Integrating clinical data mining, network analysis and experimental validation reveal the anti-inflammatory mechanism of Huangqin Qingre Chubi Capsule in rheumatoid arthritis treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Chubi Capsule (HQC) is a Chinese medicinal compound used for the treatment of damp-heat pattern rheumatism, guided by the traditional Chinese medicine syndrome differentiation practice. HQC has been used in the clinical treatment of rheumatic diseases for more than 20 years with remarkable efficacy. HQC has been experimentally shown to exert anti-arthritic effects via the Wnt signaling pathway. AIM OF THE STUDY: This study used clinical data mining, network analysis, and in vitro and in vivo tests to investigate the anti-arthritic and possible anti-inflammatory mechanism of HQC. Specifically, emphasis was placed on the function of the hsa_circ_0091,685/EIF4A3/IL-17 axis in the anti-inflammatory process. MATERIALS AND METHODS: A random walk model was used to evaluate the effects of HQC on clinical immune inflammatory marker function in patients with RA. Network analysis was used to predict the potential target genes and pathways of HQC. Hematoxylin & eosin, safranin O-fast green and toluidine blue staining, immunohistochemistry, and transmission electron microscopy were performed to evaluate the anti-arthritic effects of HQC in rat models. Cell Counting Kit-8 assay, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and RNA pull-down were used to study the anti-proliferation and anti-inflammatory mechanisms of HQC. RESULTS: Patients with RA who underwent HQC treatment showed a significant reduction in inflammatory response levels, according to retrospective clinical study. Network analysis revealed that HQC potentially targeted genes and pathways related to inflammation, especially IL-6, IL-17, TNF-α, IL-23, and IL-17 signaling pathway. Animal experiments showed that HQC inhibits inflammation through the IL-17 signaling pathway in rat models. Cellular experiments showed that HQC-containing serum inhibited the inflammatory response in patients with RA-FLS or RA by blocking hsa_circ_0091,685 and EIF4A3 expression. CONCLUSION: In RA patients, HQC reduces the inflammatory response. The antiproliferative and anti-inflammatory qualities of HQC are responsible for its therapeutic impact. The suppression of the hsa_circ_0091,685/EIF4A3/IL-17 axis was linked to these favorable outcomes.

Association between traditional Chinese Medicine and osteoarthritis outcome: A 5-year matched cohort study.

Objective: The aim of this study was to investigate the relationship between Traditional Chinese medicine (TCM) and pain reduction, hospital readmission, and joint replacement in patients with osteoarthritis (OA). Chinese herbal medicine (CHM) prescription patterns were further analyzed to confirm the association with prognosis and quality of life in OA patients. Methods: We retrospectively followed 3,850 hospitalized patients with osteoarthritis between January 2018 and December 2022 using the hospital's HIS system. Propensity score matching (PSM) was used for data matching. Cox's proportional risk model was used to assess the impact of various factors on the outcomes of patients with OA, including pain worsening, readmission, and joint replacement. The Kaplan-Meier survival curve was applied to determine the impact of TCM intervention time on patient outcomes. Data mining methods including association rules, cluster analysis, and random walks have been used to assess the efficacy of TCM. Results: The utilization rate of TCM in OA patients was 67.01% (2,511/3,747). After PSM matching, 1,228 TCM non-user patients and 1,228 TCM user patients were eventually included. The outcomes of pain worsening, re-admission rate, and joint replacement rate of the TCM non-user group were observably higher than those of the TCM user group with OA (p < 0.05). Based on the Cox proportional risk model, TCM is an independent protective factor. Compared with non-TCM users, TCM users had 58.4% lower rates of pain, 51.1% lower rates of re-admission, and 42% lower rates of joint replacement. In addition, patients in the high-exposure subgroup (TCM＞24 months) had a markedly lower risk of outcome events than those in the low-exposure subgroup (TCM ≤24 months). Data mining methods have shown that TCM therapy can significantly improve immune-inflammatory indices, VAS scores, and SF-36 scale scores in OA patients. Conclusion: s TCM acts as a protective factor to improve the prognosis of patients with OA, and the benefits of long-term use of herbal medicines are even greater.

Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

Novel XIAP mutation with early-onset Crohn's disease complicated with acute heart failure: a case report.

