Microcephaly Gene Mcph1 Deficiency Induces p19ARF-Dependent Cell Cycle Arrest and Senescence.

MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.

Pentraxin-3 and Outcomes in CKD: A Systematic Review and Meta-analysis.

Rationale & Objective: Long pentraxin-3 (PTX-3) serves as a biomarker for prognosticating adverse clinical outcomes in individuals with chronic kidney disease (CKD). The objective of the current meta-analysis was to evaluate the prognostic efficacy of PTX-3 in patients with CKD. In addition, we compared the prognostic effectiveness of PTX-3 and the short pentraxin C-reactive protein (CRP) in the identical cohort of patients with CKD. Study Design: A systematic review and meta-analysis. Setting & Participants: Patients with CKD treated with or without dialysis. Selection Criteria for Studies: A cohort study with a minimum 1-year follow-up. Data Extraction: Risk measurements, adjusted hazard risk with 95% CI, and modified variables. Analytical Approach: To aggregate the adjusted effect estimates, a fixed-effects or random-effects model was employed. Results: Nine studies covering 1,825 patients with CKD were selected in the present review. Six of the 9 studies exclusively included patients receiving hemodialysis. The collected findings indicated that patients with CKD in the highest tertile of PTX-3 demonstrated significantly higher risks of all-cause mortality (HR, 1.92; 95% CI, 1.44-2.56), cardiovascular death (HR, 1.98; 95% CI, 1.28-3.05), infectious death (HR, 5.26; 95% CI, 1.60-17.31), and fatal and nonfatal cardiovascular events (HR, 1.81; 95% CI, 1.35-2.42), as compared with those in the lowest tertile. These significant associations with risk were also observed when effect estimates were presented as per unit change in the PTX-3. Moreover, when comparing the prognostic value of PTX-3 and CRP in the same individuals (5 studies covering 904 patients), PTX-3 proved to be a satisfactory predictor of adverse events in these patients, whereas CRP failed to exhibit such predictive capability, regardless of the type of effect estimate used. Limitations: A relatively small sample size and some heterogeneity. Conclusions: Pentraxin 3 is associated with adverse events in individuals with CKD and may be a more reliable predictor of adverse clinical events than CRP in this population.

Systemic inflammatory markers are useful in predicting the prognosis of patients with CKD. Pentraxin-3 (PTX-3) is an emerging biomarker of inflammation compared with other members of the pentraxin family, such as C-reactive protein (CRP). This meta-analysis evaluated the prognostic value of PTX-3 in predicting adverse outcomes in patients with CKD. Also, we compared the prognostic values between PTX-3 and CRP in the subset of studies with data on CRP. We found that patients with CKD with higher circulating PTX-3 levels had a significantly heightened risk of adverse outcomes compared with those with lower PTX-3 levels. By contrast, CRP did not appear to be a good predictor of adverse events. Pentraxin-3 might be a more reliable prognostic marker than CRP in patients with CKD.

Factors influencing traumatic brain injuries in maxillofacial fractures: A 12-year retrospective analysis of 2841 patients.

BACKGROUND/AIM: Results of studies investigating the association between traumatic brain injury (TBI) and maxillofacial fractures (MFs) have varied considerably. The present study aimed to evaluate the correlation between TBIs and MFs, as well as the impact of age, sex, trauma mechanism, and season on TBIs. MATERIALS AND METHODS: This 12-year retrospective study of 2841 patients used univariate and multivariate logistic regression to assess the association between MFs and other factors impacting TBIs. RESULTS: Among 2841 patients, 1978 TBIs occurred in 829 (29.2%), with intracranial injuries (n = 828) is the most common. Of 829 patients with TBIs, 688 were male and 141 were female, corresponding to a male-to-female ratio of 4.9:1.0. The most common age group was 40-49 years (24.6%). Vehicles (including motor vehicles and electric vehicles) accidents were the primary causes of injuries. Multivariate regression analyses revealed an increased risk for TBIs among males (odds ratio [OR] 0.632, p < 0.001). Patients >40 years of age were at higher risk for TBIs, especially those ≥70 years (OR 3.966, p = 0.001). Vehicle accidents were a high-risk factor for TBIs (OR 6.894, p < 0.001), and winter was the most prevalent season for such injuries (OR 1.559, p = 0.002). Risk for TBI increased by 136.4% in combined midfacial and mandibular fractures (p = 0.016) and by 101.6% in multiple midfacial fractures (p = 0.045). TBIs were less common in single mandibular fractures, notably in single-angle fractures, with a risk of only 0.204-fold. CONCLUSION: TBIs in MFs were significantly correlated with sex, age, aetiology, season and fracture location. Maxillofacial surgeons and emergency physicians must be aware of the possible association between TBIs and MFs to assess and manage this complicated relationship in a timely manner.

