Multiomics analysis reveal the impact of 17α-Ethinylestradiol on mortality in juvenile zebrafish.

17α-Ethinylestradiol (EE2) is known for its endocrine-disrupting effects on embryonic and adult fish. However, its impact on juvenile zebrafish has not been well established. In this study, juvenile zebrafish were exposed to EE2 at concentrations of 5 ng/L (low dose, L), 10 ng/L (medium dose, M), and 50 ng/L (high dose, H) from 21 days post-fertilization (dpf) to 49 dpf. We assessed their growth, development, behavior, transcriptome, and metabolome. The findings showed that the survival rate in the EE2-H group was 66.8 %, with all surviving fish displaying stunted growth and swollen, transparent abdomens by 49 dpf. Moreover, severe organ deformities were observed in the gills, kidneys, intestines, and heart of fish in both the EE2-H and EE2-M groups. Co-expression analysis of mRNA and lncRNA revealed that EE2 downregulated the transcription of key genes involved in the cell cycle, DNA replication, and Fanconi anemia signaling pathways. Additionally, metabolomic analysis indicated that EE2 influenced metabolism and development-related signaling pathways. These pathways were also significantly identified based on the genes regulated by lncRNA. Consequently, EE2 induced organ deformities and mortality in juvenile zebrafish by disrupting signaling pathways associated with development and metabolism. The results of this study offer new mechanistic insights into the adverse effects of EE2 on juvenile zebrafish based on multiomics analysis. The juvenile zebrafish are highly sensitive to EE2 exposure, which is not limited to adult and embryonic stages. It is a potential model for studying developmental toxicity.

Knowledge-based machine learning for predicting and understanding the androgen receptor (AR)-mediated reproductive toxicity in zebrafish.

Traditional methods for identifying endocrine-disrupting chemicals (EDCs) that activate androgen receptors (AR) are costly, time-consuming, and low-throughput. This study developed a knowledge-based deep neural network model (AR-DNN) to predict AR-mediated adverse outcomes on female zebrafish fertility. This model started with chemical fingerprints as the input layer and was implemented through a five-layer virtual AR-induced adverse outcome pathway (AOP). Results indicated that the AR-DNN effectively and accurately screens new reproductive toxicants (AUC = 0.94, accuracy = 0.85), providing potential toxicity pathways. Furthermore, 1477 and 2448 chemicals that could lead to infertility were identified in the plastic additives list (PLASTICMAP, n = 7112) and the Inventory of Existing Chemical Substances in China (IECSC, n = 17741), respectively. Colourants containing steroid-like structures are the major active plastic additives that might lower female zebrafish fertility through AR binding, DNA binding, and transcriptional activation. While active IECSC chemicals primarily have the same fragments, such as benzonitrile, nitrobenzene, and quinolone. The predicted toxicity pathways were consistent with existing fish evidence, demonstrating the model's applicability. This knowledge-based approach offers a promising computational toxicology strategy for predicting and characterising the endocrine-disrupting effects and toxic mechanisms of organic chemicals, potentially leading to more efficient and cost-effective screening of EDCs.

Development and evaluation of suitable reference genes for qRT-PCR normalization of hybrids derived from Lycium barbarum and Lycium ruthenicum.

BACKGROUND: A correct and stably expressing reference gene is prerequisite for successful quantitative real-time PCR (qRT-PCR). Investigating gene expression profiling during flower development could enhance our understanding of the molecular mechanisms of flower formation and fertility in Lycium. METHODS AND RESULTS: In this study, 11 candidate reference genes in Lycium flower development were selected from transcriptome sequence data and evaluated with five traditional housekeeping genes from previous studies based on qRT-PCR amplification. Comparing the expression stability result of 16 candidate genes using GeNorm, NormFinder, BestKeeper, and Delta Ct algorithms, Lba04g01649 and Lba12g02820 were validated as the optimal reference genes for the flower development of Lycium. CONCLUSIONS: The reference genes identified in this study would improve the accuracy of qRT-PCR quantification of target gene expression in Lycium flower development and facilitate future functional genomics studies on flower development. This research could lay the foundation for the study of the reproduction and development of the Lycium flower.

