Association of severity of menstrual dysfunction with cardiometabolic risk markers among women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with a wide range of unfavorable cardiometabolic risk factors, including obesity, hypertension, insulin resistance, impaired glucose metabolism, dyslipidemia, and metabolic syndrome. Compared with women with regular menstrual cycles, women with a history of irregular menstrual periods have an increased unfavorable cardiometabolic risk. Recently, the association between the severity of oligomenorrhea and hyperinsulinemia and insulin resistance has been demonstrated. However, evidence linking the severity of menstrual cyclicity with cardiometabolic risk in PCOS women is scarce. MATERIAL AND METHODS: This work was a prospective cross-sectional study. A total of 154 women diagnosed with PCOS by the Rotterdam criteria were recruited from July 2021 to September 2022. PCOS women with eumenorrheic (eumeno group), oligomenorrhea (oligo group), and amenorrhea (ameno group) underwent history and physical examination, gonadal steroid hormone measurement, lipid profile, oral glucose tolerance test, and homeostasis model assessment of insulin resistance. RESULTS: A trend toward an increase in unfavorable cardiometabolic risk markers including obesity, hypertension, prevalence of insulin resistance, prediabetes, dyslipidemia, and metabolic syndrome was observed in the ameno group (n = 57) as compared with the eumeno (n = 24) or oligo group (n = 73). A higher prevalence of insulin resistance (odds ratio [OR]: 3.02; 95% confidence interval [CI]: 1.03-8.81) and prediabetes (OR: 3.94; 95% CI: 1.01-15.40) was observed in the ameno group than in the eumeno group, and a higher proportion of dyslipidemia (OR: 2.44; 95% CI: 1.16-5.15) was observed in the ameno group than in the oligo group in the binary logistic regression analysis after adjusting for confounding factors. CONCLUSIONS: PCOS women with amenorrhea show a higher prevalence of insulin resistance, prediabetes, and dyslipidemia compared with those with oligomenorrhea or eumenorrhea. The severity of menstrual dysfunction could be used as a readily obtainable marker for the identification of PCOS women at greatest risk of cardiometabolic diseases.

Case report: Shingles-associated probable Bickerstaff brainstem encephalitis with IgM anti-sulfatide positivity.

Background: Bickerstaff brainstem encephalitis (BBE) is a rare disease considered caused by acute demyelination of the brainstem, most often resulting from secondary autoimmune responses. To our knowledge, this is the first probable case report of shingles-associated BBE with anti-sulfatide IgM positivity. Case presentation: We report the case of an 83-year-old woman with symptoms of progressive limb weakness, difficulty swallowing food, and disturbed consciousness that occurred 4 weeks following herpes zoster infection. Autoimmune anti-sulfatide antibodies were positive and fluid-attenuated inversion recovery (FLAIR) sequences revealed clear high signal intensity in pons and bilateral thalamus. Our patient's condition improved markedly with glucocorticoid treatment. After 2 months of treatment, our patient was fully recovered. We considered that for her case, BBE is the most appropriate diagnosis. Conclusions: We emphasize the importance of a careful medical history and assessment of clinical symptoms, performing MRI, testing autoimmune antibodies for rapid diagnosis, and ruling out differential diagnoses. Further studies involving more patients with BBE with IgM anti-sulfatide autoantibodies will increase the understanding of the clinical characteristics and advance the diagnosis and treatment of this syndrome. Meanwhile, it is crucial for dermatologists to know about this severe neurological complication following shingles.

Pan-genome insights into adaptive evolution of bacterial symbionts in mixed host-microbe symbioses represented by human gut microbiota Bacteroides cellulosilyticus.

