Genistein alleviates dextran sulfate sodium-induced colitis in mice through modulation of intestinal microbiota and macrophage polarization.

OBJECTIVES: Ulcerative colitis (UC) is a colonic immune system disorder, manifested with long duration and easy relapse. Genistein has been reported to possess various biological activities. However, it remains unclear whether genistein can ameliorate UC by modulating the homeostasis of the intestinal bacterial community. METHODS: The dextran sodium sulfate (DSS)-induced UC mice were administrated with genistein (20 mg/kg/day) or genistein (40 mg/kg/day) for ten days. The general physical condition of the mice was monitored. After sacrifice, the changes in colon length and colonic pathological morphology were observed. The expression of intestinal barrier proteins, inflammatory cytokines, and macrophage markers in the colon was detected. The composition and metabolic products of the intestinal microbiota were analyzed. RESULTS: Genistein treatment visibly improved body weight change and disease activity index in DSS-induced mice. Genistein treatment ameliorated colonic pathological alterations and promoted the expression of mucin-2 and tight junction proteins. Genistein administration inhibited myeloperoxidase activity and colonic inflammatory cytokines. Furthermore, genistein administration improved the structure of the intestinal microbial community, promoted the production of short-chain fatty acids, and modulated macrophage polarization. CONCLUSIONS: These results revealed that genistein mediated macrophage polarization balance by improving intestinal microbiota and its metabolites, thereby alleviating DSS-induced colitis.

Safety and effectiveness of SARS-CoV-2 vaccines: A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the effectiveness and safety of the SARS-CoV-2 vaccines currently undergoing clinical trials. METHODS: PubMed, EMBASE, and Cochrane Library databases were searched to collect open human COVID-19 vaccines randomized controlled trials, without limiting the search time and language. The research papers collected in the above-mentioned databases were initially screened according to the title and abstract content and merged, and the repeated ones were removed. After reading the full text of the remaining research, the studies that did not meet the inclusion criteria were excluded, and finally, nine studies were obtained. After extracting the statistical data of adverse events in the study, load them into Review Manager for heterogeneity analysis. RESULTS: The incidence of adverse reactions of inactivated virus vaccines, RNA vaccines, and adenovirus vector vaccines was higher than that of placebo. Common adverse reactions included pain, swelling, and fever at the injection site. CONCLUSION: From the perspective of effectiveness, RNA vaccine > adenovirus vector vaccine > inactivated virus vaccine. From the perspective of safety, the incidence of adverse reactions of the three vaccines is higher than that of a placebo, and the incidence of adverse reactions of the adenovirus vector vaccine is higher.

Real-Time and In-Situ Monitoring of H2O2 Release from Living Cells by a Stretchable Electrochemical Biosensor Based on Vertically Aligned Gold Nanowires.

Traditional electrochemical biosensing electrodes (e.g., gold disk, glassy carbon electrode, etc.) can undergo sophisticated design to detect chemicals/biologicals from cells. However, such electrodes are typically rigid and nonstretchable, rendering it challenging to detect cellular activities in real-time and in situ when cells are in mechanically deformed states. Here, we report a new stretchable electrochemical cell-sensing platform based on vertically aligned gold nanowires embedded in PDMS (v-AuNWs/PDMS). Using H2O2 as a model analyte, we show that the v-AuNWs/PDMS electrode can display an excellent sensing performance with a wide linear range, from 40 µM to 15 mM, and a high sensitivity of 250 mA/cm2/M at a potential of -0.3 V. Moreover, living cells can grow directly on our stretchable high-surface area electrodes with strong adhesion, demonstrating their excellent biocompatibility. Further cell stimulation by adding chemicals induced H2O2 generation, which can be detected in real-time and in situ using our v-AuNWs/PDMS platform for both natural and stretched states of cells. Our results indicate the v-AuNWs/PDMS electrochemical biosensor may serve as a general cell-sensing platform for living organisms under deformed states.

Embedding Pinhole Vertical Gold Nanowire Electronic Skins for Braille Recognition.