Unveiling the causal relationship between circulating levels of micronutrients and risk of facial aging: A Mendelian randomization study.

Facial aging involves a continuous sequence of complex, interrelated events that impact numerous facial tissues. The aim of the study was to elucidate the casual relationship between circulating micronutrients and risk of facial aging. A two-sample Mendelian randomization analysis was performed using genetic data from genome-wide association studies. The inverse-variance weighted method is used for causal effect estimation, and additional tools such as Mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to refine the analysis. We conducted an in-depth examination of the correlation between several micronutrient blood levels and the risk of facial aging, and identified 3 key micronutrients (selenium, carotene, and iron) that may have a significant impact on skin health. Inverse-variance weighted results indicate that selenium levels were positively correlated with the risk of facial aging (odds ratio [OR] 1.005, P = .027), while a negative causal effect of carotene (OR 0.979, P = .024) and iron (OR 0.976, P = .009) on age-related facial alterations was observed. This study offers a new and insightful perspective on the current understanding of antiaging strategies, particularly the importance of appropriate consumption of essential micronutrients to maintain healthy skin condition.

Family-based Helicobacter pylori infection control and management strategy and screen-and-treat strategy are highly cost-effective in preventing multiple upper gastrointestinal diseases in Chinese population at national level.

BACKGROUND: The overall benefits of the newly introduced family-based Helicobacter pylori (H. pylori) infection control and management (FBCM) and screen-and-treat strategies in preventing multiple upper gastrointestinal diseases at national level in China have not been explored. We investigate the cost-effectiveness of these strategies in the whole Chinese population. MATERIALS AND METHODS: Decision trees and Markov models of H. pylori infection-related non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were developed to simulate the cost-effectiveness of these strategies in the whole 494 million households in China. The main outcomes include cost-effectiveness, life years (LY), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). RESULTS: When compared with no-screen strategy, both FBCM and screen-and-treat strategies reduced the number of new cases of NUD, PUD, PUD-related deaths, and the prevalence of GC, and cancer-related deaths. The costs saved by these two strategies were $1467 million and $879 million, quality-adjusted life years gained were 227 million and 267 million, and life years gained were 59 million and 69 million, respectively. Cost-effectiveness analysis showed that FBCM strategy costs -$6.46/QALY and -$24.75/LY, and screen-and-treat strategy costs -$3.3/QALY and -$12.71/LY when compared with no-screen strategy. Compared to the FBCM strategy, the screen-and-treat strategy reduced the incidence of H. pylori-related diseases, added 40 million QALYs, and saved 10 million LYs, but at the increased cost of $588 million. Cost-effectiveness analysis showed that screen-and-treat strategy costs $14.88/QALY and $59.5/LY when compared with FBCM strategy. The robustness of the results was also verified. CONCLUSIONS: Both FBCM and screen-and-treat strategies are highly cost-effective in preventing NUD, PUD, and GC than the no-screen strategy in Chinese families at national level. As FBCM strategy is more practical and efficient, it is expected to play a more important role in preventing familial H. pylori infection and also serves as an excellent reference for other highly infected societies.

Which Drugs are More Effective in Preventing Familial Adenomatous Polyposis Progression based on Network Meta-analysis?

BACKGROUND: Familial adenomatous polyposis (FAP) is an inherited disorder. At present, an increasing number of medications are being employed to treat FAP; however, only a few have been assessed for their efficacy and safety. Therefore, this study aimed to conduct a network meta-analysis to compare the therapeutic outcomes and adverse drug reactions of all FAP-associated medications. METHODS: Six relevant databases were searched to identify pertinent randomized controlled trials (RCTs), and information on the dosage and frequency of various drugs was extracted. Additionally, data on changes in polyp counts and dimensions, as well as treatment-related adverse reactions for different medications were collected. The Bayesian method was employed to directly or indirectly compare the impact of different treatment regimens on changes in polyp numbers and diameters, and the safety of the drugs was investigated. RESULTS: CXB at 16 mg/kg/day significantly reduced polyp numbers. Celecoxib at 8 mg/kg/day and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) were effective for tolerant FAP patients. Additionally, EPAFFA 2 g daily and sulindac (150 mg twice daily) plus erlotinib (75 mg/day) emerged as the most effective for reducing polyp size. CONCLUSION: The most effective treatment for reducing the number of colorectal polyps is celecoxib 16 mg/kg/day. On the other hand, a daily dosage of 2 g EPA-FFA demonstrates the best results in terms of decreasing colorectal polyp diameter.