A Multi-center Dental Panoramic Radiography Image Dataset for Impacted Teeth, Periodontitis, and Dental Caries: Benchmarking Segmentation and Classification Tasks.

Panoramic radiography imaging plays a crucial role in the diagnostic process of dental diseases. However, current artificial intelligence research datasets for panoramic radiography dental image processing are often limited to single-center and single-task scenarios, making it difficult to generalize their results. To address this, we present a multi-center, multi-task labeled dataset. In this study, our dataset comprises three datasets obtained from different hospitals. The first set has 4940 panoramic radiography images and corresponding labels from the Stemmatological Hospital of the General Hospital of Ningxia Medical University. The second set includes 716 panoramic radiography images and labels from the People's Hospital of Yinchuan City, Ningxia. The third dataset contains 880 panoramic radiography images and labels from a hospital in Shenzhen, Guangdong Province. This comprehensive dataset encompasses three types of dental diseases: impacted teeth, periodontitis, and dental caries. Specifically, it comprises 2555 images related to impacted teeth, 2735 images related to periodontitis, and 1246 images related to dental caries. In order to evaluate the performance of the dataset, we conducted benchmark tests for segmentation and classification tasks on our dataset. The results show that the presented dataset could be effectively used for benchmarking segmentation and classification tasks critical to the diagnosis of dental diseases. To request our multi-center dataset, please visit the address: https://github.com/qinxin99/qinxini .

Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model.

The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system. DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'-hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program, which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.

MIL-101(Fe)/WS2 composites activated Na2S2O8 with visible light for removal of tetracycline.

MIL-101(Fe)/WS2 catalyst was composited using a solvothermal method. To study the physical and chemical properties of the composite material, a series of characterizations such as scanning electron microscope (SEM), X-ray diffraction (XRD), and catalytic experiments were carried out. The photocatalysis of the prepared catalyst in the degradation of tetracycline was investigated using persulfate (PS, Na2S2O8) as a cocatalyst under visible light illumination. The above system can remove about 80% of tetracycline within 40 min. After three cyclic experiments, the material showed good recycling. According to material characterization and various experimental results, the enhanced performance of the material was attributed to the reduction of the recombination efficiency of photogenerated e- and h+, and activated persulfate to produce a large number of free radicals such as O2•-, SO4•- and 1O2 produced by the active sites provided by the catalyst's high specific surface area.

Serum amyloid A and risks of all-cause and cardiovascular mortality in chronic kidney disease: a systematic review and dose-response meta-analysis.

BACKGROUNDS: The available literature on the correlation between serum amyloid A (SAA) and prognosis of chronic kidney disease (CKD) are limited, and the findings from existing studies are inconclusive. This meta-analysis aimed to evaluate the available evidence regarding the link between SAA and risks of all-cause and cardiovascular mortality in CKD patients. Additionally, we aimed to investigate the potential dose-response relationships, provided that adequate data is accessible. METHODS: Pubmed and Embase were searched for related literature (last update: 12 July 2023). The pooled effect estimates were calculated using random- or fixed-effects models depending on heterogeneity among studies. RESULTS: This meta-analysis incorporated 8 studies encompassing 2331 CKD patients. The findings revealed an 85% increase in all-cause mortality risk [hazard risk (HR) 1.85, 95% confidence interval (CI) 1.29-2.65] and a 39% increase in cardiovascular mortality risk (HR 1.07, 95% CI 1.07-1.80) when comparing the highest tertile of baseline SAA levels to the lowest tertile. Furthermore, a positive linear relationship between SAA and all-cause mortality risk was observed (Pnon-linearity = 0.959), with a 17.7% increase in risk for each 10 mg/L SAA increase (HR 1.177, 95% CI 1.055-1.313). Similarly, a linear relationship between SAA and cardiovascular mortality risk was identified (Pnon-linearity = 0.477) with a 19.3% increase in risk for each 10 mg/L SAA increase (HR 1.193, 95% CI 1.025-1.388). CONCLUSIONS: This meta-analysis provided evidence that SAA levels are positively and linearly associated with risks of all-cause and cardiovascular mortality among CKD patients.

