Transformer models have emerged as pivotal tools within the realm of drug discovery,distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes.Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data,these models showcase remarkable efficacy across various tasks,including new drug design and drug target identification.The adaptability of pre-trained trans-former-based models renders them indispensable assets for driving data-centric advancements in drug discovery,chemistry,and biology,furnishing a robust framework that expedites innovation and dis-covery within these domains.Beyond their technical prowess,the success of transformer-based models in drug discovery,chemistry,and biology extends to their interdisciplinary potential,seamlessly combining biological,physical,chemical,and pharmacological insights to bridge gaps across diverse disciplines.This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields.In our review,we elucidate the myriad applications of transformers in drug discovery,as well as chemistry and biology,spanning from protein design and protein engineering,to molecular dynamics(MD),drug target iden-tification,transformer-enabled drug virtual screening(VS),drug lead optimization,drug addiction,small data set challenges,chemical and biological image analysis,chemical language understanding,and single cell data.Finally,we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.

Objective:To explore the expression of nectin-4 and vanin-1 in esophageal squamous cell carcinoma(ESCC)and its influence on the malignant biological behaviors of ESCC cells,as well as the underlying mechanisms.Methods:Transcriptome sequencing combined with GO and KEGG enrichment analysis was used to identify the downstream target gene(vanin-1)regulated by nectin-4.The mRNA expression of vanin-1 in ESCC tissues was studied using the Timer2.0 database,and the mRNA and protein expression of vanin-1 in normal esophageal epithelial HET-1 and ESCC cells was detected by qPCR and Western blot,identifying ESCC KYSE-410 and KYSE-510 cells with the most significant differential expression.The expression of vanin-1 in KYSE-410 and KYSE-510 cells was knocked down using siRNA.The effects of vanin-1 knockdown on cell proliferation,migration,and invasion were measured using CCK-8 assay,wound healing assay,and Transwell chamber assay.Furthermore,KEGG and GO enrichment analyses were conducted for vanin-1-related signaling pathways.Immunohistochemistry was performed to compare the expression of vanin-1 between ESCC tissues and adjacent non-tumor tissues.Results:Timer2.0 database analysis and qPCR results showed that vanin-1 was highly expressed in both ESCC tissues and cell lines(both P<0.01).WB assay also confirmed high expression of vanin-1 protein in ESCC cells(P<0.01).siRNA successfully knocked down vanin-1 expression in KYSE-410 and KYSE-510 cells.Knockdown of vanin-1 significantly inhibited the proliferation,migration,and invasion capabilities of KYSE-410 and KYSE-510 cells(P<0.05 or P<0.01 or P<0.001 or P<0.000 1).KEGG and GO enrichment analysis suggested that vanin-1 might function through pathways related to pantothenic acid and coenzyme A synthesis metabolism.Immunohistochemistry results indicated that vanin-1 was highly expressed in ESCC tissues(P<0.000 1).Conclusion:Vanin-1 is highly expressed in ESCC tissues and promotes the proliferation,migration,and invasion of KYSE-410 and KYSE-510 cells through the nectin-4/vanin-1 axis.Targeting vanin-1 might offer a new therapeutic strategy for ESCC.

Objective To study the immunomodulatory mechanism of lianqin jiedu formula based on network pharmacology meth-ods.Methods Using Troditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and GeneCards da-tabases,the active ingredients and potential targets of lianqin jiedu formula was obtained,as well as immune regulation related targets,and the intersection targets was analyzed.The protein-protein interaction(PPI)network and compound target network was constructed,key active ingredients and core action targets were screened.Molecular docking technology was used to verify the binding activity between key active components and core targets,and the intersection targets were analyzed for Gene Ontology(GO)function and Kyoto Encyclope-dia of Genes and Genomes(KEGG)pathway enrichment using the The Database for Annotation,Visualization,and Integrated Discovery(DAVID)database.Results The Lianqin jiedu formula consists of 143 components and 164 targets,of which 130 components and 79 targets were related to immunoregulation,accounting for 90.91％and 48.17％respectively;among them,there were 13 key compounds and 18 core target genes.The top 4 core targets with the highest degree values showed good binding affinity with the top 3 key compounds.The lianqin jiedu formula was involved in immunoregulation and mainly affects 272 biological processes and 58 pathways.Conclusion The lianqin jiedu formula may exert its immunoregulation effects by targeting core targets such as tumor necrosis factor(TNF)and inter-leukin-6(IL-6)through key compounds such as quercetin,kaempferol,and β-sitosterol,affecting biological processes such as pro-tein phosphorylation,cytoplasm,and nucleus,and regulating key pathways such as metabolic pathways.This study provides a reference for the treatment of subsequent immune diseases.

