Global trends in publications regarding macrophages-related diabetic foot ulcers in the last two decades.

BACKGROUND: Diabetic foot ulcers (DFUs) are one of the most severe and popular complications of diabetes. The persistent non-healing of DFUs is the leading cause of ampu-tation, which causes significant mental and financial stress to patients and their families. Macrophages are critical cells in wound healing and perform essential roles in all phases of wound healing. However, no studies have been carried out to systematically illustrate this area from a scientometric point of view. Although there have been some bibliometric studies on diabetes, reports focusing on the investigation of macrophages in DFUs are lacking. AIM: To perform a bibliometric analysis to systematically assess the current state of research on macrophage-related DFUs. METHODS: The publications of macrophage-related DFUs from January 1, 2004, to December 31, 2023, were retrieved from the Web of Science Core Collection on January 9, 2024. Four different analytical tools: VOSviewer (v1.6.19), CiteSpace (v6.2.R4), HistCite (v12.03.07), and Excel 2021 were used for the scientometric research. RESULTS: A total of 330 articles on macrophage-related DFUs were retrieved. The most published countries, institutions, journals, and authors in this field were China, Shanghai Jiao Tong University of China, Wound Repair and Regeneration, and Aristidis Veves. Through the analysis of keyword co-occurrence networks, historical direct citation networks, thematic maps, and trend topics maps, we synthesized the prevailing research hotspots and emerging trends in this field. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of macrophage-related DFUs research and insights into promising upcoming research.

Recent Advances in the Biosynthesis of Mid- and Long-Chain Dicarboxylic Acids Using Terminally Oxidizing Unconventional Yeasts.

As high-performance monomers for the manufacture of polyamide materials, mid- and long-chain dicarboxylic acids (DCAi, i ≥ 6) have received extensive attention from researchers. Biosynthesis is gradually replacing chemical synthesis due to its outstanding advantages in the industrial production of mid- and long-chain dicarboxylic acids, which is mostly achieved by using the strong terminal oxidation ability of nonmodel microorganisms such as Candida tropicalis to oxidize hydrophobic substrates such as alkanes. Here, we first summarize the metabolic pathways of oxidative alkane conversion into dicarboxylic acid by terminally oxidizing unconventional yeasts and the corresponding metabolic engineering strategies. Then, we summarize the research progress on new dicarboxylic acid production processes. Finally, the future development directions in the biosynthesis of mid- and long-chain dicarboxylic acids are prospected from synthetic biology and bioprocess engineering, which can also provide a reference for the synthesis of other biobased chemicals and biomaterials.

SEPHS1 Gene: A new master key for neurodevelopmental disorders.

The SEPHS1 (Selenophosphate Synthetase 1) gene encodes a critical enzyme for synthesizing selenophosphate, the active donor of selenium (Se) necessary for selenoprotein biosynthesis. Selenoproteins are vital for antioxidant defense, thyroid hormone metabolism, and cellular homeostasis. Mutations in SEPHS1 gene, are associated with neurodevelopmental disorders with developmental delay, poor growth, hypotonia, and dysmorphic features. Due to Se's critical role in brain development and function, SEPHS1 gene has taken center stage in neurodevelopmental research. This review explores the structure and function of the SEPHS1 gene, its role in neurodevelopment, and the implications of its dysregulation for neurodevelopmental disorders. Therapeutic strategies, including Se supplementation, gene therapy, and targeted therapies, are discussed as potential interventions to address SEPHS1 associated neurodevelopmental dysfunction. The study's findings reveal how SEPHS1 mutations disrupt neurodevelopment, emphasizing the gene's intolerance to loss of function. Future research should focus on functional characterization of SEPHS1 variants, broader genetic screenings, and therapeutic developments.

Available Strategies for Improving the Biosynthesis of Methionine: A Review.

Methionine is the only nonpolar α-amino acid containing sulfur among the eight essential amino acids and is closely related to the metabolism of sulfur-containing compounds in the human body. Widely used in feed, medicine, food, and other fields, the market demand is increasing annually. However, low productivity and high cost largely limit the industrial production of methionine, and many novel production methods still have their own disadvantages. In this paper, the available methods for synthesizing methionine are reviewed and discussed. The latest strategies for improving methionine production are further introduced, including culture medium optimization, mutation technology, expression of key genes in the metabolic pathway, knockout and recombination, as well as the engineering of membrane transporters, the fermentation-enzymatic coupling route, and innovation of CO2 biotransformation.

