Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway.

PURPOSE: Acute myeloid leukemia (AML) is a refractory hematologic malignancy that poses a serious threat to human health. Exploring alternative therapeutic strategies capable of inducing alternative modes of cell death, such as ferroptosis, holds great promise as a viable and effective intervention. METHODS: We analyzed online database data and collected clinical samples to verify the expression and function of BMAL1 in AML. We conducted experiments on AML cell proliferation, cell cycle, ferroptosis, and chemotherapy resistance by overexpressing/knocking down BMAL1 and using assays such as MDA detection and BODIPY 581/591 C11 staining. We validated the transcriptional regulation of HMGB1 by BMAL1 through ChIP assay, luciferase assay, RNA level detection, and western blotting. Finally, we confirmed the results of our cell experiments at the animal level. RESULTS: BMAL1 up-regulation is an observed phenomenon in AML patients. Furthermore, there existed a strong correlation between elevated levels of BMAL1 expression and inferior prognosis in individuals with AML. We found that knocking down BMAL1 inhibited AML cell growth by blocking the cell cycle. Conversely, overexpressing BMAL1 promoted AML cell proliferation. Moreover, our research results revealed that BMAL1 inhibited ferroptosis in AML cells through BMAL1-HMGB1-GPX4 pathway. Finally, knocking down BMAL1 can enhance the efficacy of certain first-line cancer therapeutic drugs, including venetoclax, dasatinib, and sorafenib. CONCLUSION: Our research results suggest that BMAL1 plays a crucial regulatory role in AML cell proliferation, drug resistance, and ferroptosis. BMAL1 could be a potential important therapeutic target for AML.

Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway.

Background: The COBLL1 gene has been implicated in human central obesity, fasting insulin levels, type 2 diabetes, and blood lipid profiles. However, its molecular mechanisms remain largely unexplored. Methods: In this study, we established cobll1a mutant lines using the CRISPR/Cas9-mediated gene knockout technique. To further dissect the molecular underpinnings of cobll1a during early development, transcriptome sequencing and bioinformatics analysis was employed. Results: Our study showed that compared to the control, cobll1a -/- zebrafish embryos exhibited impaired development of digestive organs, including the liver, intestine, and pancreas, at 4 days post-fertilization (dpf). Transcriptome sequencing and bioinformatics analysis results showed that in cobll1a knockout group, the expression level of genes in the Retinoic Acid (RA) signaling pathway was affected, and the expression level of lipid metabolism-related genes (fasn, scd, elovl2, elovl6, dgat1a, srebf1 and srebf2) were significantly changed (p < 0.01), leading to increased lipid synthesis and decreased lipid catabolism. The expression level of apolipoprotein genes (apoa1a, apoa1b, apoa2, apoa4a, apoa4b, and apoea) genes were downregulated. Conclusion: Our study suggest that the loss of cobll1a resulted in disrupted RA metabolism, reduced lipoprotein expression, and abnormal lipid transport, therefore contributing to lipid accumulation and deleterious effects on early liver development.

Serum untargeted lipidomic characterization in a general Chinese cohort with residual per-/polyfluoroalkyl substances by liquid chromatography-drift tube ion mobility-mass spectrometry.

Per- and polyfluoroalkyl substances (PFAS) remain controversial due to their high persistency and potential human toxicity. Although occupational exposure to PFAS has been widely investigated, the implications of PFAS occurrence in the general population remain to be unraveled. Considering that serum from most people contains PFAS, the aim of this study was to characterize the lipidomic profile in human serum from a general cohort (n = 40) with residual PFAS levels. The geometric means of ∑PFAS (11.8 and 4.4 ng/mL) showed significant differences (p < 0.05) for the samples with the highest (n = 20) and lowest (n = 20) concentrations from the general population respectively. Reverse-phase liquid chromatography coupled to drift tube ion mobility and high-resolution mass spectrometry using dual polarity ionization was used to characterize the lipid profile in both groups. The structural elucidation involved the integration of various parameters, such as retention time, mass-to-charge ratio, tandem mass spectra and collision cross section values. This approach yielded a total of 20 potential biomarkers linked to the perturbed glycerophospholipid metabolism, energy metabolism and sphingolipid metabolism. Among these alterations, most lipids were down-regulated and some specific lipids (PC 36:5, PC 37:4 and PI O-34:2) exhibited a relatively strong Spearman correlation and predictive capacity for PFAS contamination. This study could support further toxicological assessments and mechanistic investigations into the effects of PFAS exposure on the lipidome.