BACKGROUND: The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn's disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure. CASE PRESENTATION: A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient's condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient's condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. CONCLUSION: A novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn's disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.

Quercetin serves as the major component of Xiang-lian Pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARγ and dictating the alternative activation of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. AIM OF THE STUDY: To evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. MATERIALS AND METHODS: Colitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. RESULTS: Oral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARγ signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARγ signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-γ induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARγ dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. CONCLUSION: Our findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARγ, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment.

Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer.

BACKGROUND: Excessive extracellular matrix (ECM) deposition in pancreatic ductal adenocarcinoma (PDAC) severely limits therapeutic drug penetration into tumors and is associated with poor prognosis. Collagen is the most abundant matrix protein in the tumor ECM, which is the main obstacle that severely hinders the diffusion of chemotherapeutic drugs or nanomedicines. METHODS: We designed a collagenase-functionalized biomimetic drug-loaded Au nanoplatform that combined ECM degradation, active targeting, immune evasion, near-infrared (NIR) light-triggered drug release, and synergistic antitumor therapy and diagnosis into one nanoplatform. PDAC tumor cell membranes were extracted and coated onto doxorubicin (Dox)-loaded Au nanocages, and then collagenase was added to functionalize the cell membrane through lipid insertion. We evaluated the physicochemical properties, in vitro and in vivo targeting, penetration and therapeutic efficacy of the nanoplatform. RESULTS: Upon intravenous injection, this nanoplatform efficiently targeted the tumor through the homologous targeting properties of the coated cell membrane. During penetration into the tumor tissue, the dense ECM in the PDAC tissues was gradually degraded by collagenase, leading to a looser ECM structure and deep penetration within the tumor parenchyma. Under NIR irradiation, both photothermal and photodynamic effects were produced and the encapsulated chemotherapeutic drugs were released effectively, exerting a strong synergistic antitumor effect. Moreover, this nanoplatform has X-ray attenuation properties that could serve to guide and monitor treatment by CT imaging. CONCLUSION: This work presented a unique and facile yet effective strategy to modulate ECM components in PDAC, enhance tumor penetration and tumor-killing effects and provide therapeutic guidance and monitoring.

Roxadustat for treatment of anemia in a cancer patient with end-stage renal disease: A case report.

BACKGROUND: Most cancer patients are accompanied by anemia, which will be more serious when combined with end-stage renal disease (ESRD). At present, cancer-related anemia and renal anemia treatments mainly include erythropoiesis-stimulating agents (ESAs), iron supplementation, and blood transfusion, but their effects are often poor with several safety concerns. We have used roxadustat to treat anemia in a cancer patient with ESRD and achieved a successful outcome for the first time. CASE SUMMARY: A 64-year-old man was diagnosed with right renal cancer (clear cell renal cell carcinoma). He did not receive surgery or radiotherapy before admission. He was treated with oral soltan (sunitinib malate) on April 18, 2017. During oral chemotherapy, he had numerous complications, including anemia, hypertension, thyroid hypofunction, skin pigment loss, and renal function deterioration. At last, he progressed to ESRD and began hemodialysis treatment. We initially treated the patient with high-dose ESAs, iron supplementation, adequate dialysis, and even blood transfusion, but his anemia did not improve. Roxadustat is a newly developed drug for renal anemia treatment, but not for cancer-related anemia, let alone to treat anemia in cancer patients with ESRD. We prescribed oral roxadustat to the patient. After a period, his hemoglobin gradually increased. He did not have obvious discomfort symptoms, and his tumor did not progress significantly. CONCLUSION: Oral roxadustat could achieve good results in treating anemia in cancer patients with ESRD.

[Effect of Buyi Pishen acupuncture on inflammatory factor and cartilage matrix in adjuvant arthritis rats].