Strategies for improving fengycin production: a review.

Fengycin is an important member of the lipopeptide family with a wide range of applications in the agricultural, food, medical and cosmetic industries. However, its commercial application is severely hindered by low productivity and high cost. Therefore, numerous studies have been devoted to improving the production of fengycin. We summarize these studies in this review with the aim of providing a reference and guidance for future researchers. This review begins with an overview of the synthesis mechanism of fengycin via the non-ribosomal peptide synthetases (NRPS), and then delves into the strategies for improving the fengycin production in recent years. These strategies mainly include fermentation optimization and metabolic engineering, and the metabolic engineering encompasses enhancement of precursor supply, application of regulatory factors, promoter engineering, and application of genome-engineering (genome shuffling and genome-scale metabolic network model). Finally, we conclude this review with a prospect of fengycin production.

Progress of Angiogenesis Signal Pathway and Antiangiogenic Drugs in Nasopharyngeal Carcinoma.

Nasopharyngeal cancer is a rare cancer with unique ethnic and geographic distribution. Since nasopharyngeal cancer often originates from the pharyngeal crypt, early symptoms are not obvious. They are difficult to detect in time, and the disease is usually diagnosed and treated only when it has progressed to an advanced-stage. Since angiogenesis is essential for the growth and invasion of solid tumors, antiangiogenic therapy has become a common treatment strategy for many solid tumors, and it has also achieved remarkable results in the treatment of nasopharyngeal carcinoma, which is prone to recurrence and distant metastasis. In this paper, we review the latest research progress of antiangiogenic drugs for nasopharyngeal carcinoma and their antiangiogenic mechanism of action and further propose some promising antiangiogenic therapeutic targets.

Mid-Long Chain Dicarboxylic Acid Production via Systems Metabolic Engineering: Progress and Prospects.

Mid-to-long-chain dicarboxylic acids (DCAi, i ≥ 6) are organic compounds in which two carboxylic acid functional groups are present at the terminal position of the carbon chain. These acids find important applications as structural components and intermediates across various industrial sectors, including organic compound synthesis, food production, pharmaceutical development, and agricultural manufacturing. However, conventional petroleum-based DCA production methods cause environmental pollution, making sustainable development challenging. Hence, the demand for eco-friendly processes and renewable raw materials for DCA production is rising. Owing to advances in systems metabolic engineering, new tools from systems biology, synthetic biology, and evolutionary engineering can now be used for the sustainable production of energy-dense biofuels. Here, we explore systems metabolic engineering strategies for DCA synthesis in various chassis via the conversion of different raw materials into mid-to-long-chain DCAs. Subsequently, we discuss the future challenges in this field and propose synthetic biology approaches for the efficient production and successful commercialization of these acids.

Enhancing surfactin production in Bacillus subtilis: Insights from proteomic analysis of nitrate-induced overproduction and strategies for combinatorial metabolic engineering.

Surfactin biosynthesis in Bacillus subtilis is intricately regulated by environmental conditions. In the present study, addition of nitrate, a nitrogen source, increased the production of surfactin in B. subtilis ATCC 21332, whereas its absence resulted in minimal or no surfactin production. Proteomics revealed the mechanism underlying nitrate-induced surfactin overproduction, identifying three key differential proteins (preprotein translocase subunit SecA, signal recognition particle receptor FtsY, and cell division adenosine triphosphate-binding protein FtsE) relevant to surfactin transport and regulation. Combinatorial metabolic engineering strategies (enhanced nitrate reduction, fatty acid hydroxylation, rational transporter engineering, and feeding) led to a 41.4-fold increase in surfactin production compared with the initial production in the wild-type strain. This study provides insights into the molecular mechanism of nitrate-induced surfactin overproduction and strategies to enhance the performance of surfactin-producing strains.

