Role of N6-methyladenosine in tumor neovascularization.

Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m6A) modification in regulating these processes. This review explores the mechanisms by which m6A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m6A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m6A in vascular-immune crosstalk. Finally, we discuss the current development of m6A inhibitors and their potential applications, along with the contribution of m6A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m6A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m6A modulation in cancer treatment. By understanding the intricate role of m6A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m6A offers a novel approach to interfere with the tumor's ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression.

Cathepsins and cancer risk: a Mendelian randomization study.

Background: Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis. Methods: We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis. Results: After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, P = 0.001, PFDR = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, P = 0.0002, P FDR = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, P = 0.006). Conclusion: Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.

Using a DNA mini-barcode within the ITS region to identify toxic Amanita in mushroom poisoning cases.

Mushroom poisoning contributes significantly to global foodborne diseases and related fatalities. Amanita mushrooms frequently cause such poisonings; however, identifying these toxic species is challenging due to the unavailability of fresh and intact samples. It is often necessary to analyze residues, vomitus, or stomach extracts to obtain DNA sequences for the identification of species responsible for causing food poisoning. This usually proves challenging to obtain usable DNA sequences that can be analyzed using conventional molecular biology techniques. Therefore, this study aimed to develop a DNA mini-barcoding method for the identification of Amanita species. Following the evaluation and optimization of universal primers for DNA mini-barcoding in Amanita mushrooms, we found that the internal transcribed spacer (ITS) gene sequence primer ITS-a was the most suitable DNA barcode primer for identifying Amanita species. Forty-three Amanita samples were subsequently amplified and sequenced. The sequences obtained were analyzed for intra- and inter-species genetic distances, and a phylogenetic tree was constructed. The findings indicated that the designed primers had strong universality among the Amanita samples and could accurately identify the target gene fragment with a length of 290 bp. Notably, the DNA mini-barcode accurately identified the 43 Amanita samples, demonstrating high consistency with the conventional DNA barcode. Furthermore, it effectively identified DNA from digested samples. In summary, this DNA mini-barcode is a promising tool for detecting accidental ingestion of toxic Amanita mushrooms. It may be used as an optimal barcode for species identification and traceability in events of Amanita-induced mushroom poisoning. KEY POINTS: • Development of a DNA mini-barcoding method for Amanita species identification without fresh samples. • The ITS-a primer set was optimized for robust universality in Amanita samples. • The mini-barcode is suitable for screening toxic mushroom species in mushroom poisoning cases.

The causal relationship between anti-diabetic drugs and gastrointestinal disorders: a drug-targeted mendelian randomization study.

BACKGROUND: The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs. METHODS: We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn's disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control. RESULTS: Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10- 3), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10- 2), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10- 2). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10- 2). CONCLUSIONS: The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

Smart Nanoplatforms Responding to the Tumor Microenvironment for Precise Drug Delivery in Cancer Therapy.

The tumor microenvironment (TME) is a complex and dynamic entity, comprising stromal cells, immune cells, blood vessels and extracellular matrix, which is intimately associated with the occurrence and development of cancers, as well as their therapy. Utilizing the shared characteristics of tumors, such as an acidic environment, enzymes and hypoxia, researchers have developed a promising cancer therapy strategy known as responsive release of nano-loaded drugs, specifically targeted at tumor tissues or cells. In this comprehensive review, we provide an in-depth overview of the current fundamentals and state-of-the-art intelligent strategies of TME-responsive nanoplatforms, which include acidic pH, high GSH levels, high-level adenosine triphosphate, overexpressed enzymes, hypoxia and reductive environment. Additionally, we showcase the latest advancements in TME-responsive nanoparticles. In conclusion, we thoroughly examine the immediate challenges and prospects of TME-responsive nanopharmaceuticals, with the expectation that the progress of these targeted nanoformulations will enable the exploitation, overcoming or modulation of the TME, ultimately leading to significantly more effective cancer therapy.

