A novel selective ERK1/2 inhibitor, Laxiflorin B, targets EGFR mutation subtypes in non-small-cell lung cancer.

Extracellular regulated protein kinases 1/2 (ERK1/2) are key members of multiple signaling pathways, including the ErbB axis. Ectopic ERK1/2 activation contributes to various types of cancer, especially drug resistance to inhibitors of RTK, RAF and MEK, and specific ERK1/2 inhibitors are scarce. In this study, we identified a potential novel covalent ERK inhibitor, Laxiflorin B, which is a herbal compound with anticancer activity. However, Laxiflorin B is present at low levels in herbs; therefore, we adopted a semi-synthetic process for the efficient production of Laxiflorin B to improve the yield. Laxiflorin B induced mitochondria-mediated apoptosis via BAD activation in non-small-cell lung cancer (NSCLC) cells, especially in EGFR mutant subtypes. Transcriptomic analysis suggested that Laxiflorin B inhibits amphiregulin (AREG) and epiregulin (EREG) expression through ERK inhibition, and suppressed the activation of their receptors, ErbBs, via a positive feedback loop. Moreover, mass spectrometry analysis combined with computer simulation revealed that Laxiflorin B binds covalently to Cys-183 in the ATP-binding pocket of ERK1 via the D-ring, and Cys-178 of ERK1 through non-inhibitory binding of the A-ring. In a NSCLC tumor xenograft model in nude mice, Laxiflorin B also exhibited strong tumor suppressive effects with low toxicity and AREG and EREG were identified as biomarkers of Laxiflorin B efficacy. Finally, Laxiflorin B-4, a C-6 analog of Laxiflorin B, exhibited higher binding affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.

Gadd45a is a heterochromatin relaxer that enhances iPS cell generation.

Reprogramming of somatic cells to induced pluripotent stem cells rewrites the code of cell fate at the chromatin level. Yet, little is known about this process physically. Here, we describe a fluorescence recovery after photobleaching method to assess the dynamics of heterochromatin/euchromatin and show significant heterochromatin loosening at the initial stage of reprogramming. We identify growth arrest and DNA damage-inducible protein a (Gadd45a) as a chromatin relaxer in mouse embryonic fibroblasts, which also enhances somatic cell reprogramming efficiency. We show that residue glycine 39 (G39) in Gadd45a is essential for interacting with core histones, opening chromatin and enhancing reprogramming. We further demonstrate that Gadd45a destabilizes histone-DNA interactions and facilitates the binding of Yamanaka factors to their targets for activation. Our study provides a method to screen factors that impact on chromatin structure in live cells, and identifies Gadd45a as a chromatin relaxer.

The Effects of Dietary Calcium Supplements Alone or With Vitamin D on Cholesterol Metabolism: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Evidence supports the role of lifestyle interventions as a primary intervention strategy among individuals with dyslipidemia. The role of micronutrients, and calcium in particular, on cholesterol metabolism is not clear and warrants further investigation. OBJECTIVE: The aim of this study is to conduct a meta-analysis of controlled clinical trials that have examined the effects of calcium supplements on blood lipids among adults. METHODS: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases were searched up to March 2016 for calcium supplements clinical trials. Other trials were selected from searching bibliography of reviews, meta-analysis, and included trials. Clinical trials with random allocation to calcium supplementation or calcium plus vitamin D supplementation, or control were selected. Data collected included study design, participant characteristics, information of the intervention, and outcomes. Data synthesis was conducted using random effect models. RESULTS: A total of 22 trials, representing 4071 participants, met the eligibility criteria. Compared with control group, calcium supplements significantly reduced low-density lipoprotein cholesterol level by -0.12 mmol/L (95% confidence interval, -0.22 to -0.02) and increased high-density lipoprotein cholesterol level by 0.05 mmol/L (95% confidence interval, 0.00 to 0.10). Subgroup analyses revealed that the associations were consistent across study duration and vitamin D cosupplementation status. CONCLUSIONS: Calcium supplementation has beneficial effect on blood lipids. Such supplements may be useful as a nonpharmaceutical strategy in cholesterol control.

Causal associations between autoimmune diseases and sarcopenia-related traits: a bi-directional Mendelian randomization study.