Study on the intracellular adaptative mechanism of Acidithiobacillus caldus MTH-04 to NaCl stress.

To understand the adaptive mechanism of bioleaching microorganism Acidithiobacillus caldus MTH-04, its physiology and metabolic changes at the transcriptional level were systemically studied. The results of growth curves, SO42- content, pH and flow cytometry analyses indicated that the higher the NaCl concentration, the more the strain was inhibited. The transcriptome response of A. caldus to elevated NaCl concentrations included changes in carbon flux, elevated glutathione synthesis, alterations in cell wall and membrane composition, the down-regulation in genes involved in flagellar synthesis and rotation, the reduced energy generation through sulfur oxidation, and the up-regulation in genes involved in DNA and protein repair. Based on the transcriptome results, the effects of proline and glutathione on NaCl adaptation in A. caldus were analyzed separately. We found that either the exogenous addition of proline and glutathione or the intracellular overexpression of the enzymes responsible for the synthesis of these two substances contributed to the enhancement of the adaptive capacity of A. caldus under NaCl stress. The findings offer insight into the design of chloride-based techniques for the bioprocessing of minerals.

Genetic variants in HFE are associated with non-alcoholic fatty liver disease in lean individuals.

Background & Aims: Around 20% of patients with non-alcoholic fatty liver disease (NAFLD) are lean. Increasing evidence suggests that lean NAFLD is a unique subtype of the disease. We aimed to explore the metabolic profile, genetic basis, causal risk factors, and clinical sequelae underlying lean NAFLD. Methods: NAFLD was diagnosed by whole liver proton density fat fraction ≥5%. Whole liver proton density fat fraction and hepatic iron were quantified using magnetic resonance imaging in the UK Biobank. Individuals in this study were stratified according to the World Health Organization criteria of obesity, into lean, overweight, and obese. Mediation analysis, Mendelian randomisation analysis, and Bayesian networks were used to identify a risk factor or a clinical sequela of lean/obese NAFLD. Results: Lean NAFLD manifested a distinct metabolic profile, featured by elevated hepatic iron and fasting glucose. Four loci, namely, HFE rs1800562, SLC17A3-SLC17A2-TRIM38 rs9348697, PNPLA3 rs738409, and TM6SF2 rs58542926, were associated with lean NAFLD (p <5 × 10-8). HFE rs1800562 was specifically associated with lean NAFLD and demonstrated a significant mediation effect through elevating hepatic iron. Type 2 diabetes was the most pronounced clinical sequela of lean NAFLD, followed by liver cirrhosis. Conclusions: Our study suggested that HFE plays a potential steatogenic role rather than regulating iron homoeostasis in patients with lean NAFLD. The increased liver iron deposition is associated with lean NAFLD, whereas obese NAFLD is not related to hepatic iron. The clinical management of patients with lean NAFLD shall be concerned with the prevention and treatment of type 2 diabetes and liver cirrhosis. Impact and implications: Lean NAFLD has a distinct natural history from obese NAFLD. This study underscored liver iron content and the genetic variant of the iron homoeostasis gene HFE as major risks of lean NAFLD, in addition to the unique metabolic profile. The development of type 2 diabetes or liver cirrhosis shall be closely monitored and prevented in patients with lean NAFLD.

Available strategies for improving the biosynthesis of surfactin: a review.

Surfactin is an excellent biosurfactant with a wide range of application prospects in many industrial fields. However, its low productivity and high cost have largely limited its commercial applications. In this review, the pathways for surfactin synthesis in Bacillus strains are summarized and discussed. Further, the latest strategies for improving surfactin production, including: medium optimization, genome engineering methods (rational genetic engineering, genome reduction, and genome shuffling), heterologous synthesis, and the use of synthetic biology combined with metabolic engineering approaches to construct high-quality artificial cells for surfactin production using xylose, are described. Finally, the prospects for improving surfactin synthesis are discussed in detail.

Construction of Bacillus subtilis for efficient production of fengycin from xylose through CRISPR-Cas9.