Caspase-1 Deficiency Modulates Adipogenesis through Atg7-Mediated Autophagy: An Inflammatory-Independent Mechanism.

Obesity stands as a significant risk factor for type 2 diabetes, hyperlipidemia, and cardiovascular diseases, intertwining increased inflammation and decreased adipogenesis with metabolic disorders. Studies have highlighted the correlation between Caspase-1 and inflammation in obesity, elucidating its essential role in the biological functions of adipose tissue. However, the impact of Caspase-1 on adipogenesis and the underlying mechanisms remain largely elusive. In our study, we observed a positive correlation between Caspase-1 expression and obesity and its association with adipogenesis. In vivo experiments revealed that, under normal diet conditions, Caspase-1 deficiency improved glucose homeostasis, stimulated subcutaneous adipose tissue expansion, and enhanced adipogenesis. Furthermore, our findings indicate that Caspase-1 deficiency promotes the expression of autophagy-related proteins and inhibits autophagy with 3-MA or CQ blocked Caspase-1 deficiency-induced adipogenesis in vitro. Notably, Caspase-1 deficiency promotes adipogenesis via Atg7-mediated autophagy activation. In addition, Caspase-1 deficiency resisted against high-fat diet-induced obesity and glucose intolerance. Our study proposes the downregulation of Caspase-1 as a promising strategy for mitigating obesity and its associated metabolic disorders.

Association between basal metabolic rate and cardio-metabolic risk factors: Evidence from a Mendelian Randomization study.

Background: Cardio-metabolic risk factors play a crucial role in the development of cardiovascular and metabolic diseases. Basal metabolic rate (BMR) is a fundamental physiological parameter that affects energy expenditure and might contribute to variations in these risk factors. However, the exact relationship between BMR and cardio-metabolic risk factors has remained unclear. Methods: We employed Mendelian Randomization (MR) analysis to explore the association between BMR (N: 534,045) and various cardio-metabolic risk factors, including body mass index (BMI, N: 681,275), fasting glucose (N: 200,622), high-density lipoprotein (HDL) cholesterol (N = 403,943), low-density lipoprotein (LDL) cholesterol (N = 431,167), total cholesterol (N: 344,278), and triglycerides (N: 441,016), C-reactive protein (N: 436,939), waist circumference (N: 232,101), systolic blood pressure (N: 810,865), diastolic blood pressure (N: 810,865), glycated haemoglobin (N: 389,889), and N-terminal prohormone brain natriuretic peptide (N: 21,758). We leveraged genetic variants strongly associated with BMR as instrumental variables to investigate potential causal relationships, with the primary analysis using the Inverse Variance Weighted (IVW) method. Results: Our MR analysis revealed compelling evidence of a causal link between BMR and specific cardio-metabolic risk factors. Specifically, genetically determined higher BMR was associated with an increased BMI (ß = 0.7538, 95% confidence interval [CI]: 0.6418 to 0.8659, p < 0.001), lower levels of HDL cholesterol (ß = -0.3293, 95% CI: 0.4474 to -0.2111, p < 0.001), higher levels of triglycerides (ß = 0.1472, 95% CI: 0.0370 to 0.2574, p = 0.0088), waist circumference (ß = 0.4416, 95% CI: 0.2949 to 0.5883, p < 0.001), and glycated haemoglobin (ß = 0.1037, 95% CI: 0.0080 to 0.1995, p = 0.0377). However, we did not observe any significant association between BMR and fasting glucose, LDL cholesterol, total cholesterol, C-reactive protein, systolic blood pressure, diastolic blood pressure, or N-terminal prohormone brain natriuretic peptide (all p-values>0.05). Conclusion: This MR study provides valuable insights into the relationship between BMR and cardio-metabolic risk factors. Understanding the causal links between BMR and these factors could have important implications for the development of targeted interventions and therapies.