OBJECTIVE: To observe the effect of Buyi Pishen acupuncture (acupuncture for invigorating spleen and kidney) on inflammatory factor and synovial cartilage matrix in adjuvant arthritis (AA) rats, and to explore the mechanism of acupuncture for rheumatoid arthritis (RA). METHODS: A total of 60 clean male Wistar rats were randomized into a normal group, a model group, a tripterygium wilfordii polyglycoside tablet (TWP) group and an acupuncture group, 15 rats in each group. Rats in the model group, the TWP group and the acupuncture group received intradermal injection of Freund's complete adjuvant (FCA) at right hind foot pad to induce the AA model. TWP suspension of 8 mg/kg was given by gavage in the TWP group. Acupuncture was applied at "Shenshu" (BL 23), "Pishu" (BL 20) and right "Housanli" (ST 36), "Sanyinjiao" (SP 6), "Yanglingquan" (GB 34) in the acupuncture group, 15 min a time, once a day. The intervention was given 15 days in both TWP group and acupuncture group. The foot-pad swelling degree before modeling, before and after intervention and the arthritis index (AI) score before and after intervention were calculated; the serum levels of interleukin (IL)-1ß, IL-4, IL-10 and tumor necrosis factor-α (TNF-α) were detected by ELISA method; the ultrastructure and histomorphological changes of synovium issue were observed by transmission electron microscope and HE staining; the positive expression of matrix metalloproteinase (MMP)-3 and MMP-9 in synovium issue was detected by immunohistochemistry method. RESULTS: Before intervention, foot-pad swelling degree of the model group, the TWP group and the acupuncture group was increased compared with the normal group (P<0.01). After intervention, foot-pad swelling degree and AI score were increased compared with the normal group (P<0.01), foot-pad swelling degree and AI scores in the TWP group and the acupuncture group were lower than the model group (P<0.05), and those in the acupuncture group were decreased compared with the TWP group (P<0.05). The model group exhibited unclear nuclear membrane of synovial cells, chromatin pyknosis, massive inflammatory cell infiltration and hyperplasia in synovial tissue; the TWP group and the acupuncture group exhibited clear and smooth nuclear membrane of synovial cells, inapparent chromatin pyknosis, less inflammatory cell infiltration and hyperplasia in synovial tissue, the acupuncture group exhibited less matrix destruction as well. Compared with the normal group, serum levels of IL-1ß and TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were increased (P<0.01), while serum levels of IL-4 and IL-10 were decreased (P<0.01) in the model group. Compared with the model group, serum levels of IL-1ß and TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were decreased (P<0.05, P<0.01), while serum levels of IL-4 and IL-10 were increased (P<0.05) in the TWP group and the acupuncture group; compared with the TWP group, serum level of TNF-α and positive expression of MMP-3 and MMP-9 in synovium issue were decreased (P<0.05), while serum levels of IL-4 and IL-10 were increased (P<0.05) in the acupuncture group. CONCLUSION: Buyi Pishen acupuncture can effectively improve the injury of articular cartilage in AA rats, its mechanism maybe related to reducing the inflammatory reaction in synovium and inhibiting the degradation of articular cartilage matrix.

Echinacoside Ameliorates Cyclophosphamide-Induced Bladder Damage in Mice.

Interstitial cystitis (IC) is featured by apoptosis and chronic inflammation in bladder tissue. We aimed to evaluate the effect of echinacoside (ECH), which is known to modulate inflammation and apoptosis on IC using relevant models. We established a mouse model of cystitis using cyclophosphamide (CYP) and treated human urothelium cells (SV-HUC-1) with lipopolysaccharide (LPS) + ATP as in vitro model. The bladder function was tested by urodynamics. Apoptosis of bladder cells was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Expressions of apoptosis-associated and inflammation-related proteins were assessed using western blotting. Treatment with ECH significantly improved bladder function, reduced inflammatory damage, and decreased apoptosis in the models. Furthermore, ECH decreased the phosphorylation levels of IκB and NF-κB(p65), and upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), which are related to apoptosis and inflammation in CYP-induced mouse cystitis. Moreover, ECH did not reduce apoptosis of urothelial cells after treatment with PPARγ antagonist GW9662. Our findings suggest that ECH might have protective effect against IC in bladder and be mediated through modulation of the PPARγ/NF-κB pathway.

Safety and immunogenicity of a synthetic multiantigen modified vaccinia virus Ankara-based COVID-19 vaccine (COH04S1): an open-label and randomised, phase 1 trial.

Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults. Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m2 or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months. In the open-label cohort, 1·0 × 107 plaque-forming units (PFU; low dose), 1·0 × 108 PFU (medium dose), and 2·5 × 108 PFU (high dose) of COH04S1 were administered by intramuscular injection on day 0 and 28 to sentinel participants using a queue-based statistical design to limit risk. In a randomised dose expansion cohort, additional participants were randomly assigned (3:3:1), using block size of seven, to receive two placebo vaccines (placebo group), one low-dose COH04S1 and one placebo vaccine (low-dose COH04S1 plus placebo group), or two low-dose COH04S1 vaccines (low-dose COH04S1 group). The primary outcome was safety and tolerability, with secondary objectives assessing vaccine-specific immunogenicity. The primary immunological outcome was a four times increase (seroconversion) from baseline in spike-specific or nucleocapsid-specific IgG titres within 28 days of the last injection, and seroconversion rates were compared with participants who received placebo using Fisher's exact test. Additional secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ClinicalTrials.gov, NCT046339466. Findings: Between Dec 13, 2020, and May 24, 2021, 56 participants initiated vaccination. On day 0 and 28, 17 participants received low-dose COH04S1, eight received medium-dose COH04S1, nine received high-dose COH04S1, five received placebo, 13 received low-dose COH04S1 followed by placebo, and four discontinued early. Grade 3 fever was observed in one participant who received low-dose COH04S1 and placebo, and grade 2 anxiety or fatigue was seen in one participant who received medium-dose COH04S1. No severe adverse events were reported. Seroconversion was observed in all 34 participants for spike protein and 32 (94%) for nucleocapsid protein (p<0·0001 vs placebo for each comparison). Four times or more increase in SARS-CoV-2 neutralising antibodies within 56 days was measured in nine of 17 participants in the low-dose COH04S1 group, all eight participants in the medium-dose COH04S1 group, and eight of nine participants in the high-dose COH04S1 group (p=0·0035 combined dose levels vs placebo). Post-prime and post-boost four times increase in spike-specific or nucleocapsid-specific T cells secreting interferon-γ was measured in 48 (98%; 95% CI 89-100) of 49 participants who received at least one dose of COH04S1 and provided a sample for immunological analysis. Interpretation: COH04S1 was well tolerated and induced spike-specific and nucleocapsid-specific antibody and T-cell responses. Future evaluation of this COVID-19 vaccine candidate as a primary or boost vaccination is warranted. Funding: The Carol Moss Foundation and City of Hope Integrated Drug Development Venture programme.

Exploratory Compatibility Regularity of Traditional Chinese Medicine on Osteoarthritis Treatment: A Data Mining and Random Walk-Based Identification.

Osteoarthritis (OA) is a degressive and complex disease which is a growing public health problem on a global scale. On basis of an in-house database consisting of clinical records of 13,083 OA patients, the Traditional Chinese Medicine (TCM) was divided into 4 categories of medicines on the basis of the curative properties of herbs. Due to the lack of depth and internal relationship in the calculation results of TCM compatibility law data mining methods such as statistics and frequency analysis, we use a variety of multidimensional complex network methods that can efficaciously find the compatibility law of TCM, including similarity measure, graphical visualization of network diagram, random walking, and propensity score methods. We summarize common couplet medicines utilized for the treatment of osteoarthritis. The similarity measure method was used to investigate the commonly used drugs for the treatment of osteoarthritis. The method of association rule analysis is used to recognize the compatibility between the components. On basis of the propensity score methods, the evaluation displayed that, compared with single drug, the drug group increased ESR, CRP, C3, C4, IgG, and IgA more efficiently. Concluding, a random walk model was constructed to assess drug efficacy. After applying a random walk model, while revealing the compatibility among different components of TCM, their therapeutic efficacy against OA is analyzed. We obtained four groups of drug combination clusters by similarity measure and 11 pairs of highly connected drugs by association rules, which are cardinal drug combinations in the prescription for the treatment of OA. We also found that different traditional drug pairs were associated with different laboratory indexes, and drug combinations could better optimize laboratory indexes. This study presented that the TCM constituents complement one another. Besides, the therapeutic effects resulting from a variety of combinations of these constituents are quite different.

The Protective Effect of Ethyl Acetate and n-Butanol Fractions of Wine-Steamed Ligustri Lucidi Fructus on Diabetic Nephropathy in Rats.