Transformer models have emerged as pivotal tools within the realm of drug discovery, distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes. Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data, these models showcase remarkable efficacy across various tasks, including new drug design and drug target identification. The adaptability of pre-trained transformer-based models renders them indispensable assets for driving data-centric advancements in drug discovery, chemistry, and biology, furnishing a robust framework that expedites innovation and discovery within these domains. Beyond their technical prowess, the success of transformer-based models in drug discovery, chemistry, and biology extends to their interdisciplinary potential, seamlessly combining biological, physical, chemical, and pharmacological insights to bridge gaps across diverse disciplines. This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields. In our review, we elucidate the myriad applications of transformers in drug discovery, as well as chemistry and biology, spanning from protein design and protein engineering, to molecular dynamics (MD), drug target identification, transformer-enabled drug virtual screening (VS), drug lead optimization, drug addiction, small data set challenges, chemical and biological image analysis, chemical language understanding, and single cell data. Finally, we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.

OBJECTIVE: To investigate the role and mechanism of the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING) pathway in oleic acid-induced acute lung injury (ALI) in mice. METHODS: Male wild-type C57BL/6J mice were randomly divided into five groups (each n = 10): normal control group, ALI model group, and 5, 50, 500 μg/kg inhibitor pretreatment groups. The ALI model was established by tail vein injection of oleic acid (7 mL/kg), while the normal control group received no intervention. The inhibitor pretreatment groups were intraperitoneally injected with the corresponding doses of cGAS inhibitor RU.521 respectively 1 hour before modeling. At 24 hours post-modeling, blood was collected, and mice were sacrificed. Lung tissue pathological changes were observed under light microscopy after hematoxylin-eosin (HE) staining, and pathological scores were assessed. Western blotting was used to detect the protein expressions of cGAS, STING, phosphorylated TANK-binding kinase 1 (p-TBK1), phosphorylated interferon regulatory factor 3 (p-IRF3), and phosphorylated nuclear factor-κB p65 (p-NF-κB p65) in lung tissue. Immunohistochemistry was performed to observe STING and p-NF-κB positive expressions in lung tissue. Serum interferon-β (IFN-β) levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the normal control group, the ALI model group exhibited significant focal alveolar thickening, intra-alveolar hemorrhage, pulmonary capillary congestion, and neutrophil infiltration in the pulmonary interstitium and alveoli, along with markedly increased pathological scores (10.33±0.58 vs. 1.33±0.58, P < 0.05). Protein expressions of cGAS, STING, p-TBK1, p-IRF3, and p-NF-κB p65 in lung tissue significantly increased [cGAS protein (cGAS/β-actin): 1.24±0.02 vs. 0.56±0.02, STING protein (STING/β-actin): 1.27±0.01 vs. 0.55±0.01, p-TBK1 protin (p-TBK1/β-actin): 1.34±0.03 vs. 0.22±0.01, p-IRF3 protein (p-IRF3/β-actin): 1.23±0.02 vs. 0.36±0.01, p-NF-κB p65 protein (p-NF-κB p65/β-actin): 1.30±0.02 vs. 0.53±0.02, all P < 0.05], positive expressions of STING and p-NF-κB in lung tissue were significantly elevated [STING (A value): 0.51±0.03 vs. 0.30±0.07, p-NF-κB (A value): 0.57±0.05 vs. 0.31±0.03, both P < 0.05], and serum IFN-β levels were also significantly higher (ng/L: 256.02±3.84 vs. 64.15±1.17, P < 0.05). The cGAS inhibitor pretreatment groups showed restored alveolar structural integrity, reduced inflammatory cell infiltration, and decreased hemorrhage area, along with dose-dependent lower pathological scores as well as the protein expressions of cGAS, STING, p-TBK1, p-IRF3 and p-NF-κB p65 in lung tissue, with significant differences between the 500 μg/kg inhibitor group and ALI model group [pathological score: 2.67±0.58 vs. 10.33±0.58, cGAS protein (cGAS/β-actin): 0.56±0.03 vs. 1.24±0.02, STING protein (STING/β-actin): 0.67±0.03 vs. 1.27±0.01, p-TBK1 protein (p-TBK1/β-actin): 0.28±0.01 vs. 1.34±0.03, p-IRF3 protein (p-IRF3/β-actin): 0.32±0.01 vs. 1.23±0.02, p-NF-κB p65 protein (p-NF-κB p65/β-actin): 0.63±0.01 vs. 1.30±0.02, all P < 0.05]. Compared with the ALI model group, positive expressions of STING and p-NF-κB in lung tissue were significantly reduced in the 500 μg/kg inhibitor group [STING (A value): 0.40±0.01 vs. 0.51±0.03, p-NF-κB (A value): 0.43±0.02 vs. 0.57±0.05, both P < 0.05], and serum IFN-β levels were also markedly reduced (ng/L: 150.03±6.19 vs. 256.02±3.84, P < 0.05). CONCLUSIONS The cGAS/STING pathway is activated in oleic acid-induced ALI, leading to exacerbated inflammatory responses and increased lung damage. RU.521 can inhibit cGAS, thereby down-regulating the expression of pathway proteins and cytokines, and providing protection to lung tissue.
Animals ; Acute Lung Injury/chemically induced* ; Male ; Nucleotidyltransferases/metabolism* ; Mice ; Signal Transduction ; Mice, Inbred C57BL ; Membrane Proteins/metabolism* ; Oleic Acid/adverse effects* ; Transcription Factor RelA/metabolism* ; Lung/pathology* ; Interferon Regulatory Factor-3/metabolism* ; Disease Models, Animal