Inhibition of pseudo-allergic reactions by vitamin K3 directly targeting GAB1 in mast cells.

BACKGROUND: Vitamin K3 (VK3), a fat-soluble synthetic analog of the vitamin K family, has coagulant, anti-inflammatory, antibacterial, and anticancer properties. Pseudo allergy is a IgE-independent immune response associated with mast cells. This study investigated the role of VK3 in IgE-independent mast cell activation. METHODS: Substance P (SP) was used to induce LAD2-cell activation in order to analyze the effects of VK3 in vitro. Cutaneous allergy and systemic allergy mouse models were used to analyze the anti-pseudo-allergic effects of VK3. Proteome microarray assays were used to analyze VK3-binding protein. Biolayer interferometry and immunoprecipitation were used to verify interaction between VK3 and its key targets. RNA interference was used to determine the role of GAB1 in LAD2cell activation. RESULTS: VK3 inhibited SP-induced LAD2-cell activation, and resulted in the release of ß-hexosaminidase, histamine and cytokines; VK3 inhibited SP-induced pseudo allergic reactions in mice, and serum histamine and TNF-α levels decreased. Degranulation of skin mast cells was reduced; GAB1 in mast cells was stably bound to VK3. GAB1 participated in SP-induced LAD2-cell activation. GAB1 knockdown in LAD2 cells prevented SP-induced ß-hexosaminidase release, calcium mobilization and cell skeletal remodeling. VK3 directly binds to GAB1 and reduces its expression to inhibited SP-induced LAD2 cell activation. CONCLUSION: The anti-pseudo-allergic activity of VK3 was confirmed in vitro and in vivo. VK3 can inhibit SP-induced mast cell activation by directly targeting GAB1. This study provides new insights on the activity of VK3 and the mechanism of pseudoallergic reaction.

Dual-ligand lanthanide metal-organic framework based ratiometric fluorescent platform for visual monitoring of aminoglycoside residues in food samples.

Herein, a dual-emission Eu metal-organic framework (Eu-MOF) is prepared and used as the ratiometric fluorescence probe for ultrasensitive detection of aminoglycoside antibiotics (AGs). Due to the strong hydrogen bond interactions between AGs and Eu-MOF, the blue emission is enhanced while the red emission has little fluctuation in Eu-MOF with the addition of AGs, thus a good linear relationship with the logarithm of AGs concentrations from 0.001 to 100 µg/mL can be established for quantitative analysis. Good sensitivity with the detection limit of 0.33 ng/mL for apramycin, 0.32 ng/mL for amikacin and 0.30 ng/mL for kanamycin is achieved. The proposed assay demonstrates good selectivity and applicability for determination of AGs in real milk and honey samples. The Eu-MOF materials are further fabricated as fluorescent test papers for facile visual detection. The as-established ratio fluorescence platform offers a portable and economical way for rapid monitoring AGs residues in complex food samples.

Organic dye-loaded reduced titanium dioxide as a broadband saturable absorber for ultrafast fiber lasers.

As a rising star among metal oxide nanomaterials, titanium dioxide (TiO2) has been widely investigated and employed in optical applications because of its excellent optical properties. In this work, we demonstrate the efficient and broadband nonlinear photonic properties of methylene blue (MB)-loaded reduced TiO2 (TiO2-x-MB) and explore the performance of a TiO2-x-MB-microfiber photonic device in broadband ultrafast photonics. Within an erbium-doped fiber laser (EDFL) system, utilizing the TiO2-x-MB-microfiber photonic device as a saturable absorber (SA), steady mode-locked pulses together with chaotic pulses were successfully achieved at the wavelength of 1.55 µm. Furthermore, by incorporating the TiO2-x-MB SA into a thulium-doped fiber laser (TDFL) system, an ultrashort single pulse and multiple pulses were obtained at 2.0 µm. These results indicate that TiO2-x-MB is an excellent nanomaterial for use in mode-locked lasers, being an alternative candidate for ultrafast fiber lasers via exploiting the chemical and physical properties of oxide nanomaterials.