Ligustri Lucidi Fructus (LLF), the dry and ripe fruit of Ligustrum lucidum W. T. Aiton (Oleaceae), is a traditional Chinese medicine for nourishing the liver and kidney in clinics for thousands of years. Wine-steamed Ligustri Lucidi Fructus (WLL) can alleviate coolness and smoothness of LLF and enhance the function of nourishing the liver and kidney, so ancient and modern medicine usually used it in clinics. First of all, we prepared the extracts of different polar fractions of WLL to explore the effective fractions and potential mechanisms of WLL in the treatment of diabetic nephropathy (DN). Then, HPLC method was used to determine the contents of 12 active components in WLL and its different polar components. Finally, the potential relationship between 12 active components and physicochemical parameters of DN rats was explored. The pharmacological experiments showed that WLL, ethyl acetate (EtOAc), and n-butanol (n-BuOH) extracts not only significantly alleviated the clinical symptoms and kidney damage of DN rats but also had obvious anti-inflammatory and antioxidant effects. In addition, the results of HPLC analysis showed that the 12 active components of WLL mainly existed in the extracts of EtOAc and n-BuOH. The Pearson correlation analysis showed 12 active components and physicochemical parameters had different degrees of correlation. In conclusion, we proved that the extracts of EtOAc and n-BuOH were the effective fractions of WLL in treating DN in rats, and they could regulate the levels of inflammatory cytokines and decrease oxidation stress, which provides a basis for further research on the mechanism of WLL in treating DN and provides a pharmacological and chemical foundation for the development of new anti-DN drugs.

Self-amplification of oxidative stress with tumour microenvironment-activatable iron-doped nanoplatform for targeting hepatocellular carcinoma synergistic cascade therapy and diagnosis.

BACKGROUND: Hepatocellular carcinoma is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. METHODS: The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. RESULTS: The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. CONCLUSION: This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy.

[Effect of moxibustion at "Zusanli"(ST36) and "Shenshu"(BL23) on miR-155-mediated TLR4/NF-κB signaling involving amelioration of synovitis in rheumatoid arthritis rats].

OBJECTIVE: To explore the effect of moxibustion at "Zusanli"(ST36) and "Shenshu"(BL23) on synovitis, and expressions of miR-155, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), interlukine（IL-1） receptor-associated kinase (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor κB (NF-κB), IL-1ß, tumor necrosis factor receptor (TNF)-α and IL-6 mRNA and protein of synovial membrane in rheumatoid arthritis (RA) rats, so as to explore its mechanism underlying improvement of RA. METHODS: A total of 48 male Wistar rats were randomly divided into normal control, model, moxibustion and antagonist groups (n=12 rats in each group). The RA model was replicated by placing the rats in a wind, cold and wet environment and injection of Freund's complete adjuvant (CFA, 0.5 mL) into the right hindlimb foot plantar. Moxibustion was applied to bilateral ST36 and BL23 for 30 min, once daily for 21 consecutive days. Rats of the antagonist group was treated by injection of TLR4 antagonist (TAK-242, 1 mg/mL, 0.1 mg/kg) via tail vein, once per day for consecutive 21 d. The joint swelling degree (JSD) and arthritis index (AI, red swelling scale) were determined, and the expression levels of various indicators of miR-155, and TLR4, myeloid MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were assayed by quantitative real time-PCR and Western blot, separately. RESULTS: Compared with the normal control group, the JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were significantly increased in the model group (P<0.01). Compared with the model group, the increased levels of JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were notably down-regulated in both moxibustion and antagonist groups (P<0.01). The effects of moxibustion were evidently superior to the antagonist in down-regulating the abovementioned indexes (P<0.01), except TLR4 mRNA and protein. CONCLUSION: Moxibustion at ST36 and BL23 can reduce the synovitis of RA rats, which is related to its effects in suppressing the expressions of miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein (i.e., inhibition of miR-155/TLR4/NF-κB signaling).

Efficacy and safety of Shenyankangfu Tablet, a Chinese patent medicine, for primary glomerulonephritis: A multicenter randomized controlled trial.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m2, and 24-hour proteinuria level of 0.5-3.0 g, were recruited in 41 hospitals across 19 provinces in China and were randomly divided into five groups: SYKFT, losartan potassium 50 mg or 100 mg, SYKFT plus losartan potassium 50 mg or 100 mg. MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER: NCT02063100 on ClinicalTrials.gov.