Animal hosts harbor diverse assemblages of microbial symbionts that play crucial roles in the host's lifestyle. The link between microbial symbiosis and host development remains poorly understood. In particular, little is known about the adaptive evolution of gut bacteria in host-microbe symbioses. Recently, symbiotic relationships have been categorized as open, closed, or mixed, reflecting their modes of inter-host transmission and resulting in distinct genomic features. Members of the genus Bacteroides are the most abundant human gut microbiota and possess both probiotic and pathogenic potential, providing an excellent model for studying pan-genome evolution in symbiotic systems. Here, we determined the complete genome of an novel clinical strain PL2022, which was isolated from a blood sample and performed pan-genome analyses on a representative set of Bacteroides cellulosilyticus strains to quantify the influence of the symbiotic relationship on the evolutionary dynamics. B. cellulosilyticus exhibited correlated genomic features with both open and closed symbioses, suggesting a mixed symbiosis. An open pan-genome is characterized by abundant accessory gene families, potential horizontal gene transfer (HGT), and diverse mobile genetic elements (MGEs), indicating an innovative gene pool, mainly associated with genomic islands and plasmids. However, massive parallel gene loss, weak purifying selection, and accumulation of positively selected mutations were the main drivers of genome reduction in B. cellulosilyticus. Metagenomic read recruitment analyses showed that B. cellulosilyticus members are globally distributed and active in human gut habitats, in line with predominant vertical transmission in the human gut. However, existence and/or high abundance were also detected in non-intestinal tissues, other animal hosts, and non-host environments, indicating occasional horizontal transmission to new niches, thereby creating arenas for the acquisition of novel genes. This case study of adaptive evolution under a mixed host-microbe symbiosis advances our understanding of symbiotic pan-genome evolution. Our results highlight the complexity of genetic evolution in this unusual intestinal symbiont.

A novel linear B cell epitope of the canine coronavirus nucleocapsid protein identified by a monoclonal antibody.

The infection of canine coronavirus (CCoV) causes a highly contagious disease in dogs with acute gastroenteritis. The efficient serological diagnostics is critical for controlling the disease caused by CCoV. Nucleocapsid (N) protein of CCoV is an important target for developing serological approaches. However, little is known about the antigenic sites in the N protein of CCoV. In this study, we generated a monoclonal antibody (mAb) against the N protein of CCoV, designated as 13E8, through the fusion of the sp2/0 cells with the spleen cells from a mouse immunized with the purified recombinant GST-N protein. Epitope mapping revealed that mAb 13E8 recognized a novel linear B cell epitope in N protein at 294-314aa (named as EP-13E8) by using a serial of truncated N protein through Western blot and ELISA. Sequence analysis showed that the sequence of EP-13E8 was highly conserved (100 %) among different CCoV strains analyzed, but exhibited a low similarity (31.8-63.6 %) with the responding sequence in other coronaviruses of the same genus such as FCoV, PEDV and HCoV except for TGEV (95.5 % identity). Structural assay suggested that the epitope of EP-13E8 were located in the close proximity on the surface of the N protein. Overall, the mAb 13E8 against N protein generated and its epitope EP-13E8 identified here paid the way for further developing epitope-based serological diagnostics for CCoV.

Human milk sphingomyelin: Function, metabolism, composition and mimicking.

Human milk, which contains various nutrients, is the "gold standard" for infant nutrition. Healthy human milk meets all the nutritional needs of early infant development. Polar lipids mainly exist in the milk fat globule membrane, accounting for approximately 1-2% of human milk lipids; sphingomyelin (SM) accounts for approximately 21-24% of polar lipids. SM plays an important role in promoting the development of the brain and nervous system, regulating intestinal flora, and improving skin barriers. Though SM could be synthesized de novo, SM nutrition from dietary is also important for infants. The content and composition of SM in human milk has been reported, however, the molecular mechanisms of nutritional functions of SM for infants required further research. This review summarizes the functional mechanisms, metabolic pathways, and compositional, influencing factors, and mimicking of SM in human milk, and highlights the challenges of improving maternal and infant early/long-term nutrition.

LCN2: Versatile players in breast cancer.