PPARG-mediated autophagy activation alleviates inflammation in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood. MATERIALS AND METHODS: PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats. RESULTS: The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation. CONCLUSIONS: Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.

Development and validation of an interpretable model integrating multimodal information for improving ovarian cancer diagnosis.

Ovarian cancer, a group of heterogeneous diseases, presents with extensive characteristics with the highest mortality among gynecological malignancies. Accurate and early diagnosis of ovarian cancer is of great significance. Here, we present OvcaFinder, an interpretable model constructed from ultrasound images-based deep learning (DL) predictions, Ovarian-Adnexal Reporting and Data System scores from radiologists, and routine clinical variables. OvcaFinder outperforms the clinical model and the DL model with area under the curves (AUCs) of 0.978, and 0.947 in the internal and external test datasets, respectively. OvcaFinder assistance led to improved AUCs of radiologists and inter-reader agreement. The average AUCs were improved from 0.927 to 0.977 and from 0.904 to 0.941, and the false positive rates were decreased by 13.4% and 8.3% in the internal and external test datasets, respectively. This highlights the potential of OvcaFinder to improve the diagnostic accuracy, and consistency of radiologists in identifying ovarian cancer.

Improved Immune Response for Colorectal Cancer Therapy Triggered by Multifunctional Nanocomposites with Self-Amplifying Antitumor Ferroptosis.

Ferroptosis, as a type of regulated cell death, can trigger the release of damage-associated molecular patterns from cancer cells and lead to the enhancement of immune recognition. Fenton reaction-mediated chemodynamic therapy could initiate ferroptosis by generating lipid peroxides, but its efficiency would be greatly restricted by the insufficient H2O2 and antioxidant system within the tumor. Herein, this work reports the successful preparation of H2O2 self-supplied and glutathione (GSH)-depletion therapeutic nanocomposites (Cu2O@Au) through in situ growth of Au nanoparticles on the surface of cuprous oxide (Cu2O) nanospheres. Upon delivery into cancer cells, the released Cu2O could consume endogenous H2S within colorectal cancer cells to form Cu31S16 nanoparticles, while the released Au NPs could catalyze glucose to generate H2O2 and gluconic acid. The self-supplying endogenous H2O2 and lower acidity could amplify the Cu ion-induced Fenton-like reaction. Meanwhile, the consumption of glucose would reduce GSH generation by disrupting the pentose phosphate pathway. Additionally, the Cu2+/Cu+ catalytic cycle promotes the depletion of GSH, leading to lipid peroxide accumulation and ferroptosis. It was found that the onset of ferroptosis triggered by Cu2O@Au could initiate immunologic cell death, promote dendritic cell maturation and T-cell infiltration, and finally enhance the antitumor efficacy of the PD-L1 antibody. In summary, this collaborative action produces a remarkable antitumor effect, which provides a promising treatment strategy for colorectal cancer.

Dihydroartemisinin alleviates erosive bone destruction by modifying local Treg cells in inflamed joints: A novel role in the treatment of rheumatoid arthritis.