Electronic skins (e-skins) have the potential to be conformally integrated with human body to revolutionize wearable electronics for a myriad of technical applications including healthcare, soft robotics, and the internet of things, to name a few. One of the challenges preventing the current proof of concept translating to real-world applications is the device durability, in which the strong adhesion between active materials and elastomeric substrate or human skin is required. Here, a new strategy is reported to embed vertically aligned standing gold nanowires (v-AuNWs) into polydimethylsiloxane, leading to a robust e-skin sensor. It is found that v-AuNWs with pinholes can have an adhesion energy 18-fold greater than that for pinhole-free v-AuNWs. Finite element modeling results show that this is due to friction force from interfacial embedment. Furthermore, it is demonstrated that the robust e-skin sensor can be used for braille recognition.

Alisol A 24-Acetate Isolated from the Alismatis Rhizoma Improves Hepatic Lipid Deposition in Hyperlipidemic Mice by ABCA1/ABCG1 Pathway.

The Alisol A 24-acetate is an effective component of the Alismatis Rhizoma (AR) extract, which is often used in the treatment of hyperlipidemia. This study explored the effect and mechanism of the Alisol A 24-acetate from AR on lipid deposition in the liver of hyperlipidemic mice. After establishing hyperlipidemic mouse model (Model) by oral high-fat diet (HFD), the animals were treated with Alisol A 24-acetate for 4 weeks. The changes of blood lipid in mice were detected by ELISA. Hematoxylin and eosin (H&E) staining was used to evaluate the degree of liver lipid deposition in hyperlipidemic mice. Quantitative reverse transcriptase PCR (RT-qPCR) was used to detect the expression of ABCG1 and ABCA1 mRNA in the liver. The expression of ABCG1 and ABCA1 protein was detected by Western blotting (WB). After 4 weeks of high-fat diet, the levels of TC, TG, and LDL-C in the mouse were increased, and the HDL-C level was decreased. After treatment with Alisol A 24-acetate, the levels of TC, TG, and LDL-C in the blood of hyperlipidemic mouse were significantly reduced, and the level of HDL-C was increased. The results of H&E staining showed that the lipid deposition in the liver of hyperlipidemic mouse was improved after treatment with Alisol A 24-acetate. RT-qPCR and WB analysis documented that ABCG1 and ABCA1 mRNA and protein expression in hyperlipidemic mice were promoted after the Alisol A 24-acetate treatment. In conclusion, Alisol A 24-acetate effectively alleviates the liver lipid deposition in hyperlipidemic mice, and this effect is achieved mostly by promoting the expression of ABCG1 and ABCA1 at the mRNA and protein levels.

Vertical Gold Nanowires Stretchable Electrochemical Electrodes.

Conventional electrodes produced from gold or glassy carbon are outstanding electrochemical platforms for biosensing applications due to their chemical inertness and wide electrochemical window, but are intrinsically rigid and planar in nature. Hence, it is challenging to seamlessly integrate them with soft and curvilinear biological tissues for real-time wearable or implantable electronics. In this work, we demonstrate that vertically gold nanowires (v-AuNWs) possess an enokitake-like structure, with the nanoparticle (head) on one side and nanowires (tail) on the opposite side of the structure, and can serve as intrinsically stretchable, electrochemical electrodes due to the stronger nanowire-elastomer bonding forces preventing from interfacial delamination under strains. The exposed head side of the electrode comprising v-AuNWs can achieve a detection limit for H2O2 of 80 µM, with a linear range of 0.2-10.4 mM at 20% strain, with a reasonably high sensitivity using chronoamperometry. This excellent electrochemical performance in the elongated state, in conjunction with low-cost wet-chemistry fabrication, demonstrates that v-AuNWs electrodes may become a next-generation sensing platform for conformally integrated, in vivo biodiagnostics.

Controllable Synthesis of Few-Layer Bismuth Subcarbonate by Electrochemical Exfoliation for Enhanced CO2 Reduction Performance.