Controllable Regulation of the Oxygen Redox Process in Lithium-Oxygen Batteries by High-Configuration-Entropy Spinel with an Asymmetric Octahedral Structure.

Designing bifunctional electrocatalysts to boost oxygen redox reactions is critical for high-performance lithium-oxygen batteries (LOBs). In this work, high-entropy spinel (Co0.2Mn0.2Ni0.2Fe0.2Cr0.2)3O4 (HEOS) is fabricated by modulating the internal configuration entropy of spinel and studied as the oxygen electrode catalyst in LOBs. Under the high-entropy atomic environment, the Co-O octahedron in spinel undergoes asymmetric deformation, and the reconfiguration of the electron structure around the Co sites leads to the upward shift of the d-orbital centers of the Co sites toward the Fermi level, which is conducive to the strong adsorption of redox intermediate LiO2 on the surface of the HEOS, ultimately forming a layer of a highly dispersed Li2O2 thin film. Thin-film Li2O2 is beneficial for ion diffusion and electron transfer at the electrode-electrolyte interface, which makes the product easy to decompose during the charge process, ultimately accelerating the kinetics of oxygen redox reactions in LOBs. Based on the above advantages, HEOS-based LOBs deliver high discharge/charge capacity (12.61/11.72 mAh cm-2) and excellent cyclability (424 cycles). This work broadens the way for the design of cathode catalysts to improve oxygen redox kinetics in LOBs.

Identification and functional study of a novel variant of PAX9 causing tooth agenesis.

OBJECTIVES: To search for pathogenic gene of a family with non-syndromic tooth agenesis, and explore the possible pathogenesis. MATERIALS AND METHODS: A Chinese family with non-syndromic tooth agenesis was recruited and screened for the pathogenic variants by whole exome sequencing technology and co-segregation analysis. The subcellular localization of wild-type and mutant protein was detected by immunofluorescence assay. Cycloheximide chase assay was performed to examine the difference in degradation rate between mutant protein and wild-type one. Dual-luciferase reporter assays were conducted to explore the alterations of mutant protein in the regulation of downstream target genes. RESULTS: A novel missense variant of PAX9 (c.296C>A:p.A99D) was found in this family. Bioinformatics software showed ß-return and the random coil were shortened in the p.A99D. The variant did not affect the subcellular localization of PAX9, but the degradation rate of p.A99D was accelerated (p < 0.05). p.A99D inhibited the activation of downstream target gene BMP4 (p < 0.05). CONCLUSIONS: This novel variant expands the pathogenic gene spectrum. The variant impaired the protein structure, accelerated the degradation of protein, and inhibited the activation of the downstream target gene BMP4, an upstream molecule in the TGF-ß/BMP pathway, which may contribute to tooth agenesis in this family.

Study on the interaction protein of transcription factor Smad3 based on TurboID proximity labeling technology.

TurboID is a highly efficient biotin-labelling enzyme, which can be used to explore a number of new intercalating proteins due to the very transient binding and catalytic functions of many proteins. TGF-ß/Smad3 signaling pathway is involved in many diseases, especially in diabetic nephropathy and inflammation. In this paper, a stably cell line transfected with Smad3 were constructed by using lentiviral infection. To further investigate the function of TGF-ß/Smad3, the protein labeling experiment was conducted to find the interacting protein with Smad3 gene. Label-free mass spectrometry analysis was performed to obtain 491 interacting proteins, and the interacting protein hnRNPM was selected for IP and immunofluorescence verification, and it was verified that the Smad3 gene had a certain promoting effect on the expression of hnRNPM gene, and then had an inhibitory effect on IL-6. It lays a foundation for further study of the function of Smad3 gene and its involved regulatory network.

Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study.

BACKGROUND: Myocardial infarction (MI) is a critical cardiovascular event with multifaceted etiology, involving several genetic and environmental factors. It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis. METHODS: This study employed a bidirectional Mendelian randomization (MR) approach to investigate the causal relationships between plasma metabolites and MI risk. We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa. In addition, the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite (1400 metabolites) and MI (20,917 individuals with MI and 440,906 individuals without MI) susceptibility. Inverse variance weighted was the primary method for estimating causal effects. MR estimates are expressed as beta coefficients or odds ratio (OR) with 95% CI. RESULTS: We identified 14 plasma metabolites associated with the occurrence of MI (P < 0.05), among which 8 plasma metabolites [propionylglycine levels (OR = 0.922, 95% CI: 0.881-0.965, P < 0.001), gamma-glutamylglycine levels (OR = 0.903, 95% CI: 0.861-0.948, P < 0.001), hexadecanedioate (C16-DC) levels (OR = 0.941, 95% CI: 0.911-0.973, P < 0.001), pentose acid levels (OR = 0.923, 95% CI: 0.877-0.972, P = 0.002), X-24546 levels (OR = 0.936, 95% CI: 0.902-0.971, P < 0.001), glycine levels (OR = 0.936, 95% CI: 0.909-0.964, P < 0.001), glycine to serine ratio (OR = 0.930, 95% CI: 0.888-0.974, P = 0.002), and mannose to trans-4-hydroxyproline ratio (OR = 0.912, 95% CI: 0.869-0.958, P < 0.001)] were correlated with a decreased risk of MI, whereas the remaining 6 plasma metabolites [1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) levels (OR = 1.051, 95% CI: 1.018-1.084, P = 0.002), behenoyl dihydrosphingomyelin (d18:0/22:0) levels (OR = 1.076, 95% CI: 1.027-1.128, P = 0.002), 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels (OR = 1.067, 95% CI: 1.027-1.109, P = 0.001), alpha-ketobutyrate levels (OR = 1.108, 95% CI: 1.041-1.180, P = 0.001), 5-acetylamino-6-formylamino-3-methyluracil levels (OR = 1.047, 95% CI: 1.019-1.076, P < 0.001), and N-acetylputrescine to (N (1) + N (8))-acetylspermidine ratio (OR = 1.045, 95% CI: 1.018-1.073, P < 0.001)] were associated with an increased risk of MI. Furthermore, we also observed that the mentioned relationships were unaffected by horizontal pleiotropy (P > 0.05). On the contrary, MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites (P > 0.05 for each comparison). CONCLUSIONS: Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI, among which 13 plasma metabolites have not been reported previously. These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.

A randomized trial of Bacteroides fragilis 839 on preventing chemotherapy-induced myelosuppression and gastrointestinal adverse effects in breast cancer patients.

BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic ß Cells Via the IRS1/GLUT4 Pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a commonly observed complication associated with obesity. The effect of fibroblast growth factor 19 (FGF19), a promising therapeutic agent for metabolic disorders, on pancreatic ß cells in obesity-associated T2DM remains poorly understood. METHODS: Human pancreatic ß cells were cultured with high glucose (HG) and palmitic acid (PA), followed by treatment with FGF19. The cell proliferation, apoptosis, and insulin secretion were evaluated by CCK-8, qRT-PCR, ELISA, flow cytometry, and western blotting. The expression of the insulin receptor substrate (IRS)/glucose transporter (GLUT) pathway was evaluated. The interaction between FGF19 and IRS1 was predicted using the STRING database and verified by co-immunoprecipitation and immunofluorescence. The regulatory effects of the IRS1/GLUT4 pathway on human pancreatic ß cells were assessed by overexpressing IRS1 and silencing IRS1 and GLUT4. RESULTS: HG+PA treatment reduced the human pancreatic ß cell proliferation and insulin secretion and promoted cell apoptosis. However, FGF19 treatment restored these alterations and significantly increased the expressions of IRS1, GLUT1, and GLUT4 in the IRS/GLUT pathway. Furthermore, FGF19 and IRS1 were found to interact. IRS1 overexpression partially promoted the proliferation of pancreatic ß cells and insulin secretion through GLUT4. Additionally, the silencing of IRS1 or GLUT4 attenuated the therapeutic effects of FGF19. CONCLUSION: In conclusion, FGF19 partly promoted the proliferation and insulin secretion of human pancreatic ß cells and inhibited apoptosis by upregulating the IRS1/GLUT4 pathway. These findings establish a theoretical framework for the clinical utilization of FGF19 in the treatment of obesity-associated T2DM.