Lipocalin 2 (LCN2) is a secreted glycoprotein that is produced by immune cells, including neutrophils and macrophages. It serves various functions such as transporting hydrophobic ligands across the cellular membrane, regulating immune responses, keeping iron balance, and fostering epithelial cell differentiation. LCN2 plays a crucial role in several physiological processes. LCN2 expression is upregulated in a variety of human diseases and cancers. High levels of LCN2 are specifically linked to breast cancer (BC) cell proliferation, apoptosis, invasion, migration, angiogenesis, immune regulation, chemotherapy resistance, and prognosis. As a result, LCN2 has gained attention as a potential therapeutic target for BC. This article offered an in-depth review of the advancement of LCN2 in the context of BC occurrence and development.

HMGB1 Release Induced by EV71 Infection Exacerbates Blood-Brain Barrier Disruption via VE-cadherin Phosphorylation.

PURPOSE: EV71 (Enterovirus 71) is a major causative agent of the outbreaks of HFMD (hand, foot, and mouth disease), which is associated with neurological damage caused by permeability disruption of BBB (blood-brain barrier). HMGB1 (high-mobility group box 1) is a widely expressed nuclear protein that triggers host inflammatory responses. Our work aimed to explore the function of HMGB1 in EV71 infection and its contributions to EV71-related BBB damage. METHODS: HeLa cells, HT-29 cells and AG6 mice were used to explore the translocation of HMGB1 in EV71 infection in vitro and in vivo. The roles of released HMGB1 on EV71 replication and associated inflammatory cytokines were investigated using recombinant HMGB1 in HeLa cells. The mechanisms of released HMGB1 in EV71-induced BBB injury were explored using recombinant HMGB1 and anti-HMGB1 neutralizing antibodies in monolayer HCMECs (immortalized human brain microvascular endothelial cells) and AG6 mice brain. RESULTS: EV71 induced HMGB1 nucleocytoplasmic translocation and extracellular release in vitro and in vivo. Released HMGB1 acted as an inflammatory mediator in EV71 infection rather than affecting viral replication in vitro. Released HMGB1 disrupted BBB integrity by enhancing VE-cadherin phosphorylation at tyrosine 685 in HCMECs, and reducing total VE-cadherin levels in HCMECs and AG6 mice in EV71 infection. And released HMGB1 induced an increase in activated astrocytes. Neutralization of HMGB1 reversed the increased endothelial hyperpermeability and phosphorylation of VE-cadherin in HCMECs. CONCLUSION: The inflammatory mediator HMGB1 released by EV71 exacerbated BBB disruption by enhancing VE-cadherin phosphorylation, which in turn aggravated EV71-induced neuroinflammation.

Efficacy of three-dimensional arterial spin labeling and how it compares against that of contrast enhanced magnetic resonance imaging in preoperative grading of brain gliomas.

PURPOSE: To evaluate the efficacy of three-dimensional arterial spin labeling (3D-ASL) imaging in preoperative grading of brain gliomas, and compare the discrepancy between images obtained from 3D-ASL and contrast enhanced magnetic resonance imaging (CE-MRI) in grading of gliomas. METHODS: Fifty-one patients with brain gliomas received plain MRI, CE-MRI and 3D-ASL scanning before surgery. In 3D-ASL images, the maximum tumor blood flow (TBF) of tumor parenchyma was measured, relative TBF-M and rTBF-WM were calculated. The cases were categorized into "ASL dominant" and "CE dominant" to compare the discrepancy between 3D-ASL and CE-MRI results. Independent samples t test, Mann-Whitney and U test and one-way analysis of variance (ANOVA) were performed to test the differences of TBF, rTBF-M and rTBF-WM values among brain gliomas with different grades. Spearman rank correlation analysis was performed to assess the correlation between TBF, rTBF-M, rTBF-WM and glioma grades respectively. To compare the discrepancy between 3D-ASL and CE-MRI results. RESULTS: In high-grade gliomas (HGG) group, TBF, rTBF-M and rTBF-WM values were higher than those in low-grade gliomas (LGG) group (p < .05). Multiple comparison showed TBF and rTBF-WM values were different between grade I and IV gliomas, grade II and IV gliomas (both p < .05), the rTBF-M value was different between grade I and IV gliomas (p < .05). The values of all 3D-ASL derived parameters were positively correlated with gliomas grading (all p < .001). TBF showed highest specificity (89.3%) and rTBF-WM showed highest sensitivity (96.4%) when discriminating LGG and HGG using ROC curve. There were 29 CE dominant cases (23 cases were HGG), 9 ASL dominant cases (4 cases were HGG). CONCLUSION: 3D-ASL is of significance to preoperative grading of brain gliomas and might be more sensitive than CE-MRI in detection of tumor perfusion.

