Nicotinamide N-methyltransferase (NNMT): a novel therapeutic target for metabolic syndrome.

Metabolic syndrome (MetS) represents a constellation of metabolic abnormalities, typified by obesity, hypertension, hyperglycemia, and hyperlipidemia. It stems from intricate dysregulations in metabolic pathways governing energy and substrate metabolism. While comprehending the precise etiological mechanisms of MetS remains challenging, evidence underscores the pivotal roles of aberrations in lipid metabolism and insulin resistance (IR) in its pathogenesis. Notably, nicotinamide N-methyltransferase (NNMT) has recently surfaced as a promising therapeutic target for addressing MetS. Single nucleotide variants in the NNMT gene are significantly correlated with disturbances in energy metabolism, obesity, type 2 diabetes (T2D), hyperlipidemia, and hypertension. Elevated NNMT gene expression is notably observed in the liver and white adipose tissue (WAT) of individuals with diabetic mice, obesity, and rats afflicted with MetS. Knockdown of NNMT elicits heightened energy expenditure in adipose and hepatic tissues, mitigates lipid accumulation, and enhances insulin sensitivity. NNMT catalyzes the methylation of nicotinamide (NAM) using S-adenosyl-methionine (SAM) as the donor methyl group, resulting in the formation of S-adenosyl-l-homocysteine (SAH) and methylnicotinamide (MNAM). This enzymatic process results in the depletion of NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and the generation of SAH, a precursor of homocysteine (Hcy). Consequently, this cascade leads to reduced NAD+ levels and elevated Hcy levels, implicating NNMT in the pathogenesis of MetS. Moreover, experimental studies employing RNA interference (RNAi) strategies and small molecule inhibitors targeting NNMT have underscored its potential as a therapeutic target for preventing or treating MetS-related diseases. Nonetheless, the precise mechanistic underpinnings remain elusive, and as of yet, clinical trials focusing on NNMT have not been documented. Therefore, further investigations are warranted to elucidate the intricate roles of NNMT in MetS and to develop targeted therapeutic interventions.

Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.

Lactobacillus crispatus 7-4 Mitigates Salmonella typhimurium-Induced Enteritis via the γ­Glutamylcysteine-Mediated Nrf2 Pathway.

Salmonella typhimurium (S. typhimurium) constitutes a major public health concern. We have previously proven that Lactobacillus crispatus 7-4 (L. crispatus 7-4) can inhibit the growth of S. typhimurium and thus can be used as a biocontrol strategy to suppress foodborne S. typhimurium infections. However, the inhibitory effect and in-depth mechanism of L. crispatus 7-4 remain to be elucidated. In this study, we found that L. crispatus 7-4 can protect against S. typhimurium-induced ileum injury by promoting intestinal barrier integrity, maintaining intestinal mucosal barrier homeostasis, and reducing intestinal inflammatory response. Furthermore, we demonstrated that this probiotic strain can increase the abundance of Lactobacillus spp. to maintain microbial homeostasis and simultaneously increase the amount of γ­glutamylcysteine (γ-GC) by activating the glutathione metabolic pathway. The increased γ-GC promoted the transcription of Nrf2 target genes, thereby improving the host antioxidant level, reducing reactive oxygen species (ROS) accumulation, and removing pro-inflammatory cytokines. In other words, L. crispatus 7-4 could activate the enterocyte Nrf2 pathway by improving γ-GC to protect against S. typhimurium-induced intestinal inflammation and oxidative damage.

Advances in the Causes and Treatment of Floating Toes after the Weil Osteotomy: A Scoping Review.