Optimized Lithium Ion Coordination via Chlorine Substitution to Enhance Ionic Conductivity of Garnet-Based Solid Electrolytes.

Garnet-type solid-state electrolytes attract abundant attentions due to the broad electrochemical window and remarkable thermal stability while their poor ionic conductivity obstructs their widespread application in all-solid-state batteries. Herein, the enhanced ionic conductivity of garnet-type solid electrolytes is achieved by partially substituting O2- sites with Cl- anions, which effectively reduce Li+ migration barriers while preserving the highly conductive cubic phase of garnet-type solid-state electrolytes. This substitution not only weakens the anchoring effect of anions on Li+ to widen the size of Li+ diffusion channel but also optimizes the occupancy of Li+ at different sites, resulting in a substantial reduction of the Li+ migration barrier and a notable improvement in ionic conductivity. Leveraging these advantageous properties, the developed Li6.35 La3 Zr1.4 Ta0.6 O11.85 -Cl0.15 (LLZTO-0.15Cl) electrolyte demonstrates high Li+ conductivity of 4.21×10-6  S cm-1 . When integrated with LiFePO4 (LFP) cathode and metallic lithium anode, the LLZTO-0.15Cl electrolyte enables the solid-state battery to operate for more than 100 cycles with a high capacity retention of 76.61% and superior Coulombic efficiency of 99.48%. This work shows a new strategy for modulating anionic framework to enhance the conductivity of garnet-type solid-state electrolytes.

Robust tests for multivariate repeated measures with small samples.

Multivariate repeated measures data naturally arise in clinical trials and other fields such as biomedical science, public health, agriculture, social science and so on. For data of this type, the classical approach is to conduct multivariate analysis of variance (MANOVA) based on Wilks' Lambda and other multivariate statistics, which require the assumptions of multivariate normality and homogeneity of within-cell covariance matrices. However, data being analyzed nowadays show marked departure from multivariate normality and homogeneity. This paper proposes a finite-sample test by modifying the sums of squares matrices to make them insensitive to the heterogeneity in MANOVA. The proposed test is invariant to affine transformation and robust against nonnormality. The proposed method can be used in various experimental designs, for example, factorial design and crossover design. Under various simulation settings, the proposed method outperforms the classical Doubly Multivariate Model and Multivariate Mixed Model proposed elsewhere, especially for unbalanced sample sizes with heteroscedasticity. The applications of the proposed method are illustrated with ophthalmology data in factorial and crossover designs. The proposed method successfully identified and validated a significant main effect and demonstrated that univariate analysis could be oversensitive to small but clinically unimportant interactions.

Outcomes of antiretroviral treatment for 0-14-year-old children living with HIV in Ganzhou, China, 2006-2023.