Fengycin is a multifunctional peptide antibiotic produced mainly by Bacillus species and the purpose of this research was to construct a Bacillus subtilis strain that can produce fengycin with the xylose as the substrate with CRSIPR-Cas9. Hence, at the beginning of this study, functional sfp and degQ were expressed in B. subtilis 168 strain to give the strain the ability to produce the fengycin with the titer of 71.21 mg/L. Subsequently, the native promoter PppsA of the cluster responsible for the fengycin synthesis was replaced by the Pveg promoter, resulting in a further 5.22-fold increase in fengycin titer. To confer xylose utilization capacity to B. subtilis, deletion of araR and constitutive overexpression of araE were performed, and the xylose consumption rate of the engineered strain BSUY06 reached 0.29 g/L/h, which is about 6.25-fold higher than that of the parent strain BSUY04-1. In the final phase of this study, the fermentation characteristics were observed and the initial xylose concentration was optimized. In this study, 40 g/L xylose was proved to be the most suitable initial concentration for growth and fengycin fermentation, which leading to a fengycin titer of 430.86 mg/L. This study demonstrated that lignocellulose, the clean and sustainable substrate with xylose as the second largest sugar, is a potential substrate for the production of fengycin.

Asperosaponin VI induces osteogenic differentiation of human umbilical cord mesenchymal stem cells via the estrogen signaling pathway.

BACKGROUND: Asperosaponin VI (ASA VI) is an active ingredient found in the traditional Chinese herb Radix Dipsaci, which is used to treat fractures. ASA VI combined with osteogenic medium can induce osteogenic differentiation of rat-derived stem cells. However, whether ASA VI alone can induce osteoblast differentiation of human mesenchymal stem cells (MSCs) remains unclear. METHODS: ASA VI human-derived binding proteins were searched in the PharmMapper database, osteogenesis-related signaling pathways were obtained through a literature search, and proteins contained in these signaling pathways were queried in the Kyoto Encyclopedia of Genes and Genomes database. SystemsDock was used to perform online molecular docking of target proteins to evaluate their binding abilities, and validation experiments were performed. RESULTS: A total of 620 ASA VI target proteins and 12 osteogenesis-related signaling pathways were queried, and 17 intersecting targets were screened. Molecular docking results showed that these targets had high binding affinity for ASA VI. We selected estrogen receptor 2 and its estrogen signaling pathway for experimental validation. The results showed that ASA VI can induce the osteogenic differentiation of MSCs through the estrogen signaling pathway. CONCLUSION: ASA VI can independently induce osteogenic differentiation of human umbilical cord MSCs, and the estrogen signaling pathway plays an important role in this process. Thus, ASA VI may have potential as an anti-osteoporosis drug.

Co-administration of FVIII with IVIG reduces immune response to FVIII in hemophilia A mice.

Hemophilia A is an X-linked recessive congenital bleeding disorder. Exogenous infusion of FVIII is the treatment of choice, and the development of immunoglobulins against FVIII (inhibitors) remains the major challenge in clinical management of the disease. Here, we investigated the effect of co-administration of FVIII with intravenous immunoglobulin (IVIG) on the development of inhibitors in previously untreated hemophilia A mice. A group of hemophilia A mice (C57BL/6FVIII-/-) received weekly injections of recombinant human FVIII (rFVIII) for twelve consecutive weeks while a second group received co-injections of rFVIII + IVIG. An in-house enzyme-linked immunosorbent assay (ELISA) was designed to detect antibodies to rFVIII. Every mouse in the first group developed antibodies to rFVIII. In contrast, mice treated with rFVIII + IVIG showed significantly lower antibody titers. Interestingly, when co-administration of IVIG was discontinued after 12 weeks in some mice (rFVIII continued), these mice experienced an increase in antibody titer. In contrast, mice that continued to receive rFVIII + IVIG retained significantly lower titers. In conclusion, prophylactic rFVIII co-administration with IVIG modulated the immune response to FVIII and resulted in decreased anti-FVIII antibody titer. These findings suggest that co-injection therapy with IVIG could potentially be effective in the management of hemophilia A patients at risk of inhibitor development.

Genetic Variants of Glycogen Metabolism Genes Were Associated With Liver PDFF Without Increasing NAFLD Risk.

Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association. Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies. Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value < 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB, CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p < 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction. Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF.