Two-dimensional (2D) engineering of materials has been recently explored to enhance the performance of electrocatalysts by reducing their dimensionality and introducing more catalytically active ones. In this work, controllable synthesis of few-layer bismuth subcarbonate nanosheets has been achieved via an electrochemical exfoliation method. These nanosheets catalyse CO2 reduction to formate with high faradaic efficiency and high current density at a low overpotential owing to the 2D structure and co-existence of bismuth subcarbonate and bismuth metal under catalytic turnover conditions. Two underlying fast electron transfer processes revealed by Fourier-transformed alternating current voltammetry (FTacV) are attributed to CO2 reduction at bismuth subcarbonate and bismuth metal. FTacV results also suggest that protonation of CO2.- is the rate determining step for bismuth catalysed CO2 reduction.

Two-port laparoscopic anterior resection through a self-made glove device versus conventional laparoscopic anterior resection for rectal cancer: a comparison of short-term surgical results.

BACKGROUND: The laparoscopic approach has become increasingly incorporated into the development of new surgical procedures. An ever-increasing number of surgeons desire methods that minimize surgical trauma and provide improved cosmetic outcomes. Since 2014, we have performed two-port laparoscopic surgery using a transumbilical multichannel glove port and a 12-mm port. The aim of this study was to compare the short-term surgical results of two-port laparoscopic anterior resection (TPLAR) with those of conventional laparoscopic anterior resection (CLAR) for rectal cancer. METHODS: Between January 2014 and May 2014, a total of 27 patients underwent TPLAR and 30 patients underwent CLAR for the treatment of rectal cancer. The short-term surgical results of these two groups of patients were analyzed retrospectively. RESULTS: The differences in operative time, blood loss, conversion rate, complication rate, distal resection margin, number of harvested lymph nodes, duration until ambulation, duration until first flatus, length of postoperative hospital stay, and overall hospital costs between the two groups were not significant. The median (range) length of the abdominal incisions of the TPLAR patients was shorter than the length of the CLAR patients (5.1 (4.5-16.3) cm vs 8.2 (7.0-10.0) cm, respectively; p < 0.001). The respective median (range) postoperative pain scores were lower in the TPLAR than in the CLAR patients at 24 h (4 (1-6) h vs 5 (2-8) h; p = 0.045), 48 h (3 (1-4) h vs 4 (range 1-8) h; P = 0.004) and 72 h (1 (0-3) h vs 2 (1-5) h; p = 0.010). The median overall score on the satisfaction-with-abdominal-incision questionnaire of the TPLAR patients was significantly higher (better) than the score of the CLAR patients. CONCLUSIONS: TPLAR for rectal cancer is safe and feasible, with short-term perioperative and oncological outcomes similar to those of CLAR. TPLAR provides less postoperative pain and better cosmetic outcomes.

Up-regulation of CX3CL1 via Nuclear Factor-κB-dependent Histone Acetylation Is Involved in Paclitaxel-induced Peripheral Neuropathy.

BACKGROUND: Up-regulation of CX3CL1 has been revealed to be involved in the neuropathic pain induced by nerve injury. However, whether CX3CL1 participates in the paclitaxel-induced painful peripheral neuropathy remains unknown. The aim of the current study was to elucidate the involvement of transcriptional factors nuclear factor-κB (NF-κB) and its causal interaction with CX3CL1 signaling in the paclitaxel-induced painful peripheral neuropathy. METHODS: Painful peripheral neuropathy induced by paclitaxel treatment was established in adult male Sprague-Dawley rats. The von Frey test were performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were performed to understand the molecular mechanisms. RESULTS: The application of paclitaxel induced an up-regulation of CX3CL1 expression in the spinal neurons, which is reduced significantly by NF-κB inhibitor ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. Blockade of either CX3CL1 (n = 12 each) or NF-κB (n = 12 each) signaling pathway attenuated mechanical allodynia induced by paclitaxel. Chromatin immunoprecipitation further found that paclitaxel induced an increased recruitment of nuclear factor-κB (NF-κB)p65 to the Cx3cl1 promoter region. Furthermore, an increased acetylation level of H4, but not H3, in Cx3cl1 promoter region in spinal neurons was detected after paclitaxel treatment, which was reversed by inhibition of NF-κB with ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. CONCLUSIONS: These findings suggest that up-regulation of CX3CL1 via NF-κB-dependent H4 acetylation might be critical for paclitaxel-induced mechanical allodynia.

