Antiviral drug research and development is an important research direction in the current and future biomedical field. The research and development of antiviral drugs not only requires the application of new strategies and new technologies, but also requires the complementary advantages and close cooperation of project teams. Based on the latest progress in this field and the author's drug research practice, this paper summarizes the underlying logic, innovative thinking and research paradigm of antiviral medicinal chemistry.

Objective This study aimed to explore the association of single nucleotide polymorphisms(SNP)in the matrix metalloproteinase 2(MMP-2)signaling pathway and the risk of vascular senescence(VS). Methods In this cross-sectional study,between May and November 2022,peripheral venous blood of 151 VS patients(case group)and 233 volunteers(control group)were collected.Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway,assessed through carotid-femoral pulse wave velocity(cfPWV),and analyzed using multivariate logistic regression.The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction(MDR)and generalized multifactor dimensionality regression(GMDR)modeling. Results Within the multivariate logistic regression models,four SNPs were screened to have significant associations with VS:chemokine(C-C motif)ligand 2(CCL2)rs4586,MMP2 rs14070,MMP2 rs7201,and MMP2 rs1053605.Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype,and those of the T/T genotype had a 19.375-fold increased risk.CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. Conclusion CCL2 rs4586,MMP-2 rs14070,MMP-2 rs7201,and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.
Male ; Adult ; Humans ; Prognosis ; Retrospective Studies ; Myeloid Differentiation Factor 88 ; China/epidemiology* ; Testicular Neoplasms/drug therapy* ; Cyclophosphamide ; Rituximab/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Prednisone/therapeutic use* ; Doxorubicin/therapeutic use* ; Vincristine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Immediate-Early Proteins/therapeutic use* ; Tumor Suppressor Proteins

OBJECTIVES: To investigate the cerebral metabolism in the patients with type 2 diabetes mellitus-associated cognitive dysfunction (T2DACD) and explore the mechanism of electroacupuncture (EA) at the acupoints for Tiaozang Xingshen (adjusting zangfu function and rescuing the spirit) in treatment of T2DACD, using magnetic resonance spectroscopy. METHODS: Fifteen patients with T2DACD (observation group) and 22 healthy subjects (control group) were enrolled. In the observation group, the patients were treated with EA for Tiaozang Xingshen at Baihui (GV 20) and Shenting (GV 24), and bilateral Feishu (BL 13), Pishu (BL 20), Shenshu (BL 23), Zusanli (ST 36), Sanyinjiao (SP 6), Hegu (LI 4) and Taichong (LR 3). EA was operated with disperse-dense wave, 2 Hz/100 Hz in frequency and 0.1 mA to 1.0 mA in current intensity; 30 min each time, once daily. One course of EA consisted of 5 treatments, at the interval of 2 days and the intervention lasted 8 courses. Before treatment in the control group, before and after treatment in the observation group, the score of Montreal cognitive assessment scale (MoCA), the score of clinical dementia rating (CDR), Flanker paradigm, Stroop paradigm, Nback paradigm, the score of self-rating anxiety scale (SAS), the score of self-rating depression scale (SDS), and the score of Hamilton depression rating scale (HAMD) were evaluated separately; the glycolipid metabolic indexes (fasting plasma glucose [FPG], glycosylated hemoglobin type A1c [HbA1c], total cholesterol [TC], triacylglycerol [TG], high-density lipoprotein cholesterol [HDL-C] and low-density lipoprotein cholesterol [LDL-C]) were determined；with the magnetic resonance spectroscopy technique adopted, the metabolites in the basal ganglia area were detected. The correlation analysis was performed for the metabolite values with MoCA score, CDR score , Flanker paradigm, Stroop paradigm, and Nback paradigm. RESULTS: Before treatment, compared with the control group, in the observation group, MoCA score was lower (P<0.001), CDR score and the levels of FPG and HbA1c were higher (P<0.001); the reaction times of Flanker non-conflict, Flanker conflict, Stroop neutrality, Stroop congruence, Stroop conflict, and 1-back were prolonged (P<0.05, P<0.001), and the accuracy of Flanker conflict, Stroop conflict, and 1-back decreased (P<0.05, P<0.01); the ratio of N-acetyl aspartate (NAA) to creatine (Cr) in the left basal ganglia area was dropped (P<0.001), and that of myo-inositol (MI) to Cr in the right side increased (P<0.05). In the observation group after treatment, compared with the levels before treatment, MoCA score was higher (P<0.001), the scores of CDR, SAS and HAMD were reduced (P<0.01, P<0.05), the reaction times of Flanker conflict and Stroop conflict shortened (P<0.001, P<0.05), and the accuracy of Flanker conflict and 1-back increased (P<0.001, P<0.05); the ratio of NAA to Cr in the left basal ganglia area and that of the gamma-aminobutyric acid (GABA) to Cr in the right increased (P<0.05), that of MI to Cr in the right decreased (P<0.05). Before treatment, in the observation group, the ratio of MI to Cr in the right basal ganglia area was positively correlated with the reaction time of Stroop congruence (r=0.671, P=0.012) and this ratio was positively correlated with the reaction time of Stroop conflict (r=0.576, P=0.039). CONCLUSIONS Electroacupuncture for "adjusting zangfu function and rescuing the mind" improves the cognitive function of T2DACD patients, which may be related to the regulation of NAA, MI and GABA levels in the basal ganglia.
Humans ; Electroacupuncture ; Acupuncture Therapy ; Acupuncture Points ; Diabetes Mellitus, Type 2/therapy* ; Glycated Hemoglobin ; Cognitive Dysfunction/therapy* ; Cholesterol ; gamma-Aminobutyric Acid