Osteogenic differentiation of 3D-printed porous tantalum with nano-topographic modification for repairing craniofacial bone defects.

Introduction: Congenital or acquired bone defects in the oral and cranio-maxillofacial (OCMF) regions can seriously affect the normal function and facial appearance of patients, and cause great harm to their physical and mental health. To achieve good bone defect repair results, the prosthesis requires good osteogenic ability, appropriate porosity, and precise three-dimensional shape. Tantalum (Ta) has better mechanical properties, osteogenic ability, and microstructure compared to Ti6Al4V, and has become a potential alternative material for bone repair. The bones in the OCMF region have unique shapes, and 3D printing technology is the preferred method for manufacturing personalized prosthesis with complex shapes and structures. The surface characteristics of materials, such as surface morphology, can affect the biological behavior of cells. Among them, nano-topographic surface modification can endow materials with unique surface properties such as wettability and large surface area, enhancing the adhesion of osteoblasts and thereby enhancing their osteogenic ability. Methods: This study used 3D-printed porous tantalum scaffolds, and constructed nano-topographic surface through hydrothermal treatment. Its osteogenic ability was verified through a series of in vitro and in vivo experiments. Results: The porous tantalum modified by nano-topographic surface can promote the proliferation and osteogenic differentiation of BMSCs, and accelerate the formation of new bone in the Angle of the mandible bone defect of rabbits. Discussion: It can be seen that 3D-printed nano-topographic surface modified porous tantalum has broad application prospects in the repair of OCMF bone defects.

Epidemiology of maxillofacial fractures in northwest China: an 11-year retrospective study of 2240 patients.

BACKGROUND: The aim of this study was to determine the epidemiological pattern of maxillofacial fractures in northwestern China by retrospectively analysing the demographics, aetiologies, concomitant injuries, fracture sites, and management. METHODS: A 10-year retrospective analysis of 2240 patients with maxillofacial fractures admitted to the General Hospital of Ningxia Medical University was conducted. The extracted data included sex, age, aetiology, fracture site, concomitant injuries, time of treatment, therapeutic approaches and complications. Statistical analyses were performed, including descriptive analysis and the chi-square test. Logistic regression was used to determine the impact factors of maxillofacial fractures and concomitant injuries. P values < 0.05 were considered statistically significant. RESULTS: The age of the included patients ranged from 1 to 85 years, and the mean age was 35.88 ± 15.69 years. The male-to-female ratio was 3.9:1. The most frequent aetiology of maxillofacial fractures was road traffic accidents (RTAs) (56.3%), and the most common fracture sites were the anterior wall of the maxillary sinus, arcus zygomaticus and mandibular body. A total of 1147 patients (51.2%) were affected by concomitant injuries, with craniocerebral injury being the most common. Logistic regression analyses revealed increased risks of mid-facial fractures in elderly individuals (odds ratio (OR) = 1.029, P < 0.001) and females (OR = 0.719, P = 0.005). Younger patients had a higher risk of mandibular fractures (OR = 0.973, P < 0.001). RTAs increased the risk for mid-facial fractures and high falls increased the risk for mandibular fractures. CONCLUSIONS: The maxillofacial fracture pattern is correlated with sex, age and aetiology. Patients were mainly young and middle-aged males, and the main cause of injury was RTAs, mostly causing compound fractures. Medical staff must be systematically educated to comprehensively examine patients with injuries resulting from RTAs. The management of patients with fractures requires thorough consideration of the patient's age, aetiology, fracture site, and concomitant injuries.

Biology and Roles in Diseases of Selenoprotein I Characterized by Ethanolamine Phosphotransferase Activity and Antioxidant Potential.

Selenoprotein I (SELENOI) has been demonstrated to be an ethanolamine phosphotransferase (EPT) characterized by a nonselenoenzymatic domain and to be involved in the main synthetic branch of phosphatidylethanolamine (PE) in the endoplasmic reticulum. Therefore, defects of SELENOI may affect the health status through the multiple functions of PE. On the other hand, selenium (Se) is covalently incorporated into SELENOI as selenocysteine (Sec) in its peptide, which forms a Sec-centered domain as in the other members of the selenoprotein family. Unlike other selenoproteins, Sec-containing SELENOI was formed at a later stage of animal evolution, and the high conservation of the structural domain for PE synthesis across a wide range of species suggests the importance of EPT activity in supporting the survival and evolution of organisms. A variety of factors, such as species characteristics (age and sex), diet and nutrition (dietary Se and fat intakes), SELENOI-specific properties (tissue distribution and rank in the selenoproteome), etc., synergistically regulate the expression of SELENOI in a tentatively unclear interaction. The N- and C-terminal domains confer 2 distinct biochemical functions to SELENOI, namely PE regulation and antioxidant potential, which may allow it to be involved in numerous physiological processes, including neurological diseases (especially hereditary spastic paraplegia), T cell activation, tumorigenesis, and adipocyte differentiation. In this review, we summarize advances in the biology and roles of SELENOI, shedding light on the precise regulation of SELENOI expression and PE homeostasis by dietary Se intake and pharmaceutical or transgenic approaches to modulate the corresponding pathological status.