BACKGROUND: Studies on antiretroviral therapy (ART) in children living with HIV (CLHIV) are limited due to the small population and low accession rate of ART. METHODS: All 0-14-year-old CLHIV admitted to the Ganzhou Center for Disease Control and Prevention from January 2006 to June 2023 were included retrospectively. The information of treatment regimens, disease progression, and laboratory tests of the patients under ART were used to explore the outcomes and impacts of long-term ART. The normality of all the data was tested by the Shapiro-Wilk test. RESULTS: From 2006 to 2023, 18 CLHIV were reported in Ganzhou. Among them, 11 received ART and were followed up for 60.0 ± 48.4 months. After receiving ART, the median viral load of them decreased from 89,600 copies/ml to 22 copies/ml (P = 0.007), the median CD4+ T cell count increased from 380.7 cells/µL to 661.9 cells/µL (P = 0.028), and the median CD8+ T cell count decreased from 1065.8 cells/µL to 983.3 cells/µL (P = 0.584). The laboratory test results regarding liver function, renal function, blood cell count, and glucolipid metabolism tended to be within normal reference ranges, and the mean height-for-age z-score and weight-for-age z-score increased. However, all the three CLHIV who received cotrimoxazole developed pneumocystis carinii pneumonia, upper respiratory infection, skin lesions, bacterial pneumonia and/or thrush; the mean body-mass-index-for-age z-score decreased from 0.52 to -0.63. CONCLUSION: For CLHIV, ART could effectively inhibit the replication of HIV and improve the immune function of patients. More studies that focus on ART in CLHIV are urgently needed.

Perception of visual variance is mediated by subcortical mechanisms.

Variance characterizes the structure of the environment. This statistical concept plays a critical role in evaluating the reliability of evidence for human decision-making. The present study examined the involvement of subcortical structures in the processing of visual variance. To this end, we used a stereoscope to sequentially present two circle arrays in a dichoptic or monocular fashion while participants compared the perceived variance of the two arrays. In Experiment 1, two arrays were presented monocularly to the same eye, dichopticly to different eyes, or binocularly to both eyes. The variance judgment was less accurate in different-eye condition than the other conditions. In Experiment 2, the first circle array was split into a large-variance and a small-variance set, with either the large-variance or small-variance set preceding the presentation of the second circle array in the same eye. The variance of the first array was judged larger when the second array was preceded by the large-variance set in the same eye, showing that the perception of variance was modulated by the visual variance processed in the same eye. Taken together, these findings provide evidence for monocular processing of visual variance, suggesting that subcortical structures capture the statistical structure of the visual world.

Evaluation of bevacizumab biosimilar on wound healing complications in patients with colorectal cancer undergoing endoscopic mucosal resection: A systematic review and meta-analysis in anorectal medicine.

Complications related to wound healing pose substantial obstacle in the management of colorectal cancer (CRC), specifically in the field of anorectal medicine. Biosimilars of bevacizumab have emerged as crucial therapeutic agents in the management of these complications. With the particular emphasis on effects of Bevacizumab Biosimilar Plus on wound healing among patients diagnosed with CRC, this review underscores the potential of this anorectal medication to improve patient outcomes and was aimed to assess the safety and efficacy of Bevacizumab Biosimilar Plus in relation to complications associated with wound healing in patients with CRC. The assessment centers on its therapeutic potential and safety profile within the domain of anorectal medicine. In accordance with the PRISMA guidelines, a comprehensive literature search was performed, resulting in the identification of 19 pertinent studies out of an initial 918. Priority was given to assessing the safety and adverse effects of Bevacizumab Biosimilar Plus in conjunction with its effectiveness in wound healing. The extracted data comprised the following: study design, patient demographics, comprehensive treatment regimens, wound healing-specific outcomes and adverse effects. The evaluation of study quality was conducted utilizing the instruments provided by the Cochrane Collaboration and the Newcastle-Ottawa Scale (NOS). Bevacizumab Biosimilar Plus demonstrates efficacy in the management of wound healing complications among patients with CRC, with a safety and efficacy profile similar to that of the original Bevacizumab, according to the analysis. Notably, several studies reported improved rates of wound healing in relation to the biosimilar. The safety profiles exhibited similarities to the anticipated anti-VEGF agent effects. In wound management, the biosimilar also demonstrated advantages in terms of prolonged efficacy. In addition, analyses of cost-effectiveness suggested that the use of biosimilars could result in cost reductions. Bevacizumab Biosimilar Plus exhibited potential as an anorectal medication for the effective management of wound healing complications in patients with CRC. This has substantial ramifications for improving the quality of patient care, encompassing the affordability and effectiveness of treatments.

