mPPTMP195 nanoparticles enhance fracture recovery through HDAC4 nuclear translocation inhibition.

Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.

Association between secondhand smoke exposure and rheumatoid arthritis in US never-smoking adults: a cross-sectional study from NHANES.

While smoking is widely acknowledged as a risk factor for rheumatoid arthritis (RA), the connection between secondhand smoke (SHS) exposure and RA in never-smoking adults remains limited and inconsistent. This study aims to explore and quantify this association using serum cotinine levels. We conducted a cross-sectional study with 14,940 adults who self-report as never smokers, using National Health and Nutrition Examination Survey data from 1999 to 2018. Based on previous literature, SHS exposure was categorized into four groups according to serum cotinine levels. Compared to individuals in the unexposed group (serum cotinine < 0.05 ng/mL), the adjusted odds ratio (OR) for RA was 1.37 (95% CI 1.14-1.64, p = 0.001) in the low exposure group (serum cotinine at 0.05 to 0.99 ng/mL) after adjusting for covariates. However, no significant association was found in the moderate exposure group (serum cotinine at 1 to 10 ng/mL) or the heavy exposure group (serum cotinine ≥ 10 ng/mL). Furthermore, we detected a non-linear, positively saturated correlation between the cotinine levels after log2 transformation and RA, with a turning point at approximately - 2.756 ng/mL (OR = 1.163, 95% CI 1.073-1.261, p = 0.0002). The stability of the results was confirmed by subgroup analysis.

Palmitoylation of KSHV pORF55 is required for Golgi localization and efficient progeny virion production.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.

Effects of organochlorine pesticides on human and rat 17ß-hydroxysteroid dehydrogenase 1 activity: Structure-activity relationship and in silico docking analysis.

The objective of this study was to examine the effect of 11 organochlorine pesticides on human and rat 17ß-Hydroxysteroid dehydrogenase 1 (17ß-HSD1) in human placental and rat ovarian microsome and on estradiol production in BeWo cells. The results showed that the IC50 values for endosulfan, fenhexamid, chlordecone, and rhothane on human 17ß-HSD1 were 21.37, 73.25, 92.80, and 117.69 µM. Kinetic analysis revealed that endosulfan acts as a competitive inhibitor, fenhexamid as a mixed/competitive inhibitor, chlordecone and rhothane as a mixed/uncompetitive inhibitor. In BeWo cells, all insecticides except endosulfan significantly decreased estradiol production at 100 µM. For rats, the IC50 values for dimethomorph, fenhexamid, and chlordecone were 11.98, 36.92, and 109.14 µM. Dimethomorph acts as a mixed inhibitor, while fenhexamid acts as a mixed/competitive inhibitor. Docking analysis revealed that endosulfan and fenhexamid bind to the steroid-binding site of human 17ß-HSD1. On the other hand, chlordecone and rhothane binds to a different site other than the steroid and NADPH-binding site. Dimethomorph binds to the steroid/NADPH binding site, and fenhexamid binds to the steroid binding site of rat 17ß-HSD1. Bivariate correlation analysis showed a positive correlation between IC50 values and LogP for human 17ß-HSD1, while a slight negative correlation was observed between IC50 values and the number of HBA. ADMET analysis provided insights into the toxicokinetics and toxicity of organochlorine pesticides. In conclusion, this study identified the inhibitory effects of 3-4 organochlorine pesticides and binding mechanisms on human and rat 17ß-HSD1, as well as their impact on hormone production.

Physical Fitness Parameters of Elite Chinese Wheelchair Curlers / Parámetros de Aptitud Física de Curlers en Silla de Ruedas Chinos de Élite

SUMMARY: Few international studies have analyzed the characteristics of elite wheelchair curlers competing on the international stage. This study aims to investigate the physical fitness parameters of elite Chinese wheelchair curlers and explore the corresponding training enlightenment. Sixteen wheelchair curlers from the Chinese national team, including six male and two female Winter Paralympic gold medalists, were selected as research participants. The following parameters were measured: age, training age, height, weight, body fat percentage, grip strength, absolute bench press strength, and 5-km wheelchair push-timing test. Compared with ordinary curlers of the Chinese wheelchair curling team, elite curlers were older in age and training age; male curlers were shorter, whereas female curlers were taller. However, their weight and body fat percentage were lower, and their grip strength, absolute strength in the bench press, and 5-k wheelchair push-timing test were better. From an athlete development and physical training perspective, wheelchair curlers should increase training years in order to accumulate competition experience. Additionally, these athletes should manage their body weight and fat percentage, and improve their upper limb strength and aerobic capacity.