Predicting the new psychoactive substance activity of antitussives and evaluating their ecotoxicity to fish.

The misuse of antitussives preparations is a continuing problem in the world, and imply that they might have potential new psychoactive substances (NPS) activity. However, few study focus on their ecological toxicity towards fish. In the present study, the machine learning (ML) methods gcForest and random forest (RF) were employed to predict NPS activity in 30 antitussives. The potential toxic target, mode of action (MOA), acute toxicity and chronic toxicity to fish were further investigated. The results showed that both gcForest and RF achieved optimal performance when utilizing combined features of molecular fingerprint (MF) and molecular descriptor (MD), with area under the curve (AUC) = 0.99, accuracy >0.94 and f1 score > 0.94, and were applied to screen the NPS activity in antitussives. A total of 15 antitussives exhibited potential NPS activity, including frequently-used substances like codeine and dextromethorphan. The binding affinity of these antitussives with zebrafish dopamine transporter (zDAT) was high, and even surpassing that of some traditional narcotics and NPS. Some antitussives formed hydrogen bonds or salt bridges with aspartate (Asp) 95, tyrosine (Tyr) 171 of zDAT. For the ecotoxicity, the MOA of these 15 antitussives in fish was predicted as narcosis. The prenoxdiazin, pholcodine, codeine, dextromethorphan and dextrorphan exhibited very toxic/toxic to fish. It was necessary to pay close attention to the ecotoxicity of these antitussives. In this study, the integration of ML, molecular docking and ECOSAR approaches are powerful tools for understanding the toxicity profiles and ecological hazards posed by new pollutants.

HERPES SIMPLEX VIRUS-1 SUSCEPTIBILITY AS A RISK FACTOR FOR SEPSIS, WITH CYTOMEGALOVIRUS SUSCEPTIBILITY ELEVATING SEVERITY: INSIGHTS FROM A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY.

ABSTRACT: Objective: We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causal relationships between herpes viruses and sepsis. Methods: Publicly available genome-wide association study data were used. Four viruses, HSV-1, HSV-2, EBV, and CMV, were selected, with serum positivity and levels of antibody in serum as the herpes virus data. Results: In forward MR, susceptibility to HSV-1 was a risk factor for sepsis. The susceptibility to CMV showed a severity-dependent effect on sepsis and was a risk factor for the 28-day mortality from sepsis, and was also a risk factor for 28-day sepsis mortality in critical care admission. The EBV EA-D antibody level after EBV infection was a protective factor for 28-day sepsis mortality in critical care admission, and CMV pp28 antibody level was a risk factor for 28-day sepsis mortality in critical care admission. No statistically significant causal relationships between HSV-2 and sepsis were found. No exposures having statistically significant association with sepsis critical care admission as an outcome were found. In reverse MR, the sepsis critical care admission group manifested a decrease in CMV pp52 antibody levels. No causal relationships with statistical significance between sepsis exposure and other herpes virus outcomes were found. Conclusion: Our study identifies HSV-1 susceptibility as a sepsis risk, with CMV susceptibility elevating severity. Varied effects of EBV and CMV antibodies on sepsis severity are noted. Severe sepsis results in a decline in CMV antibody levels. Our results help prognostic and predictive enrichment and offer valuable information for precision sepsis treatment.

Effects of New Psychoactive Substance Esketamine on Behaviors and Transcription of Genes in Dopamine and GABA Pathways in Zebrafish Larvae.

