LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass in postmenopausal women.

OBJECTIVES: To assess LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass (ABM) in postmenopausal women. METHODS: The study recruited 166 patients with ABM (case group) and 106 patients with normal bone mass (control group) based on bone mineral density (BMD) results. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction between the Low-density lipoprotein receptor-related protein 5 (LRP5) gene (rs41494349, rs2306862) and the Low-density lipoprotein receptor-related protein 6 (LRP6) gene (rs10743980, rs2302685) and the subjects' clinical characteristics of age and menopausal years. RESULTS: (1) Logistic regression analysis showed that the subjects with the CT or TT genotype at rs2306862 had a higher risk of ABM than those with the CC genotype (OR = 2.353, 95%CI = 1.039-6.186; OR = 2.434, 95%CI = 1.071, 5.531; P < 0.05). The subjects with the TC genotype at rs2302685 had a higher risk of ABM than those with the TT genotype (OR = 2.951, 95%CI = 1.030-8.457, P < 0.05). (2) When taking the three Single-nucleotide polymorphisms (SNPs) together, the accuracy was the highest with the cross-validation consistency of 10/10 (OR = 1.504, 95%CI:1.092-2.073, P < 0.05), indicating that the LRP5 rs41494349 and LRP6 rs10743980, rs2302685 were interactively associated with the risk of ABM. (3) Linkage disequilibrium (LD) results revealed that the LRP5 (rs41494349,rs2306862) were in strong LD (D' > 0.9, r2 > 0.3). AC and AT haplotypes were significantly more frequently distributed in the ABM group than in the control group, indicating that subjects carrying the AC and AT haplotypes were associated with an increased risk of ABM (P < 0.01). (4) MDR showed that rs41494349 & rs2302685 & rs10743980 & age were the best model for ABM prediction. The risk of ABM in "high-risk combination" was 1.00 times that of "low-risk combination"(OR = 1.005, 95%CI: 1.002-1.008, P < 0.05). (5) MDR showed that there was no significant association between any of the SNPs and menopausal years and ABM susceptibility. CONCLUSION: These findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms and gene-gene and gene-age interactions may increase the risk of ABM in postmenopausal women. There was no significant association between any of the SNPs and menopausal years and ABM susceptibility.

Sulforaphene targets NLRP3 inflammasome to suppress M1 polarization of macrophages and inflammatory response in rheumatoid arthritis.

This work aimed to explore the therapeutic effect and target of sulforaphene (LF) in mice with rheumatoid arthritis (RA). Lipopolysaccharide (LPS) and IFN-γ were added to induce the M1 polarization of SMG cells, and later cells were pretreated with 5 µM and 15 µM LF. M1 cell proportion was detected by flow cytometry (FCM), inflammatory factors were measured by enzyme-linked immunosorbent assay, and protein levels were analyzed by western blotting (WB) assay. Besides, small molecule-protein docking and pull-down assays were carried out to detect the binding of LF to NLRP3. After the knockdown of NLRP3 in SMG cells, the effect of LF was further detected. The RA mouse model was induced with collagen antibody and LPS, after LF intervention, H&E staining was performed to detect the pathological changes in mouse synovial membrane, whereas safranin O-fast green staining was performed to detect cartilage injury, NLRP3 inflammasome and inflammatory factor levels in tissues. LF suppressed M1 polarization of macrophages, reduced M1 cell proportion and inflammatory factor levels, and suppressed the activation of NLRP3 inflammasome. After NLRP3 knockdown, LF did not further suppress the M1 polarization of macrophages. Pull-down assay suggested that LF bound to NLRP3. As revealed by mouse experimental results, LF inhibited bone injury in mice, decreased M1 cell infiltration and inflammatory response in tissues, and inhibited NLRP3 inflammasome expression in tissues. LF targets NLRP3 to suppress the M1 polarization of macrophages and decrease tissue inflammation in RA.

Pharmacological interventions for preventing atrial fibrillation after lung surgery: systematic review and meta-analysis.

BACKGROUND: Postoperative atrial fibrillation/flutter (POAF) is one of the most common cardiac complications after lung surgery. We aimed to assess the safety and efficacy of pharmacological interventions for new-onset POAF prophylaxis in patients with lung cancer after lung surgery. METHODS: PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were searched to identify randomized controlled trials comparing the effects of pharmacological interventions to prevent POAF following lung surgery. RESULTS: A total number of 19 studies with 2,922 participants were included. Pharmacological interventions significantly reduced the incidence of POAF (odds ratio [OR] 0.36, 95% confidence interval [95% CI] 0.26-0.52) while did not increase the incidence of severe pulmonary complications (OR 1.17, 95% CI 0.57-2.41) after lung surgery compared with placebo/usual care. Among different trials, beta-blockers appeared to be the most effective with an OR of 0.13 (95% CI, 0.07-0.27) and a number needed-to-treat (NNT) of 3.63 and was considered safe with no serious adverse events recorded. The risk of POAF decreased from 25.6 to 11.4% (P < 0.001) overall and from 34.2 to 6.7% (P < 0.001) with beta-blockers as monotherapy. Pharmacological interventions did not reduce the 30-day mortality (OR 0.89, 95% CI 0.43-1.84, I2 = 0%), but showed a trend toward reducing major cardiovascular complications including myocardial ischemia/infarction, cardiac arrest, heart failure, and stroke (OR 0.41, 95% CI 0.13-1.29, I2 = 0%). CONCLUSION: Current clinical evidence supports the effectiveness of pharmacological intervention with beta-blockers, amiodarone, magnesium sulfate, or calcium-channel blockers to reduce the incidence of POAF after lung surgery in patients with lung cancer. In the absence of contraindications, prophylaxis with beta-blockers seems to be the most effective of the treatments studied.