The floating toe deformity is classified as a forefoot deformity wherein the distal portion of the toe does not establish touch with the ground, resulting in a suspended or elevated position while the finger is in a relaxed state. At first, it garnered considerable interest as a complication It is worth noting that this condition is particularly common in children under the age of 8, which usually disappears as the individual reaches maturity. Studies have shown that with the aggravation of floating toe deformity, its adverse effects on patients' gait and overall quality of life also increase. Despite the prevalence of floating toe deformity in clinical settings, there is a lack of comprehensive literature investigating its underlying causes and potential preventive strategies. This scope review follows the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) statement guidelines for scope reviews. The literature was obtained from various full-text databases, including China National Knowledge Infrastructure Database (CNKI), Wanfang Database, PubMed, and Web of Science Database. Our search focused on published literature related to floating toes, Weil osteotomy, and distal metatarsal osteotomy, up until March 1, 2023. The literature search and data analysis are conducted by two independent reviewers. If there are any disagreements, a third researcher will participate in the discussion and negotiate a decision. Furthermore, two experienced foot and ankle surgeons conducted a thorough literature analysis for this review. Sixty-two articles were included. Through the clinical analysis of the structural changes of the forefoot before and after operation, the classification of floating toe was described, the causes of pathological floating toe were summarized, and the possible intervention measures for the disease were put forward under the advice of foot and ankle surgery experts. We comprehensively summarize the current knowledge system about the etiology of floating toe and put forward the corresponding intervention strategy. We recommend that future studies will focus on the improvement of surgical procedures, such as the combination of Weil osteotomy, proximal interphalangeal (PIP) arthrodesis and flexor tendon arthrodesis.

Secondary hemophagocytic syndrome in an acquired immunodeficiency syndrome and Alpha-thalassemia patient infected with Talaromyces marneffei: A case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by a hyperinflammatory syndrome and impairment of multiple organ systems. Talaromycosis marneffei (TSM) is an opportunistic infection mostly found in immunosuppressed populations, such as those with acquired immunodeficiency syndrome (AIDS), and is prevalent in southern China. However, HLH secondary to TSM is extremely rare and has only been reported in isolated cases. A 30-year-old patient with recurrent high fever and progressive cytopenia was diagnosed with HLH secondary to disseminated TSM with AIDS and Alpha-thalassemia. The patient remained in sustained remission without recurrence after effective treatment with antifungals and glucocorticoids.

MDformer: A transformer-based method for predicting miRNA-Disease associations using multi-source feature fusion and maximal meta-path instances encoding.

There is a growing body of evidence suggesting that microRNAs (miRNAs), small biological molecules, play a crucial role in the diagnosis, treatment, and prognostic assessment of diseases. However, it is often inefficient to verify the association between miRNAs and diseases (MDA) through traditional experimental methods. Based on this situation, researchers have proposed various computational-based methods, but the existing methods often have many drawbacks in terms of predictive effectiveness and accuracy. Therefore, in order to improve the prediction performance of computational methods, we propose a transformer-based prediction model (MDformer) for multi-source feature information. Specifically, first, we consider multiple features of miRNAs and diseases from the molecular biology perspective and utilize them in a fusion. Then high-quality node feature embeddings were generated using a feature encoder based on the transformer architecture and meta-path instances. Finally, a deep neural network was built for MDA prediction. To evaluate the performance of our model, we performed multiple 5-fold cross-validations as well as comparison experiments on HMDD v3.2 and HMDD v2.0 databases, and the experimental results of the average ROC area under the curve (AUC) were higher than the comparative methods for both databases at 0.9506 and 0.9369. We conducted case studies on five highly lethal cancers (breast, lung, colorectal, gastric, and hepatocellular cancers), and the first 30 predictions for these five diseases achieved 97.3% accuracy. In conclusion, MDformer is a reliable and scientifically sound tool that can be used to accurately predict MDA. In addition, the source code is available at https://github.com/Linda908/MDformer.

DAEMDA: A Method with Dual-Channel Attention Encoding for miRNA-Disease Association Prediction.