Circulating GDF-15 in relation to the progression and prognosis of chronic kidney disease: A systematic review and dose-response meta-analysis.

BACKGROUND: Patients with chronic kidney disease (CKD) typically exhibit circulating growth differentiation factor-15 (GDF-15) at high levels. This meta-analysis aimed to evaluate the potential value of GDF-15 in predicting CKD progression and prognosis. Furthermore, when sufficient information was provided, the dose-response correlation was studied. METHODS: Studies were searched in Web of Science, Embase, and PubMed from inception until November 2022. By using random- or fixed-effects models, the pooled effect size was estimated in accordance with heterogeneity in existing research. RESULTS: This study covered 14 studies from 12 articles with 7813 subjects participating in the research. CKD patients in the top GDF-15 tertile had notably higher risks of CKD progression (HR 2.60, 95% CI 2.06-3.27), all-cause mortality (HR 2.05, 95% CI 1.44-2.92), cardiovascular mortality (HR 2.82, 95% CI 1.85-4.30), and cardiovascular events (HR 2.74, 95% CI 2.21-3.40), as compared to CKD patients in the bottom tertile. In the dose-response study, the risks for CKD progression, all-cause death, cardiovascular death, and cardiovascular events were increased by 31% (HR 1.31, 95% CI 1.06-1.61), 44% (HR 1.44, 95% CI 1.08-1.92), 67% (HR 1.67, 95% CI 1.37-2.03), and 55% (HR 1.55, 95% CI 1.31-1.83), respectively, with per 1 ng/mL increase in GDF-15. The positive linear correlations between GDF-15 and CKD progression and prognosis in a certain GDF-15 concentration range of approximately 0-3 ng/mL were indicated by the dose-response curve. CONCLUSIONS: Circulating GDF-15 independently predicted CKD progression and worse prognosis; however, the predicted correlations may fall into a specific range of GDF-15 concentrations.

The RNA polymerase of cytoplasmically replicating Zika virus binds with chromatin DNA in nuclei and regulates host gene transcription.

Zika virus (ZIKV) targets the neural progenitor cells (NPCs) in brain during intrauterine infections and consequently causes severe neurological disorders, such as microcephaly in neonates. Although replicating in the cytoplasm, ZIKV dysregulates the expression of thousands of host genes, yet the detailed mechanism remains elusive. Herein, we report that ZIKV encodes a unique DNA-binding protein to regulate host gene transcription in the nucleus. We found that ZIKV NS5, the viral RNA polymerase, associates tightly with host chromatin DNA through its methyltransferase domain and this interaction could be specifically blocked by GTP. Further study showed that expression of ZIKV NS5 in human NPCs markedly suppressed the transcription of its target genes, especially the genes involved in neurogenesis. Mechanistically, ZIKV NS5 binds onto the gene body of its target genes and then blocks their transcriptional elongation. The utero electroporation in pregnant mice showed that NS5 expression significantly disrupts the neurogenesis by reducing the number of Sox2- and Tbr2-positive cells in the fetal cortex. Together, our findings demonstrate a molecular clue linking to the abnormal neurodevelopment caused by ZIKV infection and also provide intriguing insights into the interaction between the host cell and the pathogenic RNA virus, where the cytoplasmic RNA virus encodes a DNA-binding protein to control the transcription of host cell in the nuclei.