Giant peritoneal loose body in the pelvic cavity confirmed by laparoscopic exploration: a case report and review of the literature.

A 51-year-old previously healthy male underwent a routine medical examination. Computed tomography and ultrasonography showed an oval-shaped mass that was about 50 × 40 mm in size in the left iliac fossa. Prior to surgery, the lesion was suspected to be a teratoma with core calcification or stromal tumor derived from the rectosigmoid colon. During the procedure, a yellow-white, egg-shaped mass was discovered that was completely free from the pelvic cavity in front of the rectum. The giant, peritoneal loose body was taken out through the enlarged port site. Histological examination showed that the mass consisted of well-circumscribed, unencapsulated, paucicellular tissue, with an obviously hyalinized fibrosclerotic center. A giant peritoneal body is extremely rare. We report such a case and review previously published literature.

ML365 ameliorates postoperative cognitive impairment in aged mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1ß expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1ß expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.

Compliant Grasping Control for a Tactile Self-Sensing Soft Gripper.

Soft grippers with good passive compliance can effectively adapt to the shape of a target object and have better safe grasping performance than rigid grippers. However, for soft or fragile objects, passive compliance is insufficient to prevent grippers from crushing the target. Thus, to complete nondestructive grasping tasks, precision force sensing and control are immensely important for soft grippers. In this article, we proposed an online learning self-tuning nonlinearity impedance controller for a tactile self-sensing two-finger soft gripper so that its grasping force can be controlled accurately. For the soft gripper, its grasping force is sensed by a liquid lens-based optical tactile sensing unit that contains a self-sensing fingertip and a liquid lens module and has many advantages of a rapid response time (about 0.04 s), stable output, good sensitivity (>0.4985 V/N), resolution (0.03 N), linearity (R2 > 0.96), and low cost (power consumption: 5 mW, preparation cost

Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis.

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.

GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

Discriminative and Robust Autoencoders for Unsupervised Feature Selection.

Many recent research works on unsupervised feature selection (UFS) have focused on how to exploit autoencoders (AEs) to seek informative features. However, existing methods typically employ the squared error to estimate the data reconstruction, which amplifies the negative effect of outliers and can lead to performance degradation. Moreover, traditional AEs aim to extract latent features that capture intrinsic information of the data for accurate data recovery. Without incorporating explicit cluster structure-detecting objectives into the training criterion, AEs fail to capture the latent cluster structure of the data which is essential for identifying discriminative features. Thus, the selected features lack strong discriminative power. To address the issues, we propose to jointly perform robust feature selection and k -means clustering in a unified framework. Concretely, we exploit an AE with a l2,1 -norm as a basic model to seek informative features. To improve robustness against outliers, we introduce an adaptive weight vector for the data reconstruction terms of AE, which assigns smaller weights to the data with larger errors to automatically reduce the influence of the outliers, and larger weights to the data with smaller errors to strengthen the influence of clean data. To enhance the discriminative power of the selected features, we incorporate k -means clustering into the representation learning of the AE. This allows the AE to continually explore cluster structure information, which can be used to discover more discriminative features. Then, we also present an efficient approach to solve the objective of the corresponding problem. Extensive experiments on various benchmark datasets are provided, which clearly demonstrate that the proposed method outperforms state-of-the-art methods.

Experimental study on a -86 °C cascade refrigeration unit with environmental-friendly refrigerants R290-R170.