To address the continuous emergence of drug-resistant strains of viruses and the outbreaks of novel virus infections, developing new antiviral drugs based on novel strategies has become an important and urgent research topic. In recent years, the rapidly developing multi-specific binding strategy has become a focus and been widely applied in antiviral. This review summarizes the recent progress of the multi-specific binding strategy in the antiviral field from the perspective of medicinal chemistry and discusses existing challenges as well as future opportunities for antiviral drug discovery.

Objective: To summarize the clinical characteristics of epileptic seizure associated with neurofibromatosis type 1 (NF1). Methods: From January 2017 to July 2023 at Children's Hospital Capital Institute of Pediatrics, medical records of patients with both NF1 and epileptic seizure were reviewed in this case series study. The clinical characteristics, treatment and prognosis were analyzed retrospectively. Results: A total of 15 patients(12 boys and 3 girls) were collected. Café-au-lait macules were observed in all 15 patients. There were 6 patients with neurodevelopmental disorders and the main manifestations were intellectual disability or developmental delay. The age at the first epileptic seizure was 2.5 (1.2, 5.5) years. There were various seizure types, including generalized tonic-clonic seizures in 8 patients, focal motor seizures in 6 patients, epileptic spasm in 4 patients, tonic seizures in 1 patient, absence in 1 patient, generalized myoclonic seizure in 1 patient and focal to bilateral tonic-clonic seizure in 1 patient. Among 14 patients whose brain magnetic resonance imaging results were available, there were abnormal signals in corpus callosum, basal ganglia, thalamus or cerebellum in 6 patients, dilated ventricles of different degrees in 3 patients, blurred gray and white matter boundary in 2 patients, agenesis of corpus callosum in 1 patient and no obvious abnormalities in the other patients. Among 13 epilepsy patients, 8 were seizure-free with 1 or 2 antiseizure medications(ASM), 1 with drug resistant epilepsy was seizure-free after left temporal lobectomy, and the other 4 patients who have received 2 to 9 ASM had persistent seizures. One patient with complex febrile convulsion achieved seizure freedom after oral administration of diazepam on demand. One patient had only 1 unprovoked epileptic seizure and did not have another seizure without taking any ASM. Conclusions: The first epileptic seizure in NF1 patients usually occurs in infancy and early childhood, with the main seizure type of generalized tonic-clonic seizure and focal motor seizure. Some patients have intellectual disability or developmental delay. Most epilepsy patients achieve seizure freedom with ASM.
Male ; Female ; Humans ; Child, Preschool ; Child ; Neurofibromatosis 1/diagnosis* ; Retrospective Studies ; Intellectual Disability ; Electroencephalography ; Epilepsy/etiology* ; Seizures/etiology*