Esketamine (ESK) is the S-enantiomer of ketamine racemate (a new psychoactive substance) that can result in illusions, and alter hearing, vision, and proprioception in human and mouse. Up to now, the neurotoxicity caused by ESK at environmental level in fish is still unclear. This work studied the effects of ESK on behaviors and transcriptions of genes in dopamine and GABA pathways in zebrafish larvae at ranging from 12.4 ng L- 1 to 11141.1 ng L- 1 for 7 days post fertilization (dpf). The results showed that ESK at 12.4 ng L- 1 significantly reduced the touch response of the larvae at 48 hpf. ESK at 12.4 ng L- 1 also reduced the time and distance of larvae swimming at the outer zone during light period, which implied that ESK might potentially decrease the anxiety level of larvae. In addition, ESK increased the transcription of th, ddc, drd1a, drd3 and drd4a in dopamine pathway. Similarly, ESK raised the transcription of slc6a1b, slc6a13 and slc12a2 in GABA pathway. This study suggested that ESK could affect the heart rate and behaviors accompanying with transcriptional alterations of genes in DA and GABA pathways at early-staged zebrafish, which resulted in neurotoxicity in zebrafish larvae.

The azole biocide climbazole induces oxidative stress, inflammation, and apoptosis in fish gut.

Climbazole is an azole biocide that has been widely used in formulations of personal care products. Climbazole can cause developmental toxicity and endocrine disruption as well as gut disturbance in aquatic organisms. However, the mechanisms behind gut toxicity induced by climbazole still remain largely unclear in fish. Here, we evaluate the gut effects by exposing grass carp (Ctenopharyngodon idella) to climbazole at levels ranging from 0.2 to 20 µg/L for 42 days by evaluating gene transcription and expression, biochemical analyses, correlation network analysis, and molecular docking. Results showed that climbazole exposure increased cyp1a mRNA expression and ROS level in the three treatment groups. Climbazole also inhibited Nrf2 and Keap1 transcripts as well as proteins, and suppressed the transcript levels of their subordinate antioxidant molecules (cat, sod, and ho-1), increasing oxidative stress. Additionally, climbazole enhanced NF-κB and iκBα transcripts and proteins, and the transcripts of NF-κB downstream pro-inflammatory factors (tnfα, and il-1ß/6/8), leading to inflammation. Climbazole increased pro-apoptosis-related genes (fadd, bad1, and caspase3), and decreased anti-apoptosis-associated genes (bcl2, and bcl-xl), suggesting a direct reaction to apoptosis. The molecular docking data showed that climbazole could form stable hydrogen bonds with CYP1A. Mechanistically, our findings suggested that climbazole can induce inflammation and oxidative stress through CYP450s/ROS/Nrf2/NF-κB pathways, resulting in cell apoptosis in the gut of grass carp.

[Progress in research on mRNA therapeutics for the treatment of genetic diseases].

In recent years, mRNA drugs have shown a great potential for the treatment of genetic diseases and attracted the attention of many researchers. This article has reviewed the advance in the research of mRNA drugs for the treatment of genetic diseases over the past 30 years, including their mechanisms of action and structure design, with a focus on their advantages as alternative therapies such as high specificity, low dosage, and sustained expression. Meanwhile, challenges for the effective delivery and storage methods for the mRNA drugs are discussed, with an aim to provide guidance for subsequent researches.

The Progress of Polymer Composites Protecting Safe Li Metal Batteries: Solid-/Quasi-Solid Electrolytes and Electrolyte Additives.

The impressive theoretical capacity and low electrode potential render Li metal anodes the most promising candidate for next-generation Li-based batteries. However, uncontrolled growth of Li dendrites and associated parasitic reactions have impeded their cycling stability and raised safety concerns regarding future commercialization. The uncontrolled growth of Li dendrites and associated parasitic reactions, however, pose challenges to the cycling stability and safety concerns for future commercialization. To tackle these challenges and enhance safety, a range of polymers have demonstrated promising potential owing to their distinctive electrochemical, physical, and mechanical properties. This review provides a comprehensive discussion on the utilization of polymers in rechargeable Li-metal batteries, encompassing solid polymer electrolytes, quasi-solid electrolytes, and electrolyte polymer additives. Furthermore, it conducts an analysis of the benefits and challenges associated with employing polymers in various applications. Lastly, this review puts forward future development directions and proposes potential strategies for integrating polymers into Li metal anodes.