Background: Sarcopenia is common in patients with autoimmune diseases (ADs); however, the causal associations between ADs and sarcopenia remain unclear. Therefore, this study investigated the causal associations using bi-directional Mendelian randomization analysis. Methods: Exposure-related single-nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWASs). GWAS statistics for common ADs [Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis (PSO), and multiple sclerosis (MS)] and sarcopenia-related traits [hand grip strength (HGS), appendicular fat-free mass (FFM), and walking pace] were obtained from public datasets. Inverse-variance weighting as the main method was used to evaluate the causal effect. Results: Genetically predicted CD had causal effects on whole-body FFM (ß = -0.005, p = 0.001), leg FFM (ßleft = -0.006, p = 1.8E-4; ßright = -0.007, p = 2.0E-4), and arm FFM (ßleft = -0.005, p = 0.005; ßright = -0.005, p = 0.001), while RA had causal effects on 8 sarcopenia-related traits, namely, HGS (ßleft = -2.06, p = 2.8E-38; ßright = -2.311, p = 2E-20), whole-body FFM (ß = -0.842, p = 4.7E-10), leg FFM (ßleft = -0.666, p = 2.6E-6; ßright = -0.073, p = 2.1E-3), arm FFM (ßleft = -0.63, p = 4.4E-6; ßright = -0.736, p = 4.4E-8), and walking pace (ß = -1.019, p = 6.2E-14). In the reverse direction, HGS (odds ratio [OR]left = 10.257, p = 3.6E-5; ORright = 16.445, p = 3.7E-7) had causal effects on CD, while HGS (ORleft = 0.994, p = 0.004; ORright = 0.993, p = 1.4E-4), leg FFM (ORleft = 1.003, p = 0.005; ORright = 1.005, p = 1.9E-4), and walking pace (OR = 0.985, p = 5.7E-5) were causally associated with RA. No evidence showed causal associations of UC, SLE, PSO, or MS with sarcopenia-related traits. Conclusion: Our study demonstrated that the genetic susceptibility to CD and RA was associated with high risk of sarcopenia, and some sarcopenia-related traits had causal effects on CD or RA.

Adhesin Component Member STAG2 Enhances Cisplatin Tolerance in Colorectal Cancer Cells through the Epithelial-Mesenchymal Transition Pathway.

BACKGROUND: Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2. METHODS: The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method. RESULTS: Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 µM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy. CONCLUSION: STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

Unveiling the therapeutic symphony of probiotics, prebiotics, and postbiotics in gut-immune harmony.

The gut microbiota and immune system interaction play a crucial role in maintaining overall health. Probiotics, prebiotics, and postbiotics have emerged as promising therapeutic approaches to positively influence this complex axis and enhance health outcomes. Probiotics, as live bacteria, promote the growth of immune cells, shape immune responses, and maintain gut barrier integrity. They modify the gut microbiota by fostering beneficial bacteria while suppressing harmful ones. Additionally, probiotics interact with the immune system, increasing immune cell activity and anti-inflammatory cytokine production. Prebiotics, as indigestible fibers, selectively nourish beneficial microorganisms in the gut, enhancing gut microbial diversity and activity. This, in turn, improves gut health and boosts immune responses while controlling inflammation through its immunomodulatory properties. Postbiotics, produced during probiotic fermentation, such as short-chain fatty acids and antimicrobial peptides, positively impact gut health and modulate immune responses. Ensuring quality control and standardization will be essential for successful clinical implementation of these interventions. Overall, understanding and harnessing the gut microbiota-immune system interplay offer promising avenues for improving digestive and immunological health.

The roles of bacteria and viruses in COPD-Bronchiectasis association: A prospective cohort study.

BACKGROUND: Exacerbations are implicated in bronchiectasis and COPD, which frequently co-exist [COPD-Bronchiectasis association (CBA)]. We aimed to determine the bacterial and viral spectrum at stable-state and exacerbation onset of CBA, and their association with exacerbations and clinical outcomes of CBA as compared with bronchiectasis. METHODS: We prospectively collected spontaneous sputum from adults with CBA, bronchiectasis with (BO) and without airflow obstruction (BNO) for bacterial culture and viral detection at stable-state and exacerbations. RESULTS: We enrolled 76 patients with CBA, 58 with BO, and 138 with BNO (711 stable and 207 exacerbation visits). Bacterial detection rate increased from BNO, CBA to BO at steady-state (P = 0.02), but not at AE onset (P = 0.91). No significant differences in viral detection rate were found among BNO, CBA and BO. Compared with steady-state, viral isolations occurred more frequently at exacerbation in BNO (15.8 % vs 32.1 %, P = 0.001) and CBA (19.5 % vs 30.6 %, P = 0.036) only. In CBA, isolation of viruses, human metapneumovirus and bacteria plus viruses was associated with exacerbation. Repeated detection of Pseudomonas aeruginosa (PA) correlated with higher modified Reiff score (P = 0.032) in CBA but not in BO (P = 0.178). Repeated detection of PA yielded a shorter time to the first exacerbation in CBA [median: 4.3 vs 11.1 months, P = 0.006] but not in BO (median: 8.4 vs 7.6 months, P = 0.47). CONCLUSIONS: Isolation of any viruses, human metapneumovirus and bacterialplus viruses was associated with CBA exacerbations. Repeated detection of PA confers greater impact of future exacerbations on CBA than on BO.