Moringa oleifera leaves are known for their "Virechana"(purgative) effect in Ayurvedic medicine in India. This study compared the purgative effects and mechanisms of M. oleifera leaves with the reference Rhei Radix et Rhizoma to establish a foundation for the further application of M. oleifera leaves in traditional Chinese medicine(TCM). Using network pharmacology and molecular docking methods, this study identified the material basis, common targets, and signaling pathways through which Rhei Radix et Rhizoma and M. oleifera leaves exerted their purgative pharmacological effects. A low-fiber diet-induced constipation mouse model was established to measure fecal parameters and small intestinal propulsion rate, and histological changes in the colon were observed using HE staining. Relative expression levels of relevant genes and target proteins were assessed using RT-qPCR and immunohistochemistry, respectively. The results showed that mapping the targets of Rhei Radix et Rhizoma and M. oleifera leaves onto the biological process network of constipation revealed close proximity, indicating that they may exert their therapeutic effects on constipation through similar biological processes. Molecular docking results indicated that compounds such as sennoside C and isoquercitrin could target serine/threonine protein kinases(AKT1) and mitogen-activated protein kinase 3(MAPK3), thereby affecting MAPK and calcium signaling pathways to promote defecation. Animal experiments demonstrated that both M. oleifera leaves and Rhei Radix et Rhizoma increased the number of fecal pellets and water content in constipated mice, improved small intestine motility, colon mucosal thickness, and muscle layer thickness, upregulated the gene expression levels of AKT1 and MAPK3 in the colon, and downregulated the expression of AQP3 protein. These findings suggest that M. oleifera leaves and Rhei Radix et Rhizoma share similarities in their therapeutic efficacy and mechanisms for treating constipation. Using Rhei Radix et Rhizoma as a reference can provide a better understanding of the characteristics of the "Virechana"(purgative) effect of M. oleifera leaves in TCM.
Mice ; Animals ; Cathartics ; Moringa oleifera ; Molecular Docking Simulation ; Drugs, Chinese Herbal/chemistry* ; Constipation

Objective: To screen the key genes involved in gefitinib resistance of lung adenocarcinoma PC9/GR cells which harbored 19 exon mutation of epidermal growth factor receptor (EGFR) gene, and discuss the effect and mechanism of downregulation of solute carrier family 7 member 11 (SLC7A11) on the gefitinib resistance of PC9/GR cells. Methods: RNA microarray was conducted to detect the gene expressions in PC9 and PC9/GR cells. The differently expressed genes were screened by using limma package of R language and analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Western blotting was performed to determine the expression of SLC7A11 protein in PC9 and PC9/GR cells. PC9/GR cells were infected with lentivirus plasmid containing short hairpin RNA (shRNA) targeting SLC7A11 or negative control shRNA (sh-NC), respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the efficacy of shRNA on the expression of SLC7A11 mRNA. Cell counting kit-8 (CCK-8) assay was conducted to determine the suppressing effect of gefitinib on PC9/GR cells. Mito-Tracker Red CMXRos probe and malondialdehyde (MDA) assay kit were used to evaluate gefitinib-induced ferroptosis in PC9/GR cells. Immunohistochemistry (IHC) was conducted to detect the expression of SLC7A11 protein in the tumor tissues of advanced stage lung adenocarcinoma patients harboring 19 exon mutation of EGFR gene. Thirty-six advanced stage lung adenocarcinoma patients who received EGFR-tyrosihe kinase inhibitor(TKI) as first-line treatment in Fourth Hospital of Hebei Medical Unviersity were enrolled. Kaplan-Meier survival curve was drawn to analyze the correlation between SLC7A11 expression and progression-free survival (PFS) of the patients. Results: RNA array demonstrated that 2 888 genes were differently expressed between PC9 and PC9/GR cells. KEGG analysis showed that ferroptosis-related gene was one of the most enriched region of the differently expressed genes between PC9 and PC9/GR cells. These ferroptosis-related gene cohort contained 13 genes, among which SLC7A11 exhibited the most significant difference. Western blotting showed that the expression of SLC7A11 protein in PC9/GR cells was significantly higher than that in PC9 cells (0.76±0.03 vs. 0.19±0.02, P<0.001). The 50% inhibiting concentration (IC(50)) of gefitinib was 35.08 μmol/L and 64.01 μmol/L for sh-SLC7A11 and sh-NC group PC9/GR cells, respectively. PC9/GR cells in sh-SLC7A11 group exhibited significantly lower density of mitochondria fluorescence after gefitinib treatment, compared to the sh-NC group (213.77±26.50 vs. 47.88±4.55, P<0.001). In addition, PC9/GR cells in sh-SLC7A11 group exhibited significantly higher MDA after gefitinib treatment, compared to the sh-NC group [(15.43±1.60) μmol/mg vs. (82.18±7.77) μmol/mg, P<0.001]. The PFS of the patients with low expression of SLC7A11 (n=18) was significantly longer than the patients with high expression of SLC7A11 (n=18, 16.77 months vs. 9.14 months, P<0.001). Conclusion: Downregulation of SLC7A11 could increase the sensitivity of PC9/GR cells to gefitinib by promoting ferroptosis.
Humans ; Gefitinib/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Lung Neoplasms/pathology* ; Down-Regulation ; Quinazolines/therapeutic use* ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/metabolism* ; Adenocarcinoma of Lung ; Protein Kinase Inhibitors/therapeutic use* ; RNA, Small Interfering/genetics* ; Cell Line, Tumor ; Amino Acid Transport System y+/metabolism*