Polygalae Radix: A review of its traditional uses, phytochemistry, pharmacology, toxicology, and pharmacokinetics.

Polygalae Radix (Polygalaceae), the dried root of Polygala tenuifolia Willd. and Polygala sibirica L., has been widely used as a medicine for improving cognitive function. In China, Polygalae Radix has been widely used in the treatment of insomnia, forgetfulness, depression, cough, palpitation, and other diseases. More than 140 compounds have been isolated from Polygalae Radix, including saponins, xanthones, oligosaccharide esters, and so on. The compounds and extracts isolated from Polygalae Radix possess wide-ranging pharmacological activities, such as neuroprotective, antidepressant, hypnotic-sedative, anti-inflammatory, antiviral, antitumor, antioxidant, antiaging, and antiarrhythmic effects, among others. The clinical practice of traditional Chinese medicine has proved that raw Polygalae Radix can irritate the throat. Modern studies have found that raw Polygalae Radix exhibits a certain degree of toxicity to the gastrointestinal tract after long-term use or excessive doses and that its main toxic components are saponins. Thus, Polygalae Radix is usually processed, and/or combined with other herbs to reduce gastrointestinal irritation. This review investigated the pharmacokinetics of Polygalae Radix. Future research perspectives and the existing problems of Polygalae Radix were also discussed. This review can broaden the understanding regarding Polygalae Radix and provide references for further research.

[Clinical anatomical study on the treatment of carpal tunnel syndrome with classic Acupotomy].

OBJECTIVE: To explore the safety of classic Acupotomy in the treatment of carpal tunnel syndrome. METHODS: Twenty six adult specimens (15 males and 11 females), aged 60 to 95(82.54±6.94) years old, were selected from 10% formalin antiseptic fixation. There were 52 sides(two of them could not be tested). The study period was from November 2017 to May 2018. The specimens were collected from the body donation center of the school of basic medicine, Peking University. The operation of releasing the transverse carpal ligament on the human body specimen was simulated by the classic acupotomy, and the distance from the four points to the surrounding anatomical structure was measured to calculate the direct injury rate to the nerve and blood vessels, and the shortest distance between the acupotomy and the nerve and blood vessels was defined as ≥2 mm as safety. RESULTS: In the experimental operation, the direct injury rate of nerve and blood vessel was 14% and 12% respectively. There was significant difference in the rate of direct nerve injury between the four injection points (P<0.05). There was no significant difference in the rate of direct vascular injury between the four injection points (P>0.05). Among the four points, there was a statistically significant difference in the safety of nerves(P<0.05), and the safety of point 1 and point 3 of radial injection was higher than that of point 2 and point 4 of ulnar injection(P<0.05). There was significant difference in the safety of blood vessels between the four points(P<0.05), and the safety of radial point 1 was higher than that of ulnar point 2 and point 4 (P<0.05). CONCLUSION: The safety of the classic Acupotomy for carpal tunnel syndrome is related to the location of the needle entry point, and the safety of theradial proximal end of the needle is the highest.

[Effect of Huangqin Qingre Chubi Capsules containing serum on oxidative stress and protein expression of AMPK and FoxO3a in rheumatoid arthritis patients].

To study the effect of Huangqin Qingre Chubi Capsules containing serum on the protein expressions of AMPK and FoxO3 a in peripheral blood mononuclear cells of patients with rheumatoid arthritis(RA), in order to explore the mechanism of anti-oxidation. Peripheral anticoagulant was collected from patients and normal people. Monocytes(PBMC) were isolated through density gradient centrifugation, and the logarithmic phase cells were cultured. Drug containing serum was prepared through intragastric admini-stration to SD rats. The rats were divided into five groups, namely normal group, model group, AMPK blocker group(compound C 10 µmol·L~(-1)), medium-dose HQC+AMPK blocker group, and middle-dose HQC group. The cell inhibition rate was calculated by MTT method. The levels of IL-1ß, IL-4, LPO, MDA, SOD and TAOC were detected by ELISA. The expressions of AMPK, p-AMPK, p-FoxO3 a and FoxO3 a were detected by Western blot. The HQC containing serum had an inhibitory effect on human monocytes in peripheral blood. The best concentration was observed in middle-dose HQC, and the best time was 24 hours. Middle-dose HQC group was better than model group, AMPK blocker group and middle-dose HQC + AMPK blocker group in terms of increase of SOD, p-AMPK, p-FoxO3 a and decrease of LPO. It was better than model group and AMPK blocker group in terms of increase of IL-4, TAOC, AMPK, FoxO3 a and decrease of IL-1ß, MDA. The differences were statistically significant(P<0.05 or P<0.01). The HQC containing serum may increase the levels of TAOC and SOD, decrease the level of MDA and LPO, activate AMPK, directly phosphorylate FOXO3 a, enhance its transcriptional activity, and improve the state of oxidative stress in RA patients.