Anti-tumour necrosis factor-alpha agent therapy, compared with conventional therapy, reduces the relapse of uveitis in patients with behçet's disease: A systematic review of controlled trials.

Purpose: Anti-tumour necrosis factor-alpha (TNF-α) agents are often used for Behçet's disease (BD) in clinical practice, but they have not been validated by a high level of evidence. We systematically reviewed published controlled trials to investigate the efficacy and safety of anti-TNF-α therapy and summarize the efficacy of anti-TNF-α therapy relative to the available therapeutic options. Methods: A systematic database search was conducted (PubMed, Embase and Cochrane) using specific search terms. All controlled studies of anti-TNF-α treatment of BD patients prior to December 2021 were included. Single-arm studies were excluded. The decision of whether to incorporate data into the meta-analysis or summarize the data by qualitative synthesis was based on the results of the literature screening. Results: Of 4389 screened studies, 13 (total 778 patients) were included in accordance with our retrieval strategy, comprising 1 randomized controlled trial, 1 prospective study, 10 retrospective studies, and 1 multicentre open-label study. Ten studies (76.9%) involved Behçet's uveitis (BU), 1 involved intestinal BD, and the other studies had undefined subtypes. Subgroup reviews were conducted according to the control drug. Four studies involving 167 participants reported relapse rates. Meta-analysis of three of these studies demonstrated that, compared with traditional immunosuppressant (TIS) therapy, anti-TNF-α therapy reduced the relapse rates in patients with BU. In targeted drug comparison studies, the efficacy appeared to be similar between the anti-TNF-α agent and interferon in BU patients. The rates of adverse events were comparable between a variety of different therapeutic controls. Serious adverse events were not observed in 53.8% (7/13) of the studies. Conclusions: Compared with TIS therapy, anti-TNF-a therapy reduces the relapse of uveitis in patients with BD. However, the evidence regarding anti-TNF-α therapy is very limited for the full spectrum of BD subtypes, which calls for caution.

Relationship Between Sclerostin (SOST) Expression and Genetic Loci rs851056, rs1230399 Polymorphisms and Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes in Xinjiang.

BACKGROUND: The Wnt signaling pathway plays a valuable role in bone metabolism. SOST is a major inhibitor of the Wnt signaling pathway. The expression of SOST and genetic polymorphism might be associated with bone mineral density in postmenopausal women with type 2 diabetes mellitus (T2DM). OBJECTIVE: This study aims to explore whether SOST protein expression and genetic locus rs851056, rs1230399 polymorphism is associated with bone mineral density in postmenopausal women with T2DM in Xinjiang. METHODS: A total of 136 Xinjiang postmenopausal women were divided into four groups: A (-/-), B (±), C (-/+), and D (+/+) by assessing their OGTT and bone mass. Genetic polymorphisms were determined using the mass ARRAY mass spectrometer. RESULTS: 1) Genotypes and allele frequencies at rs851056 were statistically significant differences in groups B and D patients compared to group A, respectively. 2) Individuals carrying the GG genotype had lower HDL, Ca, and ALP as compared to those carrying the GC/CC genotypes in group C. In contrast, individuals carrying the GG genotype had higher BMD (L1-4) as compared to those carrying the GC/CC genotypes in group D. 3) SOST protein expression levels were higher in groups C and D than in group A. 4). BMD (L1-4) was negatively correlated with SOST protein. 5) Multiple linear regression analysis for BMD-dependent variables showed that the decrease of BMI and TG were risk factors for BMD (L1-4), besides, the decrease of BMI, ALP, and extended years of menopause were all risk factors for BMD (femoral neck). CONCLUSION: SOST protein expression and genetic locus rs851056, rs1230399 polymorphism are associated with bone mineral density in postmenopausal women with type 2 diabetes mellitus in Xinjiang.

Discovery of Thai mangrove tetranortriterpenoids as agonists of human pregnane-X-receptor and inhibitors against human carboxylesterase 2.