Global Dynamics of Porcine Enteric Coronavirus PEDV Epidemiology, Evolution, and Transmission.

With a possible origin from bats, the alphacoronavirus Porcine epidemic diarrhea virus (PEDV) causes significant hazards and widespread epidemics in the swine population. However, the ecology, evolution, and spread of PEDV are still unclear. Here, from 149,869 fecal and intestinal tissue samples of pigs collected in an 11-year survey, we identified PEDV as the most dominant virus in diarrheal animals. Global whole genomic and evolutionary analyses of 672 PEDV strains revealed the fast-evolving PEDV genotype 2 (G2) strains as the main epidemic viruses worldwide, which seems to correlate with the use of G2-targeting vaccines. The evolving pattern of the G2 viruses presents geographic bias as they evolve tachytely in South Korea but undergo the highest recombination in China. Therefore, we clustered six PEDV haplotypes in China, whereas South Korea held five haplotypes, including a unique haplotype G. In addition, an assessment of the spatiotemporal spread route of PEDV indicates Germany and Japan as the primary hubs for PEDV dissemination in Europe and Asia, respectively. Overall, our findings provide novel insights into the epidemiology, evolution, and transmission of PEDV, and thus may lay a foundation for the prevention and control of PEDV and other coronaviruses.

UCHL1 regulated by Sp1 ameliorates cochlear hair cell senescence and oxidative damage.

Age-related hearing loss (ARHL) is the most common cause of hearing loss in the elderly. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme involved in several types of human disease. The present study aimed to investigate the effect of UCHL1 on a hydrogen peroxide (H2O2)-induced ARHL model in cochlear hair cells and uncover its underlying mechanism. Reverse transcription-quantitative (RT-q)PCR and western blot analysis were used to assess UCHL1 expression in HEI-OC1 cells exposed to H2O2. Following UCHL1 overexpression in H2O2-induced HEI-OC1 cells, cell activity was assessed by Cell Counting Kit-8 assay. The content of oxidative stress-associated markers including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and reactive oxygen species (ROS ) was measured using corresponding commercial kits. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. Cell senescence was assessed by senescence-associated ß-galactosidase staining and western blot analysis. RT-qPCR and western blot analysis were applied to measure mRNA and protein expression levels, respectively, of specificity protein 1 (Sp1) in H2O2-treated HEI-OC1 cells. In addition, the association between UCHL1 and Sp1 was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The mRNA and protein expression levels of UCHL1 were also determined in Sp1-overexpressing cells by RT-qPCR and western blot analysis, respectively. Following Sp1 overexpression in UCHL1-overexpressing H2O2-treated HEI-OC1 cells, cell activity, oxidative stress, apoptosis and senescence were assessed. Finally, the expression levels of NF-κB signaling-related proteins p-NF-κB p65 and NF-κB p65 were detected using western blot analysis. The results showed that UCHL1 was downregulated in H2O2-treated HEI-OC1 cells. In addition, UCHL1 overexpression enhanced cell viability and promoted oxidative damage, apoptosis and senescence in H2O2-induced HEI-OC1 cells. Furthermore, Sp1 was upregulated in H2O2-treated HEI-OC1 cells. Additionally, luciferase reporter and ChIP assays demonstrated that Sp1 interacted with the UCHL1 promoter to inhibit UCHL1 transcription. Sp1 overexpression reversed the effect of UCHL1 overexpression on cell viability, oxidative stress, apoptosis, senescence and activation of the NF-κB signaling pathway in H2O2-exposed HEI-OC1 cells. Collectively, the results suggested that UCHL1 transcriptional suppression by Sp1 protected cochlear hair cells from H2O2-triggered senescence and oxidative damage.