A growing number of studies have shown that aberrant microRNA (miRNA) expression is closely associated with the evolution and development of various complex human diseases. These key biomarkers' identification and observation are significant for gaining a deeper understanding of disease pathogenesis and therapeutic mechanisms. Consequently, pinpointing potential miRNA-disease associations (MDA) has become a prominent bioinformatics subject, encouraging several new computational methods given the advances in graph neural networks (GNN). Nevertheless, these existing methods commonly fail to exploit the network nodes' global feature information, leaving the generation of high-quality embedding representations using graph properties as a critical unsolved issue. Addressing these challenges, we introduce the DAEMDA, a computational method designed to optimize the current models' efficacy. First, we construct similarity and heterogeneous networks involving miRNAs and diseases, relying on experimentally corroborated miRNA-disease association data and analogous information. Then, a newly-fashioned parallel dual-channel feature encoder, designed to better comprehend the global information within the heterogeneous network and generate varying embedding representations, follows this. Ultimately, employing a neural network classifier, we merge the dual-channel embedding representations and undertake association predictions between miRNA and disease nodes. The experimental results of five-fold cross-validation and case studies of major diseases based on the HMDD v3.2 database show that this method can generate high-quality embedded representations and effectively improve the accuracy of MDA prediction.

Drynaria Naringin alleviated mechanical stress deficiency-caused bone loss deterioration via Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

Osteoporosis is a metabolic condition distinguished by the degradation of bone microstructure and mechanical characteristics. Traditional Chinese medicine (TCM) has been employed in China for the treatment of various illnesses. Naringin, an ingredient found in Drynariae TCM, is known to have a significant impact on bone metabolism. For this research, we studied the precise potential effect of Drynaria Naringin on protecting against bone loss caused by stress deficiency. In this study, a tail-suspension (TS) test was performed to establish a mouse model with hind leg bone loss. Some mice received subcutaneous injections of Drynaria Naringin for 30 d. Trabecular bone microarchitecture was evaluated using micro-computed tomography analysis and bone histological analysis. Bone formation and resorption markers were quantified in blood samples from mice or in the supernatant of MC3T3-E1 cells by ELISA analysis, Western blotting, and PCR. Immunofluorescence was utilized to visualize the location of ß-catenin. Additionally, siRNA was employed to knockdown-specific genes in the cells. Our findings highlight the efficacy of Drynaria Naringin in protecting against the deterioration of bone loss and promoting bone formation and Rspo1 expression in a mouse model following the TS test. Specifically, in vitro experiments also indicated that Drynaria Naringin may promote osteogenesis through the Wnt/ß-catenin signalling pathway. Moreover, our results suggest that Drynaria Naringin upregulates the expression of Rspo1/Lgr4, leading to the promotion of osteogenesis via the Wnt/ß-catenin signalling pathway. Therefore, Drynaria Naringin holds potential as a therapeutic medication for osteoporosis. Drynaria Naringin alleviates bone loss deterioration caused by mechanical stress deficiency through the Rspo1/Lgr4-mediated Wnt/ß-catenin signalling pathway.

The Efficacy of Acupuncture in the Treatment of Chemotherapy-Induced Peripheral Neuropathy: A Network Meta-Analysis.

Background: Chemotherapy-induced peripheral neuropathy (CIPN), one of the most common adverse events associated with chemotherapy, may affect efficacy because of the interruption of chemotherapy or change of regimen in severe cases, and may even increase cancer mortality. Relevant data supports the evidence that acupuncture can treat pain and sensory abnormalities. However, choosing the most effective acupuncture therapy is difficult because of the lack of evidence-based medicine and comparisons between different acupuncture therapies for treating CIPN. The aim of this study was to use a network meta-analysis (NMA) to evaluate the efficacy of different acupuncture therapies for CIPN. Methods: We searched Embase, PubMed, Web of Science, The Cochrane Library, The Chinese Journal Full Text Database, Chinese Biomedical Literature Database, and WanFang Database for randomized controlled trials (RCTs) of acupuncture for CIPN. The search period was from the creation of the relevant library to August 10, 2023. A total of 2 investigators independently performed literature screening, data extraction, and risk for bias evaluation. Stata 14.0 software (StataCorp LLC, College Station, Texas USA), was used for the NMA. Results: A total of 13 eligible RCTs involving 746 patients and 6 acupuncture therapies were included in the study. The NMA results showed that electroacupuncture was superior to moxibustion, manual acupuncture, acupoint injection and Western medicine in improving the total effective rate of treatment of CIPN; electroacupuncture + moxibustion was better than manual acupuncture, acupoint injection, and Western medicine. Manual acupuncture's total effective rate was better than Western medicine. However, electroacupuncture was the most effective treatment for CIPN according to the surface under the cumulative ranking curve (SUCRA) ranking. Conclusion: After a comprehensive evaluation of 6 acupuncture therapies for treating CIPN based on NMA, electroacupuncture may be the best option for treating CIPN. However, would be more convincing to get evidence from more RCTs.