Pocos estudios internacionales han analizado las características de los curlers en silla de ruedas de élite que compiten en el escenario internacional. Este estudio tiene como objetivo investigar los parámetros de aptitud física de los bigudíes chinos en silla de ruedas de élite y explorar la iluminación del entrenamiento correspondiente. Se seleccionaron como participantes de la investigación dieciséis curlers en silla de ruedas del equipo nacional chino, incluidos seis medallistas de oro masculinos y dos femeninos de los Juegos Paralímpicos de Invierno. Se midieron los siguientes parámetros: edad, edad de entrenamiento, altura, peso, porcentaje de grasa corporal, fuerza de agarre, fuerza absoluta en press de banca y prueba de sincronización de empuje en silla de ruedas de 5 km. En comparación con los curlers ordinarios del equipo chino de curling en silla de ruedas, los curlers de élite eran mayores en edad y tiempo de entrenamiento; Los curlers masculinos eran más bajos, mientras que las mujeres eran más altas. Sin embargo, su peso y porcentaje de grasa corporal fueron menores, y su fuerza de agarre, fuerza absoluta en press de banca y prueba de sincronización de empuje en silla de ruedas de 5-k fueron mejores. Desde la perspectiva del desarrollo del atleta y del entrenamiento físico, los curlers en silla de ruedas deberían aumentar los años de entrenamiento para acumular experiencia en competencia. Además, estos deportistas deben controlar su peso corporal y porcentaje de grasa, y mejorar la fuerza de sus miembros superiores y su capacidad aeróbica.

Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies.

Mesenchymal Stem Cell Derived Exosomes Repair Uterine Injury by Targeting Transforming Growth Factor-ß Signaling.

Intrauterine adhesions (IUA) refer to adhesions within the uterine cavity and cervix caused by injuries from uterine surgery. They are a significant cause of female infertility. Exosomes derived from mesenchymal stem cells (MSCs) play an active role in the treatment of IUA. However, the mechanism by which they reduce fibrosis in the damaged endometrium remains unclear. In this paper, we demonstrate that exosomes derived from placental mesenchymal stem cells (PMSCs) can restore uterine functions and improve the fertility rate of injured animals. This is achieved by promoting cell proliferation, increasing endometrial thickness, and reversing fibrosis. Regarding the molecular mechanism behind these therapeutic effects, we identify three specific miRNAs, namely, miR-125b-5p, miR-30c-5p, and miR-23a-3p, enriched in PMSC-exosomes, as the key players in the treatment of IUA. Specifically, miR-125b-5p/miR-30c-5p and miR-23a-3p inhibit the expression of smad2 and smad3 by targeting their 3'-untranslated regions, resulting in the downregulation of the transforming growth factor-ß (TGF-ß)/smad signaling pathway and the reversal of fibrosis. Notably, the safety of PMSC-exosomes in intrauterine treatment was also been confirmed. In conclusion, we illustrate that exosomes derived from PMSCs possess the capability to repair endometrial damage and enhance fertility in injured animals by regulating the TGF-ß/smad pathway via miR-125b-5p, miR-30c-5p, and miR-23a-3p. This provides insights into the precision treatment of IUA through exosome-based cell-free therapy.

Intranuclear assembly of leucine-rich peptides for selective death of osteosarcoma cells.

Herein, we show a pair of leucine-rich L- and D-phosphopeptides which self-assemble into twisting nanofibers, whose secondary structures contain a strong ß-sheet component after being dephosphorylated by alkaline phosphatase (ALP). While being incubated with ALP overexpressing osteosarcoma cells, both of the peptides self-assemble in the nuclei and induce cell death. The cell death involves multiple cell death modalities and occurs along with the disruption of cell membranes. Enzyme-instructed self-assembly (EISA) inhibits osteosarcoma cells and shows no side effect to other cells. In addition, the cancer cells hardly gain drug resistance after repeated treatment. This work reports a pair of EISA-based nanofibers to target cell nuclei, and also provides a novel chemotherapeutic agent to inhibit osteosarcoma cells without side effects and drug resistance.

Bisphenol a alternatives suppress human and rat aromatase activity: QSAR structure-activity relationship and in silico docking analysis.