Bis-iodine-labeled Curcumin as a Potential CT Imaging Agent for ß-amyloid Plaques in the Brain.

BACKGROUND: Alzheimer's disease (AD) is one of the most common causes of dementia, affecting many old people. OBJECTIVES: By designing and synthesizing intracerebral imaging probes, we tried to provide a new solution for the early diagnosis of AD. METHODS: We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments. RESULTS: In this study, bis-iodine-labeled curcumin (7, BICUR) was synthesized. In the in vitro mass spectrum binding assay, Kd values of BICUR with Aß1-40 and Aß1-42 aggregates were 46.29 nM and 64.29 nM, respectively. Aß plaques in AD brain adjacent sections were positively stained by BICUR, which was similar to some other curcumin derivatives. The Log P value of BICUR was 1.45. In the biodistribution experiment, BICUR showed the highest initial brain uptake (5.87% compared to the blood concentration) two minutes after the tail vein injection and rapid clearance from the mouse brain. In the acute toxicity experiment, BICUR showed low toxicity, and the LD50 was >100 mg/kg. Moreover, BICUR showed a high stability in vitro (86.68% unchanged BICUR after incubation for 120min in mouse brain homogenate). Besides, BICUR produced an enhanced CT imaging effect that could be sensitively detected in vitro, but it also showed an obvious differentiation from surrounding tissues after intracerebral injection. CONCLUSION: All results suggested that BICUR could probably act as a targeted CT imaging agent for Aß plaques in the brain.

12/15-Lipoxygenase Regulation of Diabetic Cognitive Dysfunction Is Determined by Interfering with Inflammation and Cell Apoptosis.

This study aimed to discuss the role of 12/15-lipoxygenase (12/15-LOX) regulation involved in diabetes cognitive dysfunction. First, Mini Mental State Examination (MMSE) test was used to evaluate cognitive ability in diabetic patients and normal controls. The plasma test showed that the plasma level of 12/15-LOX in patients with MMSE scores below 27 was significantly increased compared with that of the normal group. Second, 12/15-LOX inhibitor was administered to diabetic rats. Behavioral tests, biochemistry, enzyme-linked immunosorbent assays, and Western blotting were used in this study. We found that the levels of fasting and random blood glucose increased rapidly in diabetic rats, the levels of triglycerides and total cholesterol in the diabetic group increased, and insulin levels decreased significantly. In the Morris water maze test, the escape latency was prolonged, and the crossing times decreased in the diabetic group. Under the microscope, the apoptosis of hippocampal neurons in diabetic rats increased significantly. The levels of TNF-α, IL-6 and 12-hydroxyindoleic acid (12(S)-HETE) significantly increased, and the protein expression of 12/15-LOX, p38 MAPK, Aß1-42, caspase-3, caspase-9 and cPLA2 increased, while that of Bcl-2 decreased. However, the use of 12/15-LOX inhibitor reversed these results. Third, 12/15-LOX shRNA and p38MAPK inhibitor were administered to HT22 cells in high-glucose medium. The results of the cell experiment were consistent with those of the animal experiment. Our results indicated that the 12/15-LOX pathway participates in diabetic brain damage by activating p38MAPK to promote inflammation and neuronal apoptosis, and intervention 12/15-LOX can improve diabetic cognitive dysfunction.

Intranasal budesonide for rhinitis during a high airborne pollution period: a randomized controlled trial.