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy in patients with extensive-stage small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials.

Objective: Many clinical trials of immune checkpoint inhibitors (ICIs) in combination with chemotherapy in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) have been initiated, but the conclusions of these trials are not identical. This meta-analysis aimed to comprehensively collect these randomized clinical controlled trials (RCTs) to evaluate the efficacy and safety of ICIs combined with chemotherapy in the first-line treatment of ES-SCLC. Methods: We systematically searched PubMed, Embase, and ClinicalTrials databases, to find relevant studies published until October 2022.RevMan 5.4 software was used for statistical analysis. The Cochrane Risk of Bias Tool was adopted to evaluate the risk of bias in the included studies. The primary outcome of this study was overall survival (OS), while the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), all grand AEs (AEs), and ≥ 3 grand adverse events (≥ 3 AEs). Results: A total of 780 articles were obtained in the initial examination, which was screened by layer and finally included 8 studies including 3367 patients. Six studies evaluated the efficacy of PD-1/PD-L1 inhibitors (Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, Adebrelimab, Serpulimab) combined with chemotherapy, and two studies evaluated the efficacy of CTLA-4 inhibitors (Ipilimumab) in combination with chemotherapy. The results showed that compared to chemotherapy alone, ICIs combined with chemotherapy significantly improved patients' OS (HR=0.8, 95% CI (0.72-0.85), P<0.05), PFS (HR = 0.72, 95% CI (0.63-0.83), P < 0.05), and ORR(RR=1.08, 95% CI: 1.03-1.13, P<0.05), but patients would experience more any grand AEs and ≥3 grand AEs. Subgroup analysis showed that the PD-1/PD-L1 group performed better than the CTLA-4 group in both efficacy and safety. And ICIs plus chemotherapy significantly improved OS and PFS in patients regardless of age, gender, and performance status. Conclusion: The addition of ICIs to chemotherapy resulted in significant improvements in both PFS and OS for patients with ES-SCLC, but patients would experience more AEs.

Causal associations between inflammatory bowel disease and anxiety: A bidirectional Mendelian randomization study.

BACKGROUND: Anxiety is common in patients with inflammatory bowel disease (IBD), including those with ulcerative colitis (UC) and Crohn's disease (CD); however, the causal relationship between IBD and anxiety remains unknown. AIM: To investigate the causal relationship between IBD and anxiety by using bidirectional Mendelian randomization analysis. METHODS: Single nucleotide polymorphisms retrieved from genome-wide association studies (GWAS) of the European population were identified as genetic instrument variants. GWAS statistics for individuals with UC (6968 patients and 20464 controls; adults) and CD (5956 patients and 14927 controls; adults) were obtained from the International IBD Genetics Consortium. GWAS statistics for individuals with anxiety were obtained from the Psychiatric Genomics Consortium (2565 patients and 14745 controls; adults) and FinnGen project (20992 patients and 197800 controls; adults), respectively. Inverse-variance weighted was applied to assess the causal relationship, and the results were strengthened by heterogeneity, pleiotropy and leave-one-out analyses. RESULTS: Genetic susceptibility to UC was associated with an increased risk of anxiety [odds ratio: 1.071 (95% confidence interval: 1.009-1.135), P = 0.023], while genetic susceptibility to CD was not associated with anxiety. Genetic susceptibility to anxiety was not associated with UC or CD. No heterogeneity or pleiotropy was observed, and the leave-one-out analysis excluded the potential influence of a particular variant. CONCLUSION: This study revealed that genetic susceptibility to UC was significantly associated with anxiety and highlighted the importance of early screening for anxiety in patients with UC.

Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis.