Objective: To screen the key genes involved in gefitinib resistance of lung adenocarcinoma PC9/GR cells which harbored 19 exon mutation of epidermal growth factor receptor (EGFR) gene, and discuss the effect and mechanism of downregulation of solute carrier family 7 member 11 (SLC7A11) on the gefitinib resistance of PC9/GR cells. Methods: RNA microarray was conducted to detect the gene expressions in PC9 and PC9/GR cells. The differently expressed genes were screened by using limma package of R language and analyzed by Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Western blotting was performed to determine the expression of SLC7A11 protein in PC9 and PC9/GR cells. PC9/GR cells were infected with lentivirus plasmid containing short hairpin RNA (shRNA) targeting SLC7A11 or negative control shRNA (sh-NC), respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the efficacy of shRNA on the expression of SLC7A11 mRNA. Cell counting kit-8 (CCK-8) assay was conducted to determine the suppressing effect of gefitinib on PC9/GR cells. Mito-Tracker Red CMXRos probe and malondialdehyde (MDA) assay kit were used to evaluate gefitinib-induced ferroptosis in PC9/GR cells. Immunohistochemistry (IHC) was conducted to detect the expression of SLC7A11 protein in the tumor tissues of advanced stage lung adenocarcinoma patients harboring 19 exon mutation of EGFR gene. Thirty-six advanced stage lung adenocarcinoma patients who received EGFR-tyrosihe kinase inhibitor(TKI) as first-line treatment in Fourth Hospital of Hebei Medical Unviersity were enrolled. Kaplan-Meier survival curve was drawn to analyze the correlation between SLC7A11 expression and progression-free survival (PFS) of the patients. Results: RNA array demonstrated that 2 888 genes were differently expressed between PC9 and PC9/GR cells. KEGG analysis showed that ferroptosis-related gene was one of the most enriched region of the differently expressed genes between PC9 and PC9/GR cells. These ferroptosis-related gene cohort contained 13 genes, among which SLC7A11 exhibited the most significant difference. Western blotting showed that the expression of SLC7A11 protein in PC9/GR cells was significantly higher than that in PC9 cells (0.76±0.03 vs. 0.19±0.02, P<0.001). The 50% inhibiting concentration (IC(50)) of gefitinib was 35.08 μmol/L and 64.01 μmol/L for sh-SLC7A11 and sh-NC group PC9/GR cells, respectively. PC9/GR cells in sh-SLC7A11 group exhibited significantly lower density of mitochondria fluorescence after gefitinib treatment, compared to the sh-NC group (213.77±26.50 vs. 47.88±4.55, P<0.001). In addition, PC9/GR cells in sh-SLC7A11 group exhibited significantly higher MDA after gefitinib treatment, compared to the sh-NC group [(15.43±1.60) μmol/mg vs. (82.18±7.77) μmol/mg, P<0.001]. The PFS of the patients with low expression of SLC7A11 (n=18) was significantly longer than the patients with high expression of SLC7A11 (n=18, 16.77 months vs. 9.14 months, P<0.001). Conclusion: Downregulation of SLC7A11 could increase the sensitivity of PC9/GR cells to gefitinib by promoting ferroptosis.
Humans ; Gefitinib/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Lung Neoplasms/pathology* ; Down-Regulation ; Quinazolines/therapeutic use* ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/metabolism* ; Adenocarcinoma of Lung ; Protein Kinase Inhibitors/therapeutic use* ; RNA, Small Interfering/genetics* ; Cell Line, Tumor ; Amino Acid Transport System y+/metabolism*