BACKGROUND: Air pollution may induce or reinforce nasal inflammation regardless of allergy status. There is limited direct clinical evidence informing the treatment of airborne pollution-related rhinitis. OBJECTIVE: To assess the effectiveness of intranasal budesonide in adults with self-reported rhinitis symptoms triggered/worsened by airborne pollution. METHODS: Adults in northern China with self-reported rhinitis symptoms triggered or worsened by airborne pollution were randomized to budesonide 256 µg/day or placebo for 10 days in pollution season (October 2019 to February 2020). The primary endpoint was the mean change from baseline in 24-h reflective total nasal symptom score (rTNSS) averaged over 10 days. The secondary endpoints were subject-assessed Global Impression of Change (SGIC), mean change from baseline in individual nasal symptom severity, and mean change from baseline in individual non-nasal symptoms of cough and postnasal drip severity. One-sided P < 0.0125 was considered statistically significant. RESULTS: After an interruption by COVID-19, an interim analysis showed that the study could be ended for efficacy with n = 206 participants (103/group) since the primary efficacy endpoint demonstrated significant results. The final efficacy results showed that the 10-day-averaged rTNSS change in the budesonide group was greater than with placebo (- 2.20 vs - 1.72, P = 0.0107). Budesonide also significantly improved 10-day-averaged itching/sneezing change (- 0.75 vs - 0.51, P = 0.0009). Results for SGIC and all other individual symptoms did not show significant differences between the two groups. CONCLUSIONS: Intranasal budesonide 256 µg once daily improved the total nasal symptoms and itching/sneezing over 10 days in adults with rhinitis triggered/worsened by airborne pollution.

T-cell immunoglobulin and ITIM domain in cancer immunotherapy: A focus on tumor-infiltrating regulatory T cells.

T-cell immunoglobulin and ITIM domain (TIGIT) is a novel type of immune checkpoint. Importantly, immune checkpoint molecules promote cancer progression by various antitumor suppressive mechanisms. TIGIT is an inhibitory receptor expressed on T cells, natural killer cells, and regulatory T cells that was recently attracted attention as a major emerging target for cancer immunotherapy. Regulatory T cells (Tregs) play crucial roles in immune homeostasis. Specifically, tumor-infiltrating Tregs promote cancer progression by restricting antitumor immunity and supporting tumor immune escape. In this review, we summarized the current understanding on TIGIT and tumor-infiltrating Tregs. Here, we reviewed the latest advances in the understanding of mechanisms causing tumor-infiltrating Tregs abundance to optimize Tregs targeted therapy. Collectively, anti-TIGIT targeting Tregs hold great promise for potent cancer target therapy.

[Ectopic thyroid carcinoma in front of hyoid bone misdiagnosed as thyroglossal cyst：a case report].

A clinical case of ectopic thyroid carcinoma in front of hyoid bone was reported in this paper. The patient, a 17-year-old female, presented with an enlarging neck mass of 1-week history. Physical examination revealed a 3 cm×2 cm neck mass in front of the hyoid bone. Ultrasonographic depicted as a cystic solid mixed echogenic mass with punctate strong echogenicity. CT scan showed a cystic-solid mass in front of the hyoid bone with punctate calcifications. The patient was misdiagnosed as a thyroglossal duct cyst and underwent surgery. The final pathological diagnosis was papillary thyroid carcinoma with cyst formation.

LncRNA ANRIL Promotes Autophagy Activation Through miR-16-5p/TLR4 Axis in Allergic Rhinitis.