The effects and mechanisms of modified Xiaoyaosan on chronic unpredictable mild stress (CUMS)-induced depressive mice based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Clinical research and basic scientific experiments have shown that modified Xiaoyaosan (MXYS) has antidepressant effects, whose system mechanism however has not been thoroughly characterized. AIM OF THE STUDY: This research was aimed at evaluating the treatment effects of MXYS on chronic unpredictable mild stress (CUMS)-induced depressive mice and exploring underlying mechanisms. MATERIALS AND METHODS: Whether MXYS has effects on depression was investigated via the depressive behaviors of mice, electron microscopy, real-time quantitative polymerase chain reaction (RT-qPCR), Western blot analysis, immunofluorescence (IF) staining and the stereotaxic injection of adeno-associated viruses (AAVs). In addition, network pharmacology was applied to predict relevant molecular targets and possible mechanisms and perform further in vivo validation. RESULTS: MXYS is effective in ameliorating the depression-like symptoms of CUMS mice. It can stimulate autophagosome formation, activate the expression of microtubule-associated protein 1 light chain 3 (LC3B), autophagy-related gene 5 (Atg5), Atg7 and neuron-specific nuclear protein (NeuN), and decrease the protein expression sequestosome 1 (SQSTM1/p62). The autophagy-upregulating effect of MXYS was weakened by silencing. The network pharmacology analysis revealed that mitogen-activated protein kinase 1 (MAPK1), MAPK3, serine/threonine-protein kinase (AKT1), proto-oncogene tyrosine-protein kinase (SRC), PI 3 kinase p85 alpha (PIK3R1), catenin (cadherin-associated protein) beta 1 (CTNNB1) and human thrombin activator 1 (HRAS) may be of importance to treat depression by MXYS. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that metabolic and autophagy pathways, pathways in cancer and MAPK, phosphoinositide 3-kinase (PI3K)-Akt and rhoptry-associated protein 1 (Rap1) signaling pathways are involved in the antidepressant effects of MXYS. As suggested by Western blot, the anti-depression mechanism of MXYS is possibly associated with the extracellular signal-regulated protein kinase (ERK)/P38 MAPK signaling pathway. CONCLUSION: The findings indicate the possible antidepressant effects of MXYS on CUMS mice via triggering autophagy to alleviate neuronal apoptosis and prompting autophagy, which may involve the ERK/P38 MAPK signaling pathway.

High-Performance Supercapacitors Using Hierarchical And Sulfur-Doped Trimetallic NiCo/NiMn Layered Double Hydroxides.

A supercapacitor features high power density and long cycling life. However, its energy density is low. To ensemble a supercapacitor with high power- and energy-densities, the applied capacitor electrodes play the key roles. Herein, a high-performance capacitive electrode is designed and grown on a flexible carbon cloth (CC) substrate via a hydrothermal reaction and a subsequent ion exchange sulfuration process. It has a 3D heterostructure, consisting of sulfur-doped NiMn-layered double hydroxide (LDH) nanosheets (NMLS) and sulfur-doped NiCo-LDH nanowires (NCLS). The electrode with sheet-shaped NMLS and wire-shaped NCLS on their top (NMLS@NCLS/CC) increases the available surface area, providing more pseudocapacitive sites. It exhibits a gravimetric capacity of 555.2 C g-1 at a current density of 1 A g-1 , the retention rate of 75.1% when the current density reaches up to 20 A g-1 , as well as superior cyclic stability. The assembled asymmetric supercapacitor that is composed of a NMLS@NCLS/CC positive electrode and a sulfurized activated carbon negative electrode presents a maximum energy density of 24.2 Wh kg-1 and a maximum power density of 16000 W kg-1 . In this study, a facile strategy for designing hierarchical LDH materials is demonstrated as well as their applications in advanced energy storage systems.

Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.