Laxiflorin B is a natural ent-kaurane diterpenoid that can be isolated from the leaves of the Isodon eriocalyx var. laxiflora, a perennial shrub native to parts of China. While this compound has potent cytotoxic activity against various tumor cells, the anti-tumor targets and molecular mechanisms of Laxiflorin B are unclear. Here, we show that Laxiflorin B exhibits strong antiproliferative and proapoptotic effects on triple-negative breast cancer (TNBC) cells. At the mechanistic level, we show that ß-tubulin (TUBB) is a cellular target of Laxiflorin B. By covalently binding the Cys239 and C354 residues of the TUBB colchicine-binding site, Laxiflorin B disturbs microtubule integrity and structure in vitro and in vivo. Cytotoxicity analyses also showed that the α, ß-unsaturated carbonyl in the D ring of Laxiflorin B is responsible for mediating its covalent binding and anti-tumor activity. To assess the therapeutic effects of Laxiflorin B, we synthesized a Laxiflorin B-ALA pro-drug and delivered it by intraperitoneal injection (10 mg/kg) into a 4T1 orthotopic tumor mouse model. Drug treatment had anti-tumor effects without inducing notable weight loss or organ dysfunction. We conclude that Laxiflorin B is a promising colchicine binding site inhibitor that might be exploited in the context of TNBC treatment in the future.

Sputum pathogen spectrum and clinical outcomes of upper respiratory tract infection in bronchiectasis exacerbation: a prospective cohort study.

Upper respiratory tract infection (URTI) is common in humans. We sought to profile sputum pathogen spectrum and impact of URTI on acute exacerbation of bronchiectasis (AE). Between March 2017 and December 2021, we prospectively collected sputum from adults with bronchiectasis. We stratified AEs into events related (URTI-AE) and unrelated to URTI (non-URTI-AE). We captured URTI without onset of AE (URTI-non-AE). We did bacterial culture and viral detection with polymerase chain reaction, and explored the pathogen spectrum and clinical impacts of URTI-AE via longitudinal follow-up. Finally, we collected 479 non-AE samples (113 collected at URTI-non-AE and 225 collected at clinically stable) and 170 AE samples (89 collected at URTI-AE and 81 collect at non-URTI-AE). The viral detection rate was significantly higher in URTI-AE (46.1%) than in non-URTI-AE (4.9%) and URTI-non-AE (11.5%) (both P < 0.01). Rhinovirus [odds ratio (OR): 5.00, 95% confidence interval (95%CI): 1.06-23.56, P = 0.03] detection was independently associated with URTI-AE compared with non-URTI-AE. URTI-AE tended to yield higher viral load and detection rate of rhinovirus, metapneumovirus and bacterial shifting compared with URTI-non-AE. URTI-AE was associated with higher initial viral loads (esp. rhinovirus, metapneumovirus), greater symptom burden (higher scores of three validated questionnaires) and prolonged recovery compared to those without. Having experienced URTI-AE predicted a greater risk of future URTI-AE (OR: 10.90, 95%CI: 3.60-33.05). In summary, URTI is associated with a distinct pathogen spectrum and aggravates bronchiectasis exacerbation, providing the scientific rationale for the prevention of URTI to hinder bronchiectasis progression.

[The research progress on the registration database of out-of-hospital cardiac arrest].

Out-of-hospital cardiac arrest (OHCA) with high mortality and disable rate is a public health problem of common concern all over the world. In order to improve the survival rate of OHCA, developed countries such as Europe and the United States have established regional and even national OHCA registration database for continuous monitoring and quality improvement of OHCA, identifying the weaknesses in each link of the survival chain, and evaluating effective measures to enhance the survival rate. At present, China still lacks of registration database that can comprehensively collect the information of OHCA and effectively reflect the treatment status and research direction of OHCA. In order to shorten the huge gap of OHCA survival rate between China and developed countries such as Europe and the United States, we should learn from the experience of foreign registration databases and establish OHCA registration database suitable for China's national conditions, so as to promote the improvement of OHCA survival rate in China. This paper presents several major OHCA registry databases of the internationally recognized,such as cardiac arrest registry to enhance survival (CARES), resuscitation outcomes consortium (ROC), European registry of cardiac arrest (EuReCa), Pan-Asian resuscitation outcomes registry (PAROS), and Australian resuscitation outcome consortium (Aus-ROC), aims to provide a reference for promoting the construction of the cardiac arrest registration database in China.