Catalpol Alleviates Depression by Inhibiting NLRP3 Inflammasome via TLR4/MAPK/NF-Kb Pathway.

Background: We aimed to explore catalpol and NF-k. The role of antidepressant and anti-inflammatory effects of b inhibitor in depression induced by chronic unpredictable mild stress (CUMS). Methods: Under the guidance of Qiqihar Medical University, from January 2020 to January 2021, the weight, sucrose consumption and rest time of mice during swimming were monitored, the neurobehavioral changes of rats under CUMS were used to determine the experimental model; ELISA detection of iNOS, ROS, caspase-1, IL-1 ß And IL-18 expression level; Western blotting detection of TLR4, MAPK and NF-κB expression level; LPS-induced cell model. INOS, NLRP3, caspase-1, IL-1 in RT-qPCR and ELISA detection models ß And IL-18 expression level; the TLR4, MAPK and NF-κB level were detected by Western blotting. Results: CUMS can make rats lose weight, reduce sucrose consumption rate and prolong rest time. Catapol can enhance this effect; In the depression model, ROS, NLRP3, NF-κ B and iNOS were up-regulated Catalpol group MAPK, NF-κ Reduced expression of B and TLR4; ROS, caspase-1, IL-1ß, IL-18 and iNOS protein increased. Cell model group TLR4, MAPK and NF-κ. The high protein content of B decreased in catalpol group. Conclusion: Catalpol acts as anti-depressant and anti-inflammatory molecule indepression induced by CUMS. Combination of catalpol with NF-κB inhibitor might play a role in the treatment of depression through regulating the neuroinflammation.

Single-source Domain Expansion Network for Cross-Scene Hyperspectral Image Classification.

Currently, cross-scene hyperspectral image (HSI) classification has drawn increasing attention. It is necessary to train a model only on source domain (SD) and directly transferring the model to target domain (TD), when TD needs to be processed in real time and cannot be reused for training. Based on the idea of domain generalization, a Single-source Domain Expansion Network (SDEnet) is developed to ensure the reliability and effectiveness of domain extension. The method uses generative adversarial learning to train in SD and test in TD. A generator including semantic encoder and morph encoder is designed to generate the extended domain (ED) based on encoder-randomization-decoder architecture, where spatial randomization and spectral randomization are specifically used to generate variable spatial and spectral information, and the morphological knowledge is implicitly applied as domain invariant information during domain expansion. Furthermore, the supervised contrastive learning is employed in the discriminator to learn class-wise domain invariant representation, which drives intra-class samples of SD and ED. Meanwhile, adversarial training is designed to optimize the generator to drive intra-class samples of SD and ED to be separated. Extensive experiments on two public HSI datasets and one additional multispectral image (MSI) dataset demonstrate the superiority of the proposed method when compared with state-of-the-art techniques. The codes will be available from the website: https://github.com/YuxiangZhang-BIT/IEEE_TIP_SDEnet.

Causal relationship between thyroid dysfunction and hallux valgus: A two-sample Mendelian randomization study.