Curcumin improves asthenozoospermia by inhibiting reactive oxygen species reproduction through nuclear factor erythroid 2-related factor 2 activation.

We conducted this study for the purpose of evaluating the protective mechanisms of curcumin against oxidative stress in asthenozoospermic individuals. Asthenozoospermic individuals were grouped into AS group, curcumin treatment group and brusatol + curcumin treatment group. The sperm motility was measured by computer-aided sperm analysis. We conducted flow cytometry and spectrophotometry to assess the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Chlortetracycline (CTC) was used to examine the acrosomal reaction of spermatozoa. Also, Western blotting was carried to measure antioxidant gene Nrf2 (nuclear factor erythroid 2-related factor) expression level. As our results shown, treatment with curcumin significantly decreased ROS formation and MDA production, compared with spermatozoa of AS group; however, Nrf2 inhibitor, Brusatol, inhibited Nrf2 expression and sperm function. Our results have shown that curcumin might protect spermatozoa by regulating Nrf2 level.

The effectiveness of treatments for Kashin-Beck disease: a systematic review and network meta-analysis.

OBJECTIVES: This study aims to evaluate the efficacy of treatments for Kashin-Beck disease (KBD). METHOD: We searched PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, SinoMed, Chinese National Knowledge Infrastructure, reference lists and published systematic reviews and registries of ongoing trials through May 2015 for randomised controlled trials (RCTs) of treatments for KBD. Outcomes of interest were pain, function, stiffness, overall clinical improvement, radiographic improvement (X-ray) and adverse events. Frequentist network meta-analyses were conducted using random-effects consistency model to assess the efficacy of treatments for KBD. RESULTS: Forty-four RCTs with 9815 participants were included in the review. In children or adolescents, selenium (risk ratio 1.88, 95% confidence interval (CI) 1.51-2.33), vitamin C (2.03, 1.40-2.95) and aspirin (2.14, 1.12-4.08) were effective for radiographic structure improvement. In adults, chondroitin plus glucosamine was the best for pain (standardised mean difference 1.46, 95% CI 1.07-1.85), followed by intra-articular injection of hyaluronic acid (IAH) (1.09, 0.70-1.48), chondroitin (0.84, 0.47-1.21), diclofenac (0.63, 1.18-1.08), naproxen (0.55, 0.12-0.98), meloxicam (0.52, 0.03-1.01) and glucosamine (0.40, 0.13-0.67) compared to placebo, with similar results for other clinical outcomes in adults. However, the strength of most evidence was limited by the small number of trials with low to moderate quality. CONCLUSIONS: Selenium supplement has demonstrated some benefits for structural improvement of the disease in children. Chondroitin, glucosamine, IAH and nonsteroid anti-inflammatory drugs are effective for symptom improvements of KBD in adults. Evidence of surgical and complementary treatments for symptoms and aspirin and vitamin C for structure has yet to be established.Key Points• There were 23 nutraceuticals, pharmaceuticals and surgical and complementary treatments assessed for Kashin-Beck disease (KBD) in randomised trials.• Among the 23 treatments, chondroitin, glucosamine, IAH and non-steroid anti-inflammatory drugs are more effective than placebo to relieve symptoms for adults with KBD.• Selenium supplement is more effective than placebo for radiographic improvement in children or adolescents.• The efficacy of surgeries, aspirin, vitamin C and complementary treatments for KBD has not been established yet.