Association between platelet indices and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

BACKGROUND: Platelet indices have the potential for the evaluation of the activity of non-alcoholic fatty liver disease (NAFLD), but their associations are under hard debate. This meta-analysis aims to assess whether platelet count (PC), mean platelet volume (MPV) and platelet distribution width (PDW) are associated with NAFLD and its progression. METHODS: A literature search was conducted using electronic databases to find publications up to July 2022, where the relationship between PC, MPV, PDW and NAFLD was evaluated. Random-effects models were applied to pool effect estimates that were presented as standardized mean differences (SMD) with 95% confidence interval (CI). RESULTS: Nineteen studies involving 3592 NAFLD patients and 1194 healthy individuals were included. The pooled results showed that NAFLD patients had a lower PC (SMD=-0.66, 95% CI =-1.22 to -0.09, P=0.023) but a higher MPV (SMD=0.89, 95% CI=0.26-1.51, P=0.005) and PDW (SMD=0.55, 95% CI=0.11-0.99, P=0.014) compared to healthy controls. Patients with non-alcoholic steatohepatitis (NASH) exhibited a lower PC (SMD=-0.86, 95% CI=-1.20 to -0.52, P<0.001) and a higher MPV (SMD=0.71, 95% CI=0.40-1.02, P<0.001) than non-NASH individuals. A meta-regression analysis demonstrated that MPV was significantly positively correlated with aspartate aminotransferase (P=0.008), the total cholesterol (P=0.003), triglyceride (P=0.006) and low-density lipoprotein cholesterol (P=0.007), but was significantly negatively correlated with high-density lipoprotein cholesterol (P=0.010). CONCLUSION: This meta-analysis revealed that NAFLD patients presented a reduced PC but an increased MPV and PDW, and the changes might be associated with NAFLD severity. A higher MPV is associated with lipid metabolic disorders in NAFLD.

Association between neutrophil-to-lymphocyte ratio and polycystic ovary syndrome: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a potential biomarker for assessing the systemic inflammatory response in polycystic ovary syndrome (PCOS). This meta-analysis is aimed at evaluating whether PCOS patients present with a higher NLR and whether obesity, metabolic, and hormonal indices have effects on the states. METHODS: We performed a literature search on PubMed, Embase and Web of Science (last update: August 2, 2022). Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by applying random-effects models. Meta-regression analyses were used to explore the sources of heterogeneity and assess the relationship between NLR and several clinical parameters. Sensitivity analysis and publication bias were also assessed. RESULTS: Thirteen studies involving 826 PCOS patients and 780 healthy controls were eligible for the present meta-analysis. Generally, NLR significantly increased in PCOS women versus healthy women (SMD = 0.81, 95% CI = 0.30-1.33, P = .002). NLR disparity was subsequently investigated in obese and non-obese cohorts. Obese PCOS women exhibited a higher NLR than obese controls (SMD = 0.56, 95% CI = 0.24-0.87, P = .001), and a similar difference was shown between non-obese PCOS and non-obese controls (SMD = 0.36, 95% CI = 0.02-0.71, P = .038). No significant NLR disparity was observed between obese versus non-obese PCOS women (SMD = 0.50, 95% CI = -0.37 to 1.38, P = .259). Meta-regression analysis revealed that NLR was significantly positively associated with fasting blood glucose (P = .006) and total cholesterol levels (P = .021), but not correlated with body mass index and other parameters in PCOS patients. Sensitivity analysis indicated that no individual study significantly affected the overall pooled result, and no publishing bias was observed. CONCLUSION: PCOS women typically present with an increased NLR. Such an increase is independent of obesity and may be associated with glycolipid metabolic disorders.

Low Testosterone Level and Risk of Adverse Clinical Events among Male Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Cohort Studies.

The phenomenon of low testosterone level is extremely common in male patients with chronic kidney diseases (CKDs). This meta-analysis aimed to evaluate whether the low circulating testosterone could independently predict adverse outcomes among male patients with chronic kidney diseases (CKDs). The data till May 2022 were systematically searched from Pubmed, Web of Science, and Embase from inception. Studies meeting the PICOS (population, intervention/exposure, control/comparison, outcomes, and study design) principles were included in this meta-analysis. Study-specific effect estimates were pooled using fixed-effects (I 2 > 50%) or random-effects models (I 2 < 50%). Ultimately, 9 cohort studies covering 5331 patients with CKDs were involved in this meta-analysis. The results suggested that per 1-standard deviation (SD) decrease in total testosterone independently increased the risk of all-cause mortality by 27% [hazard risk (HR) 1.27, 95% confidence interval (CI) 1.16-1.38], cardiovascular mortality by 100% (HR 2.00, 95% CI 1.39-2.86), cardiovascular events by 20% (HR 1.20, 95% CI 1.04-1.39), and infectious events by 41% (HR 1.41, 95% CI 1.08-1.84). Besides, with per 1-SD decrease in free testosterone, the risk of overall adverse events increased by 66% (HR 1.66, 95% CI 1.34-2.05). Stratified analyses indicated that the negative relationship of the total testosterone with all-cause death risk was independent of factors involving age, race, body mass index, diabetes, hypertension, C-reactive protein, creatinine, and sex hormone binding globulin. In conclusion, it was identified that low endogenous testosterone could serve as an independent predictor of adverse clinical events among male patients with CKDs.