Treg cell-based therapy has exhibited promising efficacy in combatting rheumatoid arthritis (RA). Dihydroartemisinin (DHA) exerts broad immunomodulatory effects across various diseases, with its recent spotlight on T-cell regulation in autoimmune conditions. The modulation of DHA on Treg cells and its therapeutic role in RA has yet to be fully elucidated. This study seeks to unveil the influence of DHA on Treg cells in RA and furnish innovative substantiation for the potential of DHA to ameliorate RA. To this end, we initially scrutinized the impact of DHA-modulated Treg cells on osteoclast (OC) formation in vitro using Treg cell-bone marrow-derived monocyte (BMM) coculture systems. Subsequently, employing the collagen-induced arthritis (CIA) rat model, we validated the efficacy of DHA and probed its influence on Treg cells in the spleen and popliteal lymph nodes (PLN). Finally, leveraging deep proteomic analysis with data-independent acquisition (DIA) and parallel accumulation-serial fragmentation (PASEF) technology, we found the alterations in the Treg cell proteome in PLN by proteomic analysis. Our findings indicate that DHA augmented suppressive Treg cells, thereby impeding OC formation in vitro. Consistently, DHA mitigated erosive joint destruction and osteoclastogenesis by replenishing splenic and joint-draining lymph node Treg cells in CIA rats. Notably, DHA induced alterations in the Treg cell proteome in PLN, manifesting distinct upregulation of alloantigen Col2a1 (Type II collagen alfa 1 chain) and CD8a (T-cell surface glycoprotein CD8 alpha chain) in Treg cells, signifying DHA's targeted modulation of Treg cells, rendering them more adept at sustaining immune tolerance and impeding bone erosion. These results unveil a novel facet of DHA in the treatment of RA.

Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.

A Bibliometric and Visual Analysis of the Current Status and Trends of Forensic Mixed Stain Research.

OBJECTIVES: To explore the context and hotspot changes of forensic mixed stain research through bibliometric approach. METHODS: The literature of forensic mixed stain included in the core collection of Web of Science database from 2011 to 2022 were collected as the study object, and the annual publication number, countrie (region), institution, journal, keywords, etc. were bibliometrically and visually analyzed using the R-based Bibliometrix 1.1.6 package and VOSviewer 1.6.18 software. RESULTS: A total of 732 articles on forensic mixed stain were included from 2011 to 2022, with the annual number of articles published and the annual citation frequency showing a steady increase year by year. Among the 59 countries (regions) with the most published articles, the United States ranked first with 246 articles, followed by China with 153 articles. The literature came from 104 journals, and the total number of articles published in the top 10 journals was 633. FORENSIC SCI INT GENET ranked first with 307 articles. Visual analysis using VOSviewer software showed that keywords could be divided into four research clusters, namely the genetic marker development group (blue), the mixed stain typing analysis theory group (red), the sequencing analysis group (yellow), and the case sample research group (green). It can be divided into four development stages in terms of different time periods: early development (2011-2013), middle development (2014-2016), rapid development (2017-2020) and latest development (2021-2022). CONCLUSIONS: The number of publications by domestic and foreign scholars in the study of mixed stain in forensic science is showing a relatively stable trend. Machine learning, next generation sequencing and other research have been the hottest topics that have attracted the most attention in recent years, which is expected to further develop the theory of mixed stain typing and sequencing analysis in forensic mixed stain research.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer.

BACKGROUND: Identifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC. MATERIALS AND METHODS: In this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness. RESULTS: Age at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702-0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755-0.894] versus 0.659 [0.563-0.755], p = 0.007). CONCLUSION: The nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

Clinical observation on inverted T-shaped herb-separated moxibustion for chronic pelvic pain in sequelae of pelvic inflammatory diseases. / 倒Tå­—å½¢éš”è¯ç¸æ²»ç–—ç›†è ”ç‚Žæ€§ç–¾ç— åŽé—ç—‡æ ¢æ€§ç›†è ”ç—›ç–—æ•ˆè§‚å¯Ÿ.