In this study, Saccharomyces cerevisiae R0 was used as the chassis cell to synthesize oleanolic acid from scratch through the heterologous expression of β-amyrin synthase(β-AS) from Glycyrrhiza uralensis, cytochrome P450 enzyme CYP716A154 from Catharanthus roseus, and cytochrome P450 reductase AtCPR from Arabidopsis thaliana. The engineered strain R1 achieved shake flask titres of 5.19 mg·L~(-1). By overexpressing enzymes in the pentose phosphate pathway(PPP)(ZWF1, GND1, TKL1, and TAL), the NADH kinase gene in the mitochondrial matrix(POS5), truncated 3-hydroxy-3-methylglutaryl-CoA reductase(tPgHMGR1) from Panax ginseng, and farnesyl diphosphate synthase gene(SmFPS) from Salvia miltiorrhiza, the precursor supply and intracellular reduced nicotinamide adenine dinucleotide phosphate(NADPH) supply were enhanced, resulting in an 11.4-fold increase in squalene yield and a 3.6-fold increase in oleanolic acid yield. Subsequently, increasing the copy number of the heterologous genes tPgHMGR1, β-AS, CYP716A154, and AtCPR promoted the metabolic flow towards the final product, oleanolic acid, and increased the yield by three times. Shake flask fermentation data showed that, by increasing the copy number, precursor supply, and intracellular NADPH supply, the final engineered strain R3 could achieve an oleanolic acid yield of 53.96 mg·L~(-1), which was 10 times higher than that of the control strain R1. This study not only laid the foundation for the green biosynthesis of oleanolic acid but also provided a reference for metabolic engineering research on other pentacyclic triterpenoids in S. cerevisiae.
Oleanolic Acid/biosynthesis* ; Saccharomyces cerevisiae/metabolism* ; Industrial Microbiology ; Microorganisms, Genetically-Modified/metabolism* ; Plants/enzymology* ; Fermentation ; Metabolic Engineering