Introduction: Previous observational studies have reported that thyroid dysfunction is associated with hallux valgus (HV). However, the causal effect of thyroid dysfunction on hallux valgus is still unknown. To assess whether there is a causal relationship between thyroid dysfunction and hallux valgus, we performed a two-sample Mendelian randomization (MR) study. Methods: The data of the two-sample Mendelian randomization study were obtained from public databases. In this study, hypothyroidism, hyperthyroidism, free thyroxine (FT4), and thyrotropin (TSH) were chosen as exposures. The single nucleotide polymorphisms (SNP) of hypothyroidism and hyperthyroidism were from the genome-wide association studies (GWAS) of the IEU database, including 337,159 subjects. Data for FT4 and TSH (72,167 subjects) were extracted from the ThyroidOmics Consortium. HV was used as the outcome. The SNPs associated with HV were selected from a GWAS of 202,617 individuals in the fignngen database. The inverse variance weighted (IVW) method was used as the primary analysis. Four complementary methods were applied, including MR-presso, MR-Egger, and weighted median. In addition, Cochran's Q test, MR-presso, MR-Egger regression, and the leave-one-out test were used as sensitivity analysis, and the MR-pleiotropy test was performed to examine pleiotropy. Results: According to the results of IVW, we found that there was a causal relationship between hypothyroidism and HV, and hypothyroidism increased the incidence of HV (OR = 2.838 (95% CI: 1.116-7.213); p = 0.028). There were no significant causal effects of hyperthyroidism, FT4, and TSH on HV (p > 0.05). Sensitivity analyses showed that the results were robust and reliable, and no horizontal pleiotropy was detected. Conclusions: Our findings provided genetic support that hypothyroidism might increase the risk of HV. It will predict the occurrence of HV in patients with hypothyroidism and provide suggestions for early prevention and intervention.

An emerging plume head interacting with the Hawaiian plume tail.

The Hawaiian-Emperor seamount chain has shown two subparallel geographical and geochemical volcanic trends, Loa and Kea, since ∼5 Ma, for which numerous models have been proposed that usually involve a single mantle plume sampling different compositional sources of the deep or shallow mantle. However, both the dramatically increased eruption rate of the Hawaiian hotspot since ∼5 Ma and the nearly simultaneous southward bending of the Hawaiian chain remain unexplained. Here, we propose a plume-plume interaction model where the compositionally depleted Kea trend represents the original Hawaiian plume tail and the relatively enriched Loa trend represents an emerging plume head southeast of the Hawaiian plume tail. Geodynamic modeling further suggests that the interaction between the existing Hawaiian plume tail and the emerging Loa plume head is responsible for the southward bending of the Hawaiian chain. We show that the arrival of the new plume head also dramatically increases the eruption rate along the hotspot track. We suggest that this double-plume scenario may also represent an important mechanism for the formation of other hotspot tracks in the Pacific plate, likely reflecting a dynamic reorganization of the lowermost mantle.

Durability Performance and Corrosion Mechanism of New Basalt Fiber Concrete under Organic Water Environment.

Under corrosive environments, concrete material properties can deteriorate significantly, which can seriously affect structural safety. Therefore, it has important engineering applications to improve the durability performance at a lower economic cost. This paper proposes a new, highly durable concrete using inexpensive construction materials such as basalt fiber, sodium methyl silicate, and inorganic aluminum salt waterproofing agent. With the massive application of sewage treatment projects, the problem of concrete durability degradation is becoming more and more serious. In this paper, five types of concrete are developed for the sewage environment, and the apparent morphology and fine structure of the specimens after corrosion in sewage were analyzed. The density, water absorption, and compressive strength were measured to investigate the deterioration pattern of concrete properties. It was found that ordinary concrete was subject to significant corrosion, generating large deposits of algae on the surface and accompanied by sanding. The new concrete showed superior corrosion resistance compared to conventional concrete. Among other factors, the inorganic aluminum salt waterproofing agent effect was the most prominent. The study found that the strength of ordinary concrete decreased by about 15% in the test environment, while the new concrete had a slight increase. Comprehensive evaluation showed that the combination of basalt fiber and inorganic aluminum salt waterproofing agent had the best effect. Its use is recommended.