Production of fengycin from D-xylose through the expression and metabolic regulation of the Dahms pathway.

D-Xylose is a key component of lignocellulosic biomass and the second-most abundant carbohydrate on the planet. As one of the most powerful cyclo-lipopeptide antibiotics, fengycin displays strong wide-spectrum antifungal and antiviral, as well as potential anti-cancer activity. Pyruvate is a key metabolite linking the biosynthesis of fatty acids and amino acids, the precursors for fengycin. In this study, the genes encoding the Dahms xylose-utilization pathway were integrated into the amyE site of Bacillus subtilis 168, and based on the metabolic characteristics of the Dahms pathway, the acetate kinase (ackA) and lactate dehydrogenase (ldh) genes were knocked out. Then, the metabolic control module II was designed to convert glycolaldehyde, another intermediate of the Dahms pathway, in addition to pathways for the conversion of acetaldehyde into malic acid and oxaloacetic acid, resulting in strain BSU03. In the presence of module II, the content of acetic and lactic acid decreased significantly, and the xylose uptake efficiency increased. At the same time, the yield of fengycin increased by 87% compared to the original strain. Additionally, the underlying factors for the increase of fengycin titer were revealed through metabonomic analysis. This study therefore demonstrates that this regulation approach can not only optimize the intracellular fluxes for the Dahms pathway, but is also conducive to the synthesis of secondary metabolites similar to fengycin. KEY POINTS: • The expression and effect of the Dahms pathway on the synthesis of fengycin in Bacillus subtilis 168. • The expression of regulatory module II can promote the metabolic rate of the Dahms pathway and increase the synthesis of the fengycin.

Enhancing the capability of Klebsiella pneumoniae to produce 1, 3-propanediol by overexpression and regulation through CRISPR-dCas9.

Klebsiella pneumoniae is a common strain of bacterial fermentation to produce 1, 3-propanediol (1, 3-PDO). In general, the production of 1, 3-PDO by wild-type K. pneumoniae is relatively low. Therefore, a new gene manipulation of K. pneumoniae was developed to improve the production of 1, 3-PDO by overexpressing in the reduction pathway and attenuating the by-products in the oxidation pathway. Firstly, dhaB and/or dhaT were overexpressed in the reduction pathway. Considering the cost of IPTG, the constitutive promoter P32 was selected to express the key gene. By comparing K.P. pET28a-P32-dhaT with the original strain, the production of 1, 3-PDO was increased by 19.7%, from 12.97 to 15.53 g l-1 (in a 250 ml shaker flask). Secondly, three lldD and budC regulatory sites were selected in the by-product pathway, respectively, using the CRISPR-dCas9 system, and the optimal regulatory sites were selected following the 1, 3-PDO production. As a result, the 1, 3-PDO production by K.P. L1-pRH2521 and K.P. B3-pRH2521 reached up to 19.16 and 18.74 g l-1 , which was increased by 47.7% and 44.5% respectively. Overexpressing dhaT and inhibiting expression of lldD and budC were combined to further enhance the ability of K. pneumoniae to produce 1, 3-PDO. The 1, 3-PDO production by K.P. L1-B3-PRH2521-P32-dhaT reached 57.85 g l-1 in a 7.5 l fermentation tank (with Na+ neutralizer), which is higher than that of the original strain. This is the first time that the 1, 3-PDO production was improved in K. pneumoniae by overexpressing the key gene and attenuating by-product synthesis in the CRISPR-dCas9 system. This study reports an efficient approach to regulate the expression of genes in K. pneumoniae to increase the 1, 3-PDO production, and such a strategy may be useful to modify other strains to produce valuable chemicals.

Celiac Disease and the Susceptibility of COVID-19 and the Risk of Severe COVID-19: A Mendelian Randomization Study.