Interaction of 17α-ethinylestradiol and methyltestosterone in western mosquitofish (Gambusia affinis) across two generations.

The interactions between estrogen and androgen in aquatic animals remain largely unknown. In this study, two generations (F0 and F1) of western mosquitofish (Gambusia affinis) were continuously exposed to 17α-ethinylestradiol (EE2, 10 ng/L), methyltestosterone (MT, 10 ng/L (MTL); 50 ng/L (MTH)), and mixtures (EE2+MTL and EE2+MTH). Various endpoints, including sex ratio (phenotypic and genetic), secondary sex characteristics, gonadal histology, and transcriptional profile of genes, were examined. The results showed that G. affinis exposed to MTH and EE2+MTH had a > 89.7 % of phenotypic males in F1 generation, with 34.5 and 50.0 % of these males originated from genetic females, respectively. Moreover, females from F0 and F1 generations exposed to MTH and EE2+MTH exhibited masculinized anal fins and skeletons. The combined effect of MT and EE2 on most endpoints was dependent on MT. Furthermore, significant transcriptional alterations in certain target genes were observed in both the F0 and F1 generations by EE2 and MT alone and by mixtures, showing some degree of interactions. These findings that the effects of EE2+MTH were primarily on the phenotypic sex of G. affinis in offspring generation suggest that G. affinis under chronic exposure to the binary mixture contaminated water could have sex-biased populations.

Screening androgen receptor agonists of fish species using machine learning and molecular model in NORMAN water-relevant list.

Androgen receptor (AR) agonists have strong endocrine disrupting effects in fish. Most studies mainly investigate AR binding capacity using human AR in vitro. However, there is still few methods to rapidly predict AR agonists in aquatic organisms. This study aimed to screen AR agonists of fish species using machine learning and molecular models in water-relevant list from NORMAN, a network of reference laboratories for monitoring contaminants of emerging concern in the environment. In this study, machine learning approaches (e.g., Deep Forest (DF)), Random Forests and artificial neural networks) were applied to predict AR agonists. Zebrafish, fathead minnow, mosquitofish, medaka fish and grass carp are all important aquatic model organisms widely used to evaluate the toxicity of new pollutants, and the molecular models of ARs from these five fish species were constructed to further screen AR agonists using AlphaFold2. The DF method showed the best performances with 0.99 accuracy, 0.97 sensitivity and 1 precision. The Asn705, Gln711, Arg752, and Thr877 residues in human AR and the corresponding sites in ARs from the five fish species were responsible for agonist binding. Overall, 245 substances were predicted as suspect AR agonists in the five fish species, including, certain glucocorticoids, cholesterol metabolites, and cardiovascular drugs in the NORMAN list. Using machine learning and molecular modeling hybrid methods rapidly and accurately screened AR agonists in fish species, and helping evaluate their ecological risk in fish populations.

Integrated physiological, transcriptome, and metabolome analyses of the hepatopancreas of Litopenaeus vannamei under cold stress.

Temperature is a limiting factor in the growth of aquatic organisms and can directly affect many chemical and biological processes, including metabolic enzyme activity, aerobic respiration, and signal transduction. In this study, physiological, transcriptomic, and metabolomic analyses were performed to characterize the response of Litopenaeus vannamei to cold stress. We subjected L. vannamei to gradually decreasing temperatures (24 °C, 20 °C, 18 °C, 14 °C, and 12 °C) and studied the changes in the hepatopancreas. The results showed that extreme cold stress (12 °C) caused structural damage to the hepatopancreas of L. vannamei. However, shrimp exhibited response mechanisms to enhance cold tolerance, through regulating changes in key genes and metabolites in amino acid, lipid metabolism, and carbohydrate metabolism, including (a) increased level of methylation in cells to enhance cold tolerance; (b) increased content of critical amino acids, such as proline, alanine, glutamic acid and taurine, to ameliorate energy metabolism, protect cells from cold-induced osmotic imbalance, and promote ion transport and DNA repair; (c) accumulation of unsaturated fatty acids to improve cell membrane fluidity; and (d) regulation of the metabolic pattern shift to rely on anaerobic metabolism with a gradual decrease in aerobic metabolism and enhance glycolysis to produce enough ATP to maintain energy metabolic balance. When the temperature dropped further, cold stress impaired antioxidant and immune defense responses in shrimp. This study provides an integrated analysis of the physiology, transcriptome, and metabolome of L. vannamei in response to cold stress.