Ultralow-temperature refrigeration faces significant issues linked to the security of the cold chain for the production, storage, transportation, and distribution of COVID-19 vaccines. The use of environmentally friendly refrigerants in cascade refrigeration systems (CRS) to provide low-temperature range is motivated by the high demand for ultralow-temperature refrigeration units. In the current study, a CRS is built to generate a low temperature of -86 °C for the storage of COVID-19 vaccines. In the CRS, the natural refrigerant combination R290-R170 is used as high-temperature and low-temperature fluids. The pull-down performance of the -86 °C freezer is explored experimentally, and the stable operating performance is determined at two different dry bulb and wet bulb temperatures. Various status monitors are set up to analyze the CRS's operation features, and several temperature monitors are put in the freezer to analyze temperature variations. The power consumption of the CRS is examined and evaluated. Finally, several key findings are summarized. The current work is the first to involve experimental measurements on -86 °C temperature generated by a CRS, which can substantially enhance experiment data in ultralow-temperature refrigeration and contribute to a more in-depth understanding of the operation performance of a -86 °C ultralow-temperature freezer.

[miR-497 inhibits the growth and metastasis of SGC-7901 human gastric cancer anoikis resistant cells via blocking Wnt/ß-catenin signaling pathway].

Objective To investigate the effects of microRNA497 (miR-497) on the metastasis of gastric cancer and its possible molecular mechanism. Methods SGC-7901 gastric cancer parent cells were cultured in an ultra-low adhesion environment, and the anoikis resistance model of SGC-7901 cells was created after re-adhesion. Clone formation assay, flow cytometry, TranswellTM test and scratch healing test were used to detect the differences of biological behavior compared with their parent cells. Fluorescence quantitative PCR was performed to detect the expression of miR-497. Western blot analysis was used to detect the changes of key proteins of Wnt/ß-catenin signaling pathway and epithelial mesenchymal transformation (EMT) related proteins such as vimentin and E-cadherin. Parent cells and anoikis resistant SGC-7901 cells were transfected with miR-497 inhibitor or miR-497 mimic, and CCK-8 assay was used to detect the proliferation activity. TranswellTM invasion assay was performed to detect the invasion ability of cells. TranswellTM migration test and scratch healing assay was used to determine the migration ability. Western blot analysis was used to detect the expressions of Wnt1, ß-catenin, vimentin and E-cadherin. By transfecting miR-497 mimic into the anoikis resistance SGC-7901 cells and inoculating them subcutaneously in nude mice, the changes in the volume and mass of tumor tissues were measured and recorded. Western blot analysis was used to determine the expressions of Wnt1, ß-catenin, vimentin and E-cadherin of tumor tissues. Results Compared with the parent cells, the anoikis resistance SGC-7901 gastric cancer cells had faster proliferation rate, stronger colony formation, lower apoptosis rate, stronger invasion and migration ability. The expression of miR-497 was significantly decreased. After down-regulation of miR-497, the proliferation ability, invasion and migration ability were significantly enhanced. The expressions of Wnt1, ß-catenin and vimentin increased significantly, while E-cadherin decreased notably. The results of up-regulation miR-497 were the opposite. The tumor growth rate, tumor volume and mass of miR-497 overexpression group were significantly lower than those of control group. The expressions of Wnt1, ß-catenin and vimentin decreased significantly, while the expression of E-cadherin increased significantly. Conclusion The expression of miR-497 is low in the anoikis resistance SGC-7901 cells. miR-497 can inhibit the growth and metastasis of gastric cancer cells by blocking Wnt/ß-catenin signaling pathway and EMT.

JFD, a Novel Natural Inhibitor of Keap1 Alkylation, Suppresses Intracellular Mycobacterium Tuberculosis Growth through Keap1/Nrf2/SOD2-Mediated ROS Accumulation.