INTRODUCTION: Previous observational studies have found that the susceptibility of coronavirus disease 2019 (COVID-19) and the risk of severe COVID-19 are not increased in patients with celiac disease (CeD). However, the findings of observational studies are prone to bias due to reverse causation and confounding factors, especially in the case of a newly emerged disease. In this study, we aimed to further clarify the underlying relationship by both observational and Mendelian randomization (MR) analysis. METHODS: This observational study was conducted in the UK Biobank cohort. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of COVID-19 susceptibility and severe COVID-19. To understand the causality between CeD and COVID-19 susceptibility and severe COVID-19, we performed a 2-sample MR analysis. RESULTS: Our observational study showed that patients with CeD had a lower susceptibility of COVID-19 (odds ratio [OR] = 0.699, P = 0.006) while CeD was not significantly associated with severe COVID-19 (P > 0.05). The findings from our MR study further demonstrated that both the susceptibility to COVID-19 (OR = 0.963, P = 0.006) and severe COVID-19 (OR = 0.919, P = 0.049) were lower in patients with CeD, although the former seemed to be specific to the UK Biobank cohort. DISCUSSION: Our results suggested that it may be unnecessary to take extra COVID-19 precaution in patients with CeD.

Mendelian Randomization Analysis Reveals No Causal Relationship Between Nonalcoholic Fatty Liver Disease and Severe COVID-19.

BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has witnessed more than 4.5 million deaths as of the time of writing. Whether nonalcoholic fatty liver disease (NAFLD) increases the risk for severe COVID-19 remains unclear. We sought to address this question using 2-sample Mendelian randomization (TSMR) analysis approaches in large cohorts. METHODS: We performed large-scale TSMR analyses to examine whether there is a causal relationship between NAFLD, serum alanine aminotransferase, grade of steatosis, NAFLD Activity Score, or fibrosis stage and severe COVID-19. To maximize the power of this analysis, we performed a genome-wide meta-analysis to identify single nucleotide polymorphisms associated with NAFLD. We also examined the impact of 20 major comorbid factors of NAFLD on severe COVID-19. RESULTS: Univariate analysis of the UK Biobank data demonstrated a significant association between NAFLD and severe COVID-19 (odds ratio [OR], 3.06; P = 1.07 × 10-6). However, this association disappeared after demographic and comorbid factors were adjusted (OR, 1.57; P = .09). TSMR study indicated that NAFLD (OR, 0.97; P = .61), alanine aminotransferase level (OR, 1.03; P = .47), grade of steatosis (OR, 1.08; P = .41), NAFLD Activity Score (OR, 1.02; P = .39), and fibrosis stage (OR, 1.01; P = .87) were not associated with severe COVID-19. Among all NAFLD-related comorbid factors, body mass index (OR, 1.73; P = 7.65 × 10-9), waist circumference (OR, 1.76; P = 2.58 × 10-5), and hip circumference (OR, 1.33; P = 7.26 × 10-3) were the only ones demonstrated a causal impact on severe COVID-19. CONCLUSIONS: There is no evidence supporting that NAFLD is a causal risk factor for severe COVID-19. Previous observational associations between NAFLD and COVID-19 are likely attributed to the correlation between NAFLD and obesity.

Novel insights into the consequences of obesity: a phenotype-wide Mendelian randomization study.

Obesity is thought to significantly impact the quality of life. In this study, we sought to evaluate the health consequences of obesity on the risk of a broad spectrum of human diseases. The causal effects of exposing to obesity on health outcomes were inferred using Mendelian randomization (MR) analyses using a fixed effects inverse-variance weighted model. The instrumental variables were SNPs associated with obesity as measured by body mass index (BMI) reported by GIANT consortium. The spectrum of outcome consisted of the phenotypes from published GWAS and the UK Biobank. The MR-Egger intercept test was applied to estimate horizontal pleiotropic effects, along with Cochran's Q test to assess heterogeneity among the causal effects of instrumental variables. Our MR results confirmed many putative disease risks due to obesity, such as diabetes, dyslipidemia, sleep disorder, gout, smoking behaviors, arthritis, myocardial infarction, and diabetes-related eye disease. The novel findings indicated that elevated red blood cell count was inferred as a mediator of BMI-induced type 2 diabetes in our bidirectional MR analysis. Intriguingly, the effects that higher BMI could decrease the risk of both skin and prostate cancers, reduce calorie intake, and increase the portion size warrant further studies. Our results shed light on a novel mechanism of the disease-causing roles of obesity.