The Epigenetic Regulation of Nonhistone Proteins by SETD7: New Targets in Cancer.

Epigenetic modifications are essential mechanism by which to ensure cell homeostasis. One such modification is lysine methylation of nonhistone proteins by SETD7, a mono-methyltransferase containing SET domains. SETD7 methylates over 30 proteins and is thus involved in various classical pathways. As such, SETD7 has been implicated in both the basic functions of normal tissues but also in several pathologies, such as cancers. In this review, we summarize the current knowledge of SETD7 substrates, especially transcriptional-related proteins and enzymes, and their putative roles upon SETD7-mediated methylation. We focus on the role of SETD7 in cancers, and speculate on the possible points of intervention and areas for future research.

Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor.

Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.

YT521-B homology domain family proteins as N6-methyladenosine readers in tumors.

N6-methyladenosine (m6A) is the most abundant internal chemical modification of eukaryotic mRNA and plays diverse roles in gene regulation. The m6A modification plays a significant role in numerous cancer types, including kidney, stomach, lung, bladder tumors, and melanoma, through varied mechanisms. As direct m6A readers, the YT521-B homology domain family proteins (YTHDFs) play a key role in tumor transcription, translation, protein synthesis, tumor stemness, epithelial-mesenchymal transition (EMT), immune escape, and chemotherapy resistance. An in-depth understanding of the molecular mechanism of YTHDFs is expected to provide new strategies for tumor treatment. In this review, we provide a systematic description of YTHDF protein structure and its function in tumor progression.

The association between low calf circumference and mortality: a systematic review and meta-analysis.

PURPOSE: Low calf circumference is an important indicator of malnutrition and has been widely studied, especially among older adults. However, data on the association between low calf circumference and mortality have been inconsistent. This systematic review was aimed to quantify this association. METHODS: The internet databases (PubMed, Embase, ScienceDirect and Cochrane Library databases) were systematically searched from inception to November 01, 2021 for studies investigating the association between low calf circumference and mortality. A random effects model was adopted to pool the relevant data. RESULTS: Low calf circumference was associated with a higher risk of mortality than normal calf circumference, with a pooled HR of 2.42 (95% CI 1.97-2.97, I2 = 74.3%). In addition, this association between low calf circumference and morality was still statistically significant in the subgroup analysis across different settings, including hospitals (pooled HR = 2.63, 95% CI 1.93-3.58), nursing homes (pooled HR = 2.49, 95% CI 1.76-3.54), and communities (pooled HR = 2.22, 95% CI 1.60-3.07). Other subgroup analyses based on different cutoffs of calf circumference showed that, compared to individual with normal calf circumference, participants with low calf circumference had an increased risk of mortality (pooled HR = 2.66, 95% CI 2.06-3.43) when using the Asian Working Group for Sarcopenia (AWGS) criterion (≤ 34 cm for males and ≤ 33 cm for females). Similar results were found when the Mini Nutritional Assessment (MNA) criterion (≤ 31 cm) was used, with a pooled HR of 2.11 (95% CI 1.59-2.81). CONCLUSION: Calf circumference, which is simple and convenient to measure, could be used to stratify the high-risk group, as low calf circumference was significantly associated with mortality among patients. Interventions, including exercise and nutrition programs, could be conducted promptly once low calf circumference is detected.

Network Meta-Analysis of Acupoint Catgut Embedding in Treatment of Simple Obesity.