Objective To investigate the protective effects of Qiji Special Dietary Food on exercise-induced myocardial injury in mice.Methods An exercise-induced myocardial injury model was established using a treadmill running protocol,and at the same time,the modeled mice were administered Qiji Special Dietary Food via oral gavage,followed by a 4-week treadmill exhaustion test.Serum levels of cardiac troponin T(cTnT),creatine kinase(CK),and lactate dehydrogenase(LDH)were measured.Myocardial tissues were analyzed for superoxide dismutase(SOD)activity and malondialdehyde(MDA)content.Histopathological alterations and ultrastructural changes in myocardial tissue were evaluated using light microscopy and transmission electron microscopy(TEM).Results After 4 weeks of exhaustive training,compared to the control group,the model group exhibited significantly elevated serum cTnT,CK,and myocardial MDA levels(P<0.01),along with reduced myocardial SOD activity(P<0.01).Compared to the model group,high-,medium-,and low-dose treatment significantly attenuated the exhaustive exercise-induced increases in serum cTnT level and myocardial MDA content(P<0.01),restoring these indicators to the levels comparable to those of the normal control group(P<0.05).Additionally,all treatment groups had markedly increased myocardial SOD activity,with no significant difference from the normal group.Histopathological and ultrastructural analyses revealed markedly alleviated myocardial damage in the treatment groups,with the medium-dose group exhibiting the most pronounced protective effects.Conclusion Qiji Special Dietary Food demonstrates significant protective effects against exercise-induced myocardial injury in mice,which maybe associated with its antioxidant activity and mitigation of oxidative stress.

Objective To investigate the alterations in skeletal muscle function and mass in an experimental mouse model of high-intensity exercise in a hot and humid environment.Methods Twenty-four male C57BL/6J mice(7～8 weeks old,weighing 21.30±0.67 g)were randomly assigned to a control group(CON group),a normal temperature and humidity exercise group(NE group),and a high temperature and humidity exercise group(HE group),with 8 mice in each group.The HE group was subjected to a high-temperature simulation chamber,maintaining a temperature of 37～39℃and humidity of 70%～80%,for a 60-minute exercise intervention at a 10° incline and 80%of maximum velocity(12 min of exercise followed by 8 min of rest,for 3 cycles).The CON group did not exercise,while the NE group exercised in the same manner in a normal temperature and humidity environment.The overall condition of the mice was evaluated by monitoring their body weight and analyzing their body composition.Their serum creatinine and urea levels were detected using an automated biochemical analyzer.After exercise,skeletal muscle function in the mice of each group was assessed by measuring their grip strength and exhaustion time.The skeletal muscle contractility and resistance to fatigue were evaluated using an in situ/in vivo/ex vivo muscle testing system.HE staining was employed to observe the morphological and structural changes in the skeletal muscles,and the average cross-sectional area and diameter of the muscle fibers were analyzed.Genes related to protein synthesis(Eif4ebp1,p70S6k)and breakdown(Foxo3,Fbxo32,Trim63)and heat stress-related genes(Hsf-1,Hspa1a,Hsp90aa)were quantified using RT-qPCR.Results ① Compared with the CON and NE groups,the HE group exhibited significant decreases in body weight(P<0.01)and lean body mass(P<0.05),an upward trend of creatinine level(P<0.05),and increases in the urea content(P<0.01).② The mice in the HE group had notably reduced grip strength(P<0.001),diminished skeletal muscle contraction,and weakened resistance to fatigue(P<0.05)than the CON and NE groups.③ The HE group demonstrated a reduction in the average cross-sectional area of muscle fibers(P<0.05)and a decrease in average fiber diameter(P<0.05),with particular up-regulation of Fbxo32,Trim63 and Eif4ebp1(P<0.01)and down-regulation of p70S6k(P<0.05)in comparison to the NE and CON groups.④ The expression levels of heat stress-related genes were higher in the HE group than the CON and NE groups(P<0.05).Conclusion High-intensity exercise in a hot and humid environment can lead to a decline in skeletal muscle function and mass in mice,potentially due to the disturbance of skeletal muscle protein synthesis and degradation triggered by excessive heat stress.

