-specific infections of the male reproductive system. According to the clinical incidence of acute epididymitis and chronic epididymitis, which is more common in chronic epididymitis. There are many clinical trials confirmed that acupuncture treatment can relieve pain and improve symptoms of epididymitis to some extent. In this systematic review, we aim to evaluate the effectiveness and safety of acupuncture for epididymitis. METHODS AND ANALYSIS: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to November 2018. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of epididymitis. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of acupuncture for epididymitis. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process trial. REGISTRATION NUMBER: PROSPERO CRD42018111348.