An azole fungicide climbazole damages the gut-brain axis in the grass carp.

Azole antifungal climbazole has frequently been detected in aquatic environments and shows various effects in fish. However, the underlying mechanism of toxicity through the gut-brain axis of climbazole is unclear. Here, we investigated the effects of climbazole at environmental concentrations on the microbiota-intestine-brain axis in grass carp via histopathological observation, gene expression and biochemical analyses, and high-throughput sequencing of the 16 S rRNA. Results showed that exposure to 0.2 to 20 µg/L climbazole for 42 days significantly disrupted gut microbiota and caused brain neurotoxicity in grass carp. In this study, there was an alteration in the phylum and genus compositions in the gut microbiota following climbazole treatment, including reducing Fusobacteria (e.g., Cetobacterium) and increasing Actinobacteria (e.g., Nocardia). Climbazole disrupted intestinal microbial abundance, leading to increased levels of lipopolysaccharide and tumor necrosis factor-alpha in the gut, serum, and brain. They passed through the impaired intestinal barrier into the circulation and caused the destruction of the blood-brain barrier through the gut-brain axis, allowing them into the brain. In the brain, climbazole activated the nuclear factor kappaB pathway to increase inflammation, and suppressed the E2-related factor 2 pathway to produce oxidative damage, resulting in apoptosis, which promoted neuroinflammation and neuronal death. Besides, our results suggested that this neurotoxicity was caused by the breakdown of the microbiota-gut-brain axis, mediated by reduced concentrations of dopamine, short chain fatty acids, and intestinal microbial activity induced by climbazole.

Monkeypox Virus Crosstalk with HIV: An Integrated Skin Transcriptome and Machine Learning Study.

The emergence of the monkeypox virus (MPXV) outbreak presents a formidable challenge to human health. Emerging evidence suggests that individuals with HIV have been disproportionately affected by MPXV, with adverse clinical outcomes and higher mortality rates. However, the shared molecular mechanisms underlying MPXV and HIV remain elusive. We identified differentially expressed genes (DEGs) from two public data sets, GSE219036 and GSE184320, and extracted common DEGs between MPXV and HIV. We further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interactions (PPI), candidate drug assessment, and immune correlation of hub genes analysis. We validated the key biomarkers using multiple machine learning (ML) methods including random forest (RF), t-distributed stochastic neighbor embedding (tSNE), and uniform manifold approximation and projection (UMAP). A total of 59 common DEGs were identified between MPXV and HIV. Our functional analysis highlighted multiple pathways, including the ERK cascade, NF-κB signaling, and various immune responses, playing a collaborative role in the progression of both diseases. The PPI and gene co-expression networks were constructed, and five key genes with significant immune correlations were identified and validated by multiple ML models, including SPRED1, SPHK1, ATF3, AKT3, and AKT1S1. Our study emphasizes the common pathogenesis of HIV and MPXV and highlights the pivotal genes and shared pathways, providing new opportunities for evidence-based management strategies in HIV patients co-infected with MPXV.

Ephedrine and cocaine cause developmental neurotoxicity and abnormal behavior in zebrafish.

Ephedrine (EPH) and cocaine (COC) are illegal stimulant drugs, and have been frequently detected in aquatic environments. EPH and COC have negative effects on the nervous system and cause abnormal behaviors in mammals and fish at high concentrations, but their mechanisms of neurotoxicity remain unclear in larvae fish at low concentrations. To address this issue, zebrafish embryos were exposed to EPH and COC for 14 days post-fertilization (dpf) at 10, 100, and 1000 ng L-1. The bioaccumulation, development, behavior, cell neurotransmitter levels and apoptosis were detected to investigate the developmental neurotoxicity (DNT) of EPH and COC. The results showed that EPH decreased heart rate, while COC increased heart rate. EPH caused cell apoptosis in the brain by AO staining. In addition, behavior analysis indicated that EPH and COC affected spontaneous movement, touch-response, swimming activity and anxiety-like behaviors. EPH and COC altered the levels of the neurotransmitters dopamine (DA) and γ-aminobutyric acid (GABA) with changes of the transcription of genes related to the DA and GABA pathways. These findings indicated that EPH and COC had noticeable DNT in the early stage of zebrafish at environmentally relevant concentrations.