Human pregnane-X-receptor (hPXR) is considered to be the key target for the treatment of cholestasis and liver injury. Agonists of hPXR are potential drug leads. Potent and selective inhibitors of human carboxylesterase 2 (hCES2) could be utilized to alleviate the toxicity induced by ester drugs. In this work, fifteen new tetranortriterpenoids with structure diversity, named thaigranatins F-T (1-15), including four limonoids containing a C1-O-C29 bridge (1-4), four mexicanolides (5-8), three phragmalins (9-11), two limonoids belonging to the small group of trichiliton A (12-13), and two apotirucallanes (14-15), were isolated from seeds of the Thai mangrove, Xylocarpus granatum. The structures of these compounds were established by high resolution-electrospray ionization mass spectroscopy, extensive NMR spectroscopic investigations, single-crystal X-ray diffraction analyses, and the comparison of experimental electronic circular dichroism spectra. Most notably, thaigranatins L (7) and P (11) exhibited agonistic effects on hPXR at the concentration of 10.0 µM and 10.0 nM, respectively, whereas thaigranatins J (5), M (8), and T (15) showed inhibitory activities against hCES2 with IC50 values of 6.63, 11.35, and 5.05 µM, respectively. The 8α,30α-epoxy moiety of mexicanolide and the Δ8,14 double bond of phragmalin are pivotal for agonistic effects of these limonoids on hPXR, whereas the 6-OAc group of mexicanolide is crucial for its inhibitory activity against hCES2. Additionally, the flexible C-17-side-chain with appropriate hydroxy groups is considered to be important for the inhibitory activity of apotirucallane against hCES2.

Fabrication of pH-responsive TA-keratin bio-composited hydrogels encapsulated with photoluminescent GO quantum dots for improved bacterial inhibition and healing efficacy in wound care management: In vivo wound evaluations.

Wounds origins serious complications of lives of human beings which may leads to death. The important issue for the problem is infection during wound care management which delays wound healing process. These kinds of infections may be caused by the overuse or misuse of antibiotics, antidotes, usage of new drugs, not properly sterilized surgical instruments, not appropriate for pH level and imperfect wound dressing etc. during or after surgery. Hence in this report, antimicrobial action of pH responsive TA/KA composited hydrogel crosslinked with GO-QDs (TA/KA-GOQDs) using citric acid as cross-linker has been reported by demonstrating in-vitro and in-vivo studies for wound care management. The prepared samples of GOQDs, TA/KA hydrogel and TA/KA-GOQDs were characterized using FT-IR, XRD, SEM and TEM techniques. pH responsive hydrogel property of TA/KA was evaluated by swelling studies. In-vitro antibacterial studies was carried out by direct contact test method. Further, the prepared samples were tested in a wound healing model of rate with the wound of size 1.5 cm2 for in-vivo studies. After 16 days of treatment, the prepared samples for wound healing causes 100% wound areas closure. Histological observations were made by MT and HE staining process which proves keratinocytes proliferation by biocompatible and biocomposited TA/KA-GOQDs. The pH responsive TA/KA-GOQDs proved as efficient wound healing agent by faster keratinocytes proliferation within a compact period.

Fabrication of a ferrocene-based monolithic column with a network structure and its application in separation of protein and small molecules.

A novel ferrocene-based monolith with a network structure was fabricated via in situ free radical polymerization using vinyl ferrocene as the co-monomer within a stainless-steel column (50 × 4.6 mm i.d.) for the separation of proteins from complex bio-samples, taking merit of the specific absorption of ferrocene to protein, including human plasma, egg white, and standard proteins. The morphology and pore size distribution indicate that the optimized monolith has a relatively uniform structure with the network. The results showed that 26 fractions were separated from human plasma, and the column efficiency of the aromatic small molecule, naphthalene, was up to 30,560 plates m-1. The homemade monolith showed excellent selectivity for intact proteins, mainly depending on the hydrophobic chromatography mechanism of ferrocene. In addition, the electrostatic interaction and hydrogen-bond interaction were the additional interactions in the chromatographic separation owing to the sandwich structure of ferrocene present in the monolithic column.

Synthesis and anti-HBV activities evaluation of new ethyl 8-imidazolylmethyl-7-hydroxyquinoline-3-carboxylate derivatives in vitro.

Some new ethyl 8-imidazolylmethyl-7-hydroxyquinoline-3-carboxylate derivatives have been synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in HepG2.2.15 cells stable transfection with HBV. Compounds 13a, 11b, 11c, 12c, 13c, 11g, and 12g inhibited the expression of the viral antigens HBsAg or HBeAg in a low concentration, of which 11c (IC(50 )= 12.6 microM, SI = 12.4), 12c (IC(50 )= 3.5 microM, SI = 37.9), and 12g (IC(50) = 2.6 microM, SI = 61.6) showed more active abilities to inhibit the replication of HBV DNA than the positive control lamivudine (3TC, IC(50) = 343.2 microM, SI = 7.0).