The use of alternative substances to replace bisphenol A (BPA) has been encouraged. The objective of this study was to evaluate the effects of BPA and 9 BPA alternatives on human and rat aromatase (CYP19A1) in human and rat placental microsomes. The results revealed that bisphenol A, AP, B, C, E, F, FL, S, and Z, and 4,4'-thiodiphenol (TDP) inhibited human CYP19A1 and bisphenol A, AP, B, C, FL, Z, and TDP inhibited rat CYP19A1. The IC50 values of human CYP19A1 ranged from 3.3 to 172.63 µM and those of rat CYP19A1 ranged from 2.20 to over 100 µM. BPA alternatives were mixed/competitive inhibitors and inhibited estradiol production in BeWo placental cells. Molecular docking analysis showed that BPA alternatives bind to the domain between heme and steroid and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were one hydrogen bond donor, one hydrophobic region, and one ring aromatic hydrophobic region. Bivariate correlation analysis showed that molecular weight, alkyl atom weight, and LogP of BPA alternatives were inversely correlated with their IC50 values. In conclusion, BPA alternatives can inhibit human and rat CYP19A1 and the lipophilicity and the substituted alkyl size determines their inhibitory strength.

Enhanced inhibition of human and rat aromatase activity by benzene ring substitutions in bisphenol A: QSAR structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a widely used plastic material, but its potential endocrine disrupting effect has restricted its use. The BPA alternatives have raised concerns. This study aimed to compare inhibitory potencies of 11 BPA analogues on human and rat placental aromatase (CYP19A1). The inhibitory potency on human CYP19A1 ranged from bisphenol H (IC50, 0.93 µM) to tetramethyl BPA and tetrabromobisphenol S (ineffective at 100 µM) when compared to BPA (IC50, 73.48 µM). Most of them were mixed/competitive inhibitors and inhibited estradiol production in human BeWo cells. Molecular docking analysis showed all BPA analogues bind to steroid active site or in between steroid and heme of CYP19A1 and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were 4 hydrophobic regions for BPA analogues, with bisphenol H occupying 4 regions. Bivariate correlation analysis showed that LogP (lipophilicity) and LogS (water solubility) of BPA analogues were correlated with their IC50 values. Computerized drug metabolism and pharmacokinetics analysis showed that bisphenol H, tetrabromobisphenol A, and tetrachlorobisphenol A had low solubility, which might explain their weaker inhibition on estradiol production on BeWo cells. In conclusion, BPA analogues mostly can inhibit CYP19A1 and the lipophilicity determines their inhibitory strength.

Review of mendelian randomization studies on age at natural menopause.

Menopause marks the end of the reproductive phase of life. Based on epidemiological studies, abnormal age at natural menopause (ANM) is thought to contribute to a number of adverse outcomes, such as osteoporosis, cardiovascular disease, and cancer. However, the causality of these associations remains unclear. A powerful epidemiological method known as Mendelian randomization (MR) can be used to clarify the causality between ANM and other diseases or traits. The present review describes MR studies that included ANM as an exposure, outcome and mediator. The findings of MR analyses on ANM have revealed that higher body mass index, poor educational level, early age at menarche, early age at first live birth, early age at first sexual intercourse, and autoimmune thyroid disease appear to be involved in early ANM etiology. The etiology of late ANM appears to be influenced by higher free thyroxine 4 and methylene tetrahydrofolate reductase gene mutations. Furthermore, early ANM has been found to be causally associated with an increased risk of osteoporosis, fracture, type 2 diabetes mellitus, glycosylated hemoglobin, and the homeostasis model of insulin resistance level. In addition, late ANM has been found to be causally associated with an increased systolic blood pressure, higher risk of breast cancer, endometrial cancer, endometrioid ovarian carcinoma, lung cancer, longevity, airflow obstruction, and lower risk of Parkinson's disease. ANM is also a mediator for breast cancer caused by birth weight and childhood body size. However, due to the different instrumental variables used, some results of studies are inconsistent. Future studies with more valid genetic variants are needed for traits with discrepancies between MRs or between MR and other types of epidemiological studies.