OBJECTIVES: To compare the clinical effect between inverted T-shaped herb-separated moxibustion combined with western medication and simple western medication on chronic pelvic pain(CPP)in sequelae of pelvic inflammatory diseases. METHODS: A total of 60 patients with CPP in sequelae of pelvic inflammatory diseases were randomly divided into an observation group and a control group, 30 cases in each group. The control group was given ibuprofen tablets 10 days before menstruation, 0.2 g each time, once a day for 10 days. After menstruation, the medication was stopped, and the treatment was given for 3 menstrual cycles.On the basis of the treatment in the control group, the observation group was treated with inverted T-shaped herb-separated moxibustion at the connection between Zhongwan(CV 12)and Zhongji(CV 3), and the connection between Zigong(EX-CA 1)on both sides.The treatment was performed once a week, with an interval of 6 days. The moxibustion was stopped during the menstrual period, the treatment was given for 3 menstrual cycles.Before and after treatment, the visual analogue scale(VAS)score of lower abdominal and lumbosacral pain, local symptom (uterine tenderness, adnexal tenderness and uterosacral ligament tenderness) score and quality of life assessment (QOL) score of the two groups were observed. RESULTS: After treatment, the lower abdominal and lumbosacral pain VAS scores, the local symptom scores of uterine tenderness, adnexal tenderness, uterosacral ligament tenderness and total scores in the two groups were lower than those before treatment(P<0.01).The lower abdominal and lumbosacral pain VAS score in the observation group was lower than that in the control group(P<0.01),and the changes of local symptom scores of uterine tenderness, adnexal tenderness and uterosacral ligament tenderness and total score in the observation group were greater than those in the control group(P<0.01). After treatment, the QOL scores of the two groups were higher than those before treatment(P<0.01), and the score in the observation group was higher than that in the control group(P<0.01). CONCLUSIONS: Inverted T-shaped herb-separated moxibustion combined with western medication can effectively reduce the pain in patients with CPP in sequelae of pelvic inflammatory diseases, relieve the local symptoms, improve the quality of life, and the curative effect is better than western medication alone.

Hypoxia-induced ALKBH5 aggravates synovial aggression and inflammation in rheumatoid arthritis by regulating the m6A modification of CH25H.

Previous studies have shown that epigenetic factors are involved in the occurrence and development of rheumatoid arthritis (RA). However, the role of N6-methyladenosine (m6A) methylation in RA has not been determined. The aim of this study was to investigate the role and regulatory mechanisms of hypoxia-induced expression of the m6A demethylase alkB homolog 5 (ALKBH5) in RA fibroblast-like synoviocytes (FLSs). Synovial tissues were collected from RA and osteoarthritis (OA) patients, and RA FLSs were obtained. ALKBH5 expression in RA FLSs and collagen-induced arthritis (CIA) model rats was determined using quantitative reverse transcription-PCR (qRT-PCR), western blotting and immunohistochemistry (IHC). Using ALKBH5 overexpression and knockdown, we determined the role of ALKBH5 in RA FLS aggression and inflammation. The role of ALKBH5 in RA FLS regulation was explored using m6A-methylated RNA sequencing and methylated RNA immunoprecipitation coupled with quantitative real-time PCR. The expression of ALKBH5 was increased in RA synovial tissues, CIA model rats and RA FLSs, and a hypoxic environment increased the expression of ALKBH5 in FLSs. Increased expression of ALKBH5 promoted the proliferation and migration of RA-FLSs and inflammation. Conversely, decreased ALKBH5 expression inhibited the migration of RA-FLSs and inflammation. Mechanistically, hypoxia-induced ALKBH5 expression promoted FLS aggression and inflammation by regulating CH25H mRNA stability. Our study elucidated the functional roles of ALKBH5 and mRNA m6A methylation in RA and revealed that the HIF1α/2α-ALKBH5-CH25H pathway may be key for FLS aggression and inflammation. This study provides a novel approach for the treatment of RA by targeting the HIF1α/2α-ALKBH5-CH25H pathway.

Pharmacological and mechanistic aspects of quercetin in osteoporosis.