Exploration of the common pathogenic link between COVID-19 and diabetic foot ulcers: An in silico approach.

Background and Aims: The Coronavirus Disease-19 (COVID-19) is posing an ongoing threat to human health. Patients of diabetic foot ulcer (DFU) are susceptible to COVID-19-induced adverse outcomes. Nevertheless, investigations into their mutual molecular mechanisms have been limited to date. In the present work, we tried to uncover the shared pathogenesis and regulatory gene targets of COVID-19 and DFU. Methods: In this study, we chose GSE161281 as the COVID-19 data set, which contained severe acute respiratory syndrome coronavirus 2 infected human induced embryonic stem cell-derived peripheral neurons (n = 2) with uninfected controls (n = 2). The GSE134431 designated as the DFU data set, comprising full-thickness DFU (n = 13) and diabetic foot skin (n = 8) samples from diabetic patients. The differential expressed genes (DEGs) were identified from GSE161281 and GSE134431, and the common DEGs between COVID-19 and DFU were extracted. Multifactor regulatory network and co-expression network of the common DEGs were analyzed, along with candidate drug prediction. Results: Altogether, six common DEGs (dickkopf-related protein 1 [DKK1], serine proteinase inhibitor A3 [SERPINA3], ras homolog family member D [RHOD], myelin protein zero like 3 [MPZL3], Claudin-11 [CLDN11], and epidermal growth factor receptor pathway substrate 8-like 1 [EPS8L1]) were found between COVID-19 and DFU. Functional analyses indicated that pathways of apoptotic and Wnt signaling may contribute to progression of COVID-19. Gene co-expression network implied the shared pathways of immune regulation and cytokine response participated collectively in the development of DFU and COVID-19. A multifactor regulatory network was constructed integrating the corresponding microRNAs (miRNAs) and transcription factors. Additionally, we proposed potential drug objects for the combined therapy. Conclusion: Our study revealed the shared molecular mechanisms underlying COVID-19 and DFU. The identified pivotal targets and common pathways can provide new perspectives for further research and assist the development of management strategies in patients of DFU complicated with COVID-19.

Genetic evidence implicating circulating lipids and lipid drug targets in pterygium.

There is limited knowledge about the impact of circulating lipids and lipid-modifying drugs on pterygium development, with conflicting results reported. Our study aimed to address these questions by applying the Mendelian randomization (MR) approach. A two-step MR model was developed. In the first step, bidirectional two-sample MR was employed to establish the causal relationship between circulating lipids and pterygium risk. In the second step, drug-target MR analysis was conducted to assess the causal effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitors on pterygium outcomes. Genetically predicted low-density lipoprotein cholesterol (LDL-c) levels were found to be significantly associated with an increased risk of pterygium (Inverse variance weighted [IVW] odds ratio [OR] = 2.227; P = 1.53 × 10-4). Similarly, higher total cholesterol (TC) levels exhibited a suggestive association with greater susceptibility to pterygium (IVW OR = 1.806; P = 1.70 × 10-3). Through drug-target MR, a positive causal association was noted between HMGCR-mediated LDL-c levels and pterygium (IVW OR = 6.999; P = 0.016), suggesting that statins may be effective in reducing pterygium risk. The present findings suggest that circulating TC and LDL-c are risk factors for pterygium. Additionally, the results indicate that HMGCR inhibitors, which lower LDL-c levels, have a potential protective effect on pterygium outcomes. Further research is warranted to elucidate the underlying mechanisms involved in pterygium pathogenesis, with a particular focus on cholesterol metabolism.