BACKGROUND: Allergic rhinitis (AR) is an allergic disease of nasal mucosa. LncRNAs are key modulators affecting AR development. Neverthelss, the impact of lncRNA ANRIL in AR is not clear. OBJECTIVE: This work decided to study the mechanism underlying the impact of ANRIL on TLR4 expression through targeting miR-16-5p during autophagy and epithelial barrier dysfunction in the progression of AR. METHODS: Human nasal epithelial cells were exposed to TNF-α to establish AR cell model, AR mice model was constructed by ovalbumin (OVA) treatment. QRT-PCR or western blot assays were applied to measure the levels of mRNA and proteins. Dual-luciferase reporter gene detection and RIP assay were conducted to verify the association between ANRIL and miR-16-5p. Autophagy flux assessment by mRFP-GFP-LC3 method was performed to detect autophagy level. RESULTS: AR progression could induce the autophagy, and the expressions of tight junction proteins were downregulated in AR cell model. Moreover, knockdown of ANRIL reversed the effect of AR on autophagy-related protein and tight junction proteins MiR-16-5p was found to be bound with ANRIL and miR-16-5p inhibitor could reverse ANRIL knockdown-induced downregulation of autophagy-related proteins and epithelial barrier dysfunction. In addition, miR-16-5p directly targeted TLR4. Furthermore, knockdown of ANRIL reversed miR-16-5p and TLR4 expression, autophagy level, and tight junction protein levels in nasal mucosa of AR mice. CONCLUSION: This study illustrated that ANRIL acted as a promotion factor in AR induced autophagy and epithelial barrier dysfunction by enhancing the expression of TLR4 via interacting with miR-16-5p.

Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation.

Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19. Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking. Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC50 values ranging from 0.6 to 2.4 µM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site. Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.

Discovery of Potent and Isoform-selective Histone Deacetylase Inhibitors Using Structure-based Virtual Screening and Biological Evaluation.

Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC-27, AGS, MDA-MB-231, A549, MCF-7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC-27 cells-derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC-targeting inhibitor for solid tumor therapy.

Evolution Analysis of Free Fatty Acids and Aroma-Active Compounds during Tallow Oxidation.

To explore the role of fatty acids as flavor precursors in the flavor of oxidized tallow, the volatile flavor compounds and free fatty acid (FFAs) in the four oxidization stages of tallow were analyzed via gas chromatography (GC)-mass spectrometry (MS), the aroma characteristics of them were analyzed by GC-olfactory (GC-O) method combined with sensory analysis and partial least-squares regression (PLSR) analysis. 12 common FFAs and 35 key aroma-active compounds were obtained. Combined with the results of odor activity value (OAV) and FD factor, benzaldehyde was found to be an important component in unoxidized tallow. (E,E)-2,4-Heptadienal, (E,E)-2,4-decadienal, (E)-2-nonenal, octanal, hexanoic acid, hexanal and (E)-2-heptenal were the key compounds involved in the tallow flavor oxidation. The changes in FFAs and volatile flavor compounds during oxidation and the metabolic evolution of key aroma-active compounds are systematically summarized in this study. The paper also provides considerable guidance in oxidation control and meat flavor product development.

Thermodynamics and Catalytic Properties of Two Novel Energetic Complexes Based on 3-Amino-1,2,4-triazole-5-carboxylic Acid.

For energetic materials (EMs), the key point of the present research is to improve the energetic property and reduce sensitivity. In this work, two new energetic complexes, Mn(atzc)2(H2O)2·2H2O (1) and Zn(atzc)2(H2O) (2) (Hatzc = 3-amino-1,2,4-triazole-5-carboxylic acid), were synthesized by solvent evaporation and diffusion methods, respectively. The structural analyses illustrate that 1 and 2 exhibit zero-dimensional structural units, which are linked by hydrogen-bonding interactions to give three-dimensional supramolecular architectures. For complexes 1 and 2, the detonation velocities (D) are 10.4 and 10.2 km·s-1 and detonation pressures (P) are 48.7 and 48.6 GPa, respectively. They are higher than most of the reported EMs, which present prominent detonation characteristics. In addition, two complexes can accelerate the thermal decomposition of ammonium perchlorate and exhibit excellent catalytic activity. Therefore, the two complexes can serve as a new class of promising EMs, which have potential application in the design of new high-efficiency solid catalysts.