Osteoporosis (OP) is a bone disease associated with increasing age. Currently, the most common medications used to treat OP are anabolic agents, anti-resorptive agents, and medications with other mechanisms of action. However, many of these medications have unfavorable adverse effects or are not intended for long-term use, potentially exerting a severe negative impact on a patient's life and career and placing a heavy burden on families and society. There is an urgent need to find new drugs that can replace these and have fewer adverse effects. Quercetin (Que) is a common flavonol in nature. Numerous studies have examined the therapeutic applications of Que. However, a comprehensive review of the anti-osteoporotic effects of Que has not yet been conducted. This review aimed to describe the recent studies on the anti-osteoporotic effects of Que, including its biological, pharmacological, pharmacokinetic, and toxicological properties. The outcomes demonstrated that Que could enhance OP by increasing osteoblast differentiation and activity and reducing osteoclast differentiation and activity via the pathways of Wnt/ß-catenin, BMP/SMAD/RUNX2, OPG/RANKL/RANK, ERK/JNK, oxidative stress, apoptosis, and transcription factors. Thus, Que is a promising novel drug for the treatment of OP.

Major Depressive Disorder Prediction Based on Sleep-Wake Disorders Symptoms in US Adolescents: A Machine Learning Approach from National Sleep Research Resource.

Background: There is substantial evidence from previous studies that abnormalities in sleep parameters associated with depression are demonstrated in almost all stages of sleep architecture. Patients with symptoms of sleep-wake disorders have a much higher risk of developing major depressive disorders (MDD) compared to those without. Objective: The aim of the present study is to establish and compare the performance of different machine learning models based on sleep-wake disorder symptoms data and to select the optimal model to interpret the importance of sleep-wake disorder symptoms to predict MDD occurrence in adolescents. Methods: We derived data for this work from 2020 to 2021 Assessing Nocturnal Sleep/Wake Effects on Risk of Suicide Phase I Study from National Sleep Research Resource. Using demographic and sleep-wake disorder symptoms data as predictors and the occurrence of MDD measured base on the center for epidemiologic studies depression scale as an outcome, the following six machine learning predictive models were developed: eXtreme Gradient Boosting model (XGBoost), Light Gradient Boosting mode, AdaBoost, Gaussian Naïve Bayes, Complement Naïve Bayes, and multilayer perceptron. The models' performance was assessed using the AUC and other metrics, and the final model's predictor importance ranking was explained. Results: XGBoost is the optimal predictive model in comprehensive performance with the AUC of 0.804 in the test set. All sleep-wake disorder symptoms were significantly positively correlated with the occurrence of adolescent MDD. The insomnia severity was the most important predictor compared with the other predictors in this study. Conclusion: This machine learning predictive model based on sleep-wake disorder symptoms can help to raise the awareness of risk of symptoms between sleep-wake disorders and MDD in adolescents and improve primary care and prevention.

Causal associations between digital device use and suicide risk: A bidirectional Mendelian randomization study.

BACKGROUND: The popularity of digital devices seems to provide a new observational variable for early identification and prevention of suicide with the development of the information technology era. Nevertheless, whether it is the use of digital devices that alters suicide risk or suicide risk manifests itself through change digital device use needs to be further explored. METHODS: Bidirectional Mendelian randomization (MR) analysis was used to explore potential causal relationships in the perspective of genetic prediction. We collected publicly available digital device use and suicide risk summary statistics genome-wide association data from UK Biobank, Neale Lab and FinnGen genetic databases. We used inverse variance weighting methods to assess MR estimates. For robustness of the results, we performed further tests of heterogeneity and pleiotropy. RESULTS: In the Phase 1 results, we did not observe any effect of the length of digital device use on the suicide risk, while the results of Phase 2 suggested a significant positive association between suicide risk and the length of mobile phone use (IVW OR, 1.04; 95%CI, 1.01-1.06; P = 0.002), but this significance disappeared after adjusting for confounders of mental and affective disorders. CONCLUSIONS: In this bidirectional MR analysis, we observed that People at high risk of suicide may be more addicted to digital device use, but more detailed GWAS data and research methods to validate this finding are required.