Objective:To investigate effect of testosterone on polarization of M1 macrophages induced by lipopolysaccharide(LPS).Methods:CCK-8 method was used to detect effects of LPS and testosterone on RAW 264.7 cell viability.Morphological changes of cells were observed by optical microscope.mRNA expression levels of M1-type polarizing genes TNF-α,IL-1β and IL-6 in macro-phages were detected by qRT-PCR.Expression levels of M1-polarizing protein TNF-α and CD206 in macrophages were detected by immunofluorescence and Western blot.Secretion of inflammatory cytokines was detected by ELISA.Results:Testosterone could decrease mRNA expressions of TNF-α,IL-1β and IL-6 mRNA and protein expression of TNF-α.Finally,testosterone could decrease secretion of inflammation-related factors.Conclusion:Testosterone can inhibit LPS-induced transformation of macrophages to M1 polarization phenotype.

Objective To explore the protective effects of genetically modified porcine erythrocyte suspension as a subnormothermic normoxic mechanical perfusate on hypoxic-ischemic brain injury in cynomolgus monkeys caused by traumatic hemorrhage.Methods Cynomolgus monkeys were randomly divided into positive and negative control groups(a total of 3 monkeys,with 3 left cerebral hemispheres as the positive control group and 3 right cerebral hemispheres as the negative control group)and the subnormothermic perfusion group(n=3).The positive control group was directly sampled 1 hour after circulatory arrest,while the negative control group was placed at subnormothermic conditions for 6 hours after circulatory arrest.The subnormothermic perfusion group underwent 6 hours of subnormothermic normoxic mechanical perfusion of the bilateral common carotid arteries of the cynomolgus monkey hypoxic-ischemic brain injury model using genetically modified porcine erythrocyte suspension 1 hour after circulatory arrest.Before perfusion,cross-matching experiments were conducted between the six genetically modified pig and the cynomolgus monkeys.After the start of perfusion,the levels of routine blood indicators in the perfusate were detected at 0,1,2,3,4,5 and 6 hours.Blood oxygen saturation was recorded,and the levels of Na+,K+,Ca2+,glucose and blood pH in the perfusate were measured,as well as the levels of IgG and IgM in the perfusate.After 6 hours of perfusion,the water content of the brain tissue was measured.Nissl staining was performed on the frontal cortex and hippocampal regions,and immunofluorescence staining was used to detect the expression of glial fibrillary acidic protein(GFAP),ionized calcium-binding adapter molecule 1(Iba1)and neuronal nuclear antigen(NEUN).Results The cross-matching results between the six genetically modified pig and the cynomolgus monkeys were negative.The number of red blood cells in the perfusate decreased significantly at 3 hours of perfusion,and the hemoglobin level showed a downward trend at 1,3,5 and 6 hours.The number of white blood cells and platelets decreased at all time points.The blood oxygen saturation in the subnormothermic perfusion group remained stable at 95%-98%,and the levels of blood oxygen saturation,Na+,Ca2+,glucose and pH were stable,while the K+level first increased and then decreased.There was no significant difference in the levels of IgG and IgM before and after perfusion.The water content of brain tissue at the end of perfusion in the subnormothermic perfusion group was significantly higher than that in the positive control group(P<0.001).Nissl staining results showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex of the subnormothermic perfusion group maintained better morphological integrity,with no significant increase in enlarged and deformed cells.In the hippocampal CA1 region,there was a slight increase in enlarged and deformed cells,and a few cells with undamaged structures showed reduced cell size.In the hippocampal dentate gyrus,fewer granule neurons had compromised structural integrity,with increased cell edema.NEUN immunofluorescence staining showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex and hippocampal CA1 region of the subnormothermic perfusion group had better morphological states,with clear axons.The granule cells in the hippocampal dentate gyrus were well preserved,but the nuclei were less well protected.GFAP immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had sparser protrusions that were more tightly associated with neurons.Iba1 immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had thicker and fewer protrusions.Conclusions Compared with the positive control group,subnormothermic normoxic mechanical perfusion with genetically modified porcine erythrocyte perfusate increases brain tissue edema in cynomolgus monkeys,but better preserves the morphological integrity of neurons and glial cells.The protective effects may be related to the continuous oxygen and energy supply,maintenance of ion homeostasis and perfusate pH,reduced rejection,and low metabolic state of the whole brain.