Objective: To evaluate the clinical efficacy of acupoint catgut embedding in the treatment of simple obesity through network meta-analysis. Methods: PubMed, Cochrane, Embase, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP database (VIP) were searched by using computer from 2011 to August 2021, and 35 RCT studies were retrieved. The quality of the literature was evaluated using the modified Jadad scoring table, and Stata 15.0 software was used for traditional meta-analysis and network meta-analysis. Results: Thirty-five RCTs (3040 cases in total) were included. Acupoint embedding, acupuncture, electroacupuncture, TCM, acupoint embedding + acupuncture, acupoint embedding + exercise diet therapy, acupoint embedding + TCM, exercise diet therapy, acupoint embedding + moxibustion, and acupoint embedding + cupping were investigated in the studies. The results of network meta-analysis were as follows: in terms of total effective rate, acupoint catgut embedding was superior to acupuncture, electroacupuncture, and exercise diet therapy (P < 0.05); electroacupuncture, acupoint catgut embedding + acupuncture, acupoint catgut embedding + exercise diet therapy, acupoint catgut + TCM, acupoint catgut + moxibustion, and acupoint catgut + cupping were superior to acupuncture (P < 0.05); acupoint catgut + moxibustion was superior to electroacupuncture (P < 0.05); acupoint catgut + TCM, acupoint catgut + moxibustion, and acupoint catgut + cupping were superior to TCM treatment (P < 0.05); and electroacupuncture, acupoint catgut, acupoint catgut + acupuncture, acupoint catgut + exercise diet therapy, acupoint catgut + TCM, acupoint catgut embedding + moxibustion, and acupoint catgut embedding + cupping were superior to sports diet therapy (P < 0.05). Regarding weight loss, acupuncture treatment was superior to acupoint catgut embedding therapy (P < 0.05); acupoint catgut embedding + exercise diet therapy, acupoint catgut embedding + TCM, acupoint catgut embedding + moxibustion, and acupoint catgut embedding + cupping were superior to acupuncture and electroacupuncture treatment (P < 0.05); acupoint catgut embedding + exercise diet therapy, acupoint catgut embedding + TCM, and acupoint catgut embedding + moxibustion were superior to TCM treatment (P < 0.05); and acupoint catgut embedding, acupoint catgut embedding + acupuncture, catgut embedding + exercise diet therapy, acupoint catgut embedding + TCM, acupoint catgut embedding + moxibustion, and acupoint catgut embedding + cupping were superior to exercise diet therapy (P < 0.05). In terms of BMI reduction, acupoint catgut embedding + moxibustion and acupoint catgut embedding + cupping were more evident than acupuncture treatment (P < 0.05); and acupoint catgut embedding + moxibustion was more evident than electroacupuncture treatment (P < 0.05). Conclusion: Acupoint catgut embedding and its combination with other therapies are the first choice for the treatment of simple obesity.

Computational approach to decode the mechanism of curcuminoids against neuropathic pain.

BACKGROUND: Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the main components of turmeric that commonly used to treat neuropathic pain (NP). However, the mechanism of the therapy is not sufficiently clarified. Herein, network pharmacology, molecular docking and molecular dynamics (MD) approaches were used to investigate the mechanism of curcuminoids for NP treatment. METHODS: Active targets of curcuminoids were obtained from the Swiss Target database, and NP-related targets were retrieved from GeneCards, OMIM, Drugbank and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. Furthermore, DAVID was used for GO and KEGG pathway enrichment analyses. Interactions between potential targets and curcuminoids were assessed by molecular docking and the MD simulations were run for 100ns to validate the docking results on the top six complexes. RESULTS: CUR, DMC, and BDMC had 100, 99 and 100 targets respectively. After overlapping with NP there were 33, 33 and 31 targets respectively. PPI network analysis of TOP 10 core targets, TNF, GSK3ß were common targets of curcuminoids. Molecular docking and MD results indicated that curcuminoids bind strongly with the core targets. The GO and KEGG showed that curcuminoids regulated nitrogen metabolism, the serotonergic synapse and ErbB signaling pathway to alleviate NP. Furthermore, specific targets in these three compounds were also analysed at the same time. CONCLUSIONS: This study systematically explored and compared the anti-NP mechanism of curcuminoids, providing a novel perspective for their utilization.

Marked Response of Rat Ileal and Colonic Microbiota After the Establishment of Alzheimer's Disease Model With Bilateral Intraventricular Injection of Aß (1-42).

Alzheimer's disease (AD) is a common neurodegenerative disease. More evidence has shown that gut microbiota is closely associated with AD. Also, studies have shown that the distribution of gut microbiota vary in different sections of the intestine. In this study, a rat model of AD was established using a bilateral intraventricular injection of ß-amyloid (1-42) [Aß (1-42)], and the behavior of rats, hippocampal Aß (1-42) deposition, and the ileal and colonic microbiota in each group were analyzed. We observed that the model rats had obvious memory and cognitive impairment, increased Aß (1-42) deposition, indicating that the AD model was successfully established. Through 16S rRNA-sequencing analysis, we found that α diversity, ß diversity, and dominant microbiota in the ileum and colon of normal rats were significantly different, showing spatial heterogeneity. Additionally, the surgery and injection of Aß (1-42) caused various degrees of disturbances in the ileal and colonic microbiota of rats. These findings provide new insights for the study of the gut microbiota of AD rats and help advance the development of therapeutic strategies for intervening AD through the gut microbiota.