Discovery of a small-molecule inhibitor targeting the ovarian tumor domain of a novel Tamdy orthonairoviruse associated with human febrile illness.

Tick-borne orthonairoviruses have been characterized as a global health threat to humans and animals. Tacheng Tick virus 1 (TcTV-1) from this family was provided as evidence that is associated with the febrile illness syndrome. Here, we first identify and demonstrate that the ovarian tumor (OTU) domain of TcTV-1 has remarkable deubiquitinating activity both in vitro and in vivo. By solving the crystal structure of TcTV-1 OTU (tcOTU) domain and comparing it to that of human deubiquitinating enzymes, we found that overall structures of tcOTU and human OTU family are similar, but the residues involved in the catalytic pocket vary widely. Based on the tcOTU domain we screened 5090 bioactive compounds and found mecobalamin had a good effect on suppressing the deubiquitinating activity. The structural model of tcOTU and mecobalamin suggests that mecobalamin occupies the site of the substrate Ub, by blocking the substrate binding to the enzyme. Thus, our results showed OTU domain of TcTV-1 has a robust deubiquitinating activity and mecobalamin or its derivatives might be promising candidates for the treatment or prevention of disease caused by the TcTV-1 virus.

Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab.

Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor receptors (EGFRs). Although small molecule inhibitors and monoclonal antibodies have been developed to target EGFRs, few EGFR-targeted therapeutics are approved for clinical use. Ferroptosis is a new kind of programmed death induced by the iron catalyzed excessive peroxidation of polyunsaturated fatty acids. A growing body of evidence suggests that ferroptosis plays a pivotal role in inhibiting the tumor process. However, whether and how ferroptosis-inducers (FINs) play roles in hindering HNSCCs are unclear. In this study, we analyzed the sensitivity of different HNSCCs to ferroptosis-inducers. We found that only tongue squamous cell carcinoma cells and laryngeal squamous cell carcinoma cells, but not nasopharyngeal carcinoma cells, actively respond to ferroptosis-inducers. The different sensitivities of HNSCC cells to ferroptosis induction may be attributed to the expression of KRAS and ferritin heavy chain (FTH1) since a high level of FTH1 is associated with the poor prognostic survival of HNSCCs, but knocked down FTH1 can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody Cetuximab to inhibit the survival of nasopharyngeal carcinoma cells (CNE-2), which are insensitive to both ferroptosis induction and EGFR inhibition due to a high level of FTH1 and a low level of EGFR, respectively. Our findings prove that FTH1 plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition.

Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease.

Oridonin Inhibits SARS-CoV-2 Oridonin, a natural product extracted from Rabdosia rubescens, possesses a wide range of pharmacological properties, including anti-inflammatory, anti-cancer, anti-microbial, neuroprotection, immunoregulation, etc. In article number 2100124, Baisen Zhong, Litao Sun, and co-workers demonstrate that Oridonin targets the SARS-CoV-2 3CL protease by covalently binding to cysteine145 in its active pocket to exert an anti-SARS-CoV-2 effect, which provides a novel candidate for the treatment of COVID-19.

Oridonin Inhibits SARS-CoV-2 by Targeting Its 3C-Like Protease.

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enormous threat to public health. The SARS-CoV-2 3C-like protease (3CLpro), which is critical for viral replication and transcription, has been recognized as an ideal drug target. Herein, it is identified that three herbal compounds, Salvianolic acid A (SAA), (-)-Epigallocatechin gallate (EGCG), and Oridonin, directly inhibit the activity of SARS-CoV-2 3CLpro. Further, blocking SARS-CoV-2 infectivity by Oridonin is confirmed in cell-based experiments. By solving the crystal structure of 3CLpro in complex with Oridonin and comparing it to that of other ligands with 3CLpro, it is identified that Oridonin binds at the 3CLpro catalytic site by forming a C-S covalent bond, which is confirmed by mass spectrometry and kinetic study, blocking substrate binding through a nonpeptidomimetic covalent binding mode. Thus, Oridonin is a novel candidate to develop a new antiviral treatment for COVID-19.