It is an effective strategy to treat tuberculosis by enhancing reactive oxygen species- (ROS-) mediated killing of Mycobacterium tuberculosis in macrophages, but there are no current therapeutic agents targeting this pathway. Honeysuckle has been used as the traditional medicine for tuberculosis treatment for 1500 years. Japoflavone D (JFD) is a novel biflavonoid isolated from Honeysuckle promoting ROS accumulation by Nrf2 pathway in hepatocarcinoma cells. However, its activity to kill M. tuberculosis in macrophages and molecular mechanism has not been reported. Our results showed that JFD enhances the M. tuberculosis elimination by boosting ROS levels in THP-1 cells. Moreover, the massive ROS accumulation activates p38 to induce apoptosis. Notably, the mechanism revealed that JFD suppresses the nuclear transport of Nrf2, thereby inhibiting SOD2 transcription, leading to a large ROS accumulation. Further studies showed that JFD disrupts the Keap1 alkylation at specific residues Cys14, Cys257, and Cys319, which is crucial for Nrf2 activation, thereby interrupts the nuclear transport of Nrf2. In pharmacokinetic study, JFD can stay as the prototype for 24 h in mice and can be excreted in feces without any toxicity. Our data reveal for the first time that a novel biflavonoid JFD as a potent inhibitor of Keap1 alkylation can suppress the nuclear transport of Nrf2. And it is the first research of the inhibitor of Keap1 alkylation. Furthermore, JFD robustly promotes M. tuberculosis elimination from macrophages by inhibiting Keap1/Nrf2/SOD2 pathway, resulting in the ROS accumulation. This work identified Keap1 alkylation as a new drug target for tuberculosis and provides a preliminary basis for the development of antituberculosis lead compounds based on JFD.

FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma.

Glioma is the most common primary brain tumor. Filamin-binding LIM protein 1 (FBLIM1) has been identified in multiple cancers and is suspected of playing a part in the development of tumors. However, the potential function of FBLIM1 mRNA in glioma has not been investigated. In this study, the clinical information and transcriptome data of glioma patients were, respectively, retrieved from the TCGA and CGGA databases. The expression level of FBLIM1 mRNA was shown to be aberrant in a wide variety of malignancies. Significantly, when glioma samples were compared to normal brain samples, FBLIM1 expression was shown to be significantly elevated in the former. A poor prognosis was related to high FBLIM1 expression, which was linked to more advanced clinical stages. Notably, multivariate analyses demonstrated that FBLIM1 expression was an independent predictor for the overall survival of glioma patients. Immune infiltration analysis disclosed that FBLIM1 expression had relevance with many immune cells. The results of RT-PCR suggested that FBLIM1 expression was markedly elevated in glioma specimens. Functional experiments unveiled that the knockdown of FBLIM1 mRNA suppressed glioma cell proliferation. In general, we initially discovered that FBLIM1 mRNA might be a possible prognostic marker in glioma.

New Approach for Targeted Treatment of Mild COVID-19 by Honeysuckle through Network Pharmacology Analysis.

OBJECTIVE: To investigate the potential pharmacological value of extracts from honeysuckle on patients with mild coronavirus disease 2019 (COVID-19) infection. METHODS: The active components and targets of honeysuckle were screened by Traditional Chinese Medicine Database and Analysis Platform (TCMSP). SwissADME and pkCSM databases predict pharmacokinetics of ingredients. The Gene Expression Omnibus (GEO) database collected transcriptome data for mild COVID-19. Data quality control, differentially expressed gene (DEG) identification, enrichment analysis, and correlation analysis were implemented by R toolkit. CIBERSORT evaluated the infiltration of 22 immune cells. RESULTS: The seven active ingredients of honeysuckle had good oral absorption and medicinal properties. Both the active ingredient targets of honeysuckle and differentially expressed genes of mild COVID-19 were significantly enriched in immune signaling pathways. There were five overlapping immunosignature genes, among which RELA and MAP3K7 expressions were statistically significant (P < 0.05). Finally, immune cell infiltration and correlation analysis showed that RELA, MAP3K7, and natural killer (NK) cell are with highly positive correlation and highly negatively correlated with hematopoietic stem cells. CONCLUSION: Our analysis suggested that honeysuckle extract had a safe and effective protective effect against mild COVID-19 by regulating a complex molecular network. The main mechanism was related to the proportion of infiltration between NK cells and hematopoietic stem cells.