No association effect of genetic polymorphism was observed between polycystic ovary syndrome and cardiovascular diseases risk: a mendelian randomization study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is one of the risk factors for cardiovascular diseases (CVDs). However, the possible association between PCOS and common CVDs remains inconclusive. The aim of this study was to explore the potential relationship between PCOS and CVDs using genetic polymorphisms. METHODS: We conducted two-sample Mendelian randomization (MR) analyses. In our study, 14 single nucleotide polymorphisms (SNPs) in Europeans and another 13 SNPs in Asians were applied as instrumental variables for PCOS. The largest published meta-genome-wide association studies of European ancestry and the BioBank Japan Project of Asian ancestry were used to collect the outcome data. MR analysis was performed using inverse variance weighting as the primary method. Several sensitivity analyses and instrumental variable strength evaluations were also performed to verify the reliability of results. RESULTS: Our analysis revealed that any potential causal association between genetically-predicted PCOS and the risk of CVDs do not exist. These CVDs include peripheral artery disease, atrial fibrillation, arrhythmia, cardiovascular diseases, heart failure, peripheral vascular disease, hypertension, ischemic stroke, myocardial infarction and venous thromboembolisms. Associations could not be found even after the SNPs linked to these possible confounders (body mass index, waist-to-hip ratio, and serum testosterone) were deleted. Sensitivity analysis demonstrated no presence of horizontal pleiotropy or heterogeneity. CONCLUSION: The present mendelian randomization study suggests that genetically-predicted PCOS may not be associated with the risk of CVDs.

Linkage of Blood MALT1 with CD4+ T Cell Subset, Inflammation, Lipid, and Its Potency as a Biomarker for Predicting Major Adverse Cardiovascular Events in Coronary Heart Disease Patients.

OBJECTIVE: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) promotes CD4+ T cell differentiation, vascular inflammation, and atherogenesis to engage in coronary heart disease (CHD) progression. This study intended to explore the correlation of blood MALT1 with clinical characteristics, CD4+ T cell subset and prognosis in CHD patients. METHODS: MALT1 in peripheral blood mononuclear cells of 258 CHD patients and 50 healthy controls (HCs) was determined by RT-qPCR. Additionally, blood T helper (Th)1, Th2, Th17, and regulatory T (Treg) cells were measured through flow cytometry; major adverse cardiovascular events (MACE) were recorded during the routine follow up in CHD patients. RESULTS: Blood MALT1 was elevated in CHD patients compared to HCs. Interestingly, blood MALT1 positively associated with hyperlipidemia, triglyceride, C-reactive protein, and Gensini score in CHD patients. It also negatively linked with Th2 cells, Treg cells, and positively related to Th17 cells but not Th1 cells in CHD patients. More importantly, MACE-free survival was shortened in CHD patients with high blood MALT1 compared to those with low blood MALT1 (cut off by the median) while less significance was observed when cut off by quartiles. Separately, blood MALT1 was elevated in CHD patients occurred MACE within 1-year, 2-year, 3-year, and 4-year duration compared to those who did not. CONCLUSION: Blood MALT1 links with unbalanced CD4+ T-cell subset, elevated inflammation, and coronary-artery stenosis serving as a candidate biomarker for predicting MACE risk in CHD patients.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

A mid-infrared high-performance spectropolarimetry filter based on dual-mode independent modulation.

Spectropolarimetry detection provides multi-dimensional accurate information with broad applications from biomedicine to remote sensing. Existing methods for simultaneously obtaining spectra and polarizations are either large and complex systems or miniaturized devices with too low spectral resolution or poor polarization selectivity, which inherently generate cross-talk of substantial information. Here, we propose a compact and single-chip integrated high-performance mid-infrared spectropolarimetry filter (SPF), whose narrowband spectral and polarization characteristics can be independently modulated by different polarization modes. A SPF is designed with a polarization extinction ratio (ER) over 106, spectral resolution (SR, λ/Δλ) up to 822 and a transmission efficiency of 90% in the mid-infrared band. The experimental ER and SR are over 3 × 104 and up to 387 respectively with a transmission efficiency of 60%. These results agree well with the theoretical results and can accurately obtain spectral and polarization information simultaneously. This device has been used in tumor diagnostics to well distinguish striated muscle and rhabdomyosarcoma tissue for demonstration. It can be easily extended to different wavelength ranges and provides a new and powerful approach for multi-dimensional optical information acquisition, target detection and accurate identification.

Identification of acute myeloid leukemia by infrared difference spectrum of peripheral blood.

Acute myeloid leukemia (AML) is a high mortality and recurrence rates hematologic malignancy. Thus, whatever early detection or subsequent visit are both of high significance. Traditional AML diagnosis is conducted via peripheral blood (PB) smear and bone marrow (BM) aspiration. But BM aspiration is a painful burden for patients especially in early detection or subsequent visit. Herein, the use of PB to evaluate and identify the leukemia characteristics will be an attractive alternative source for early detection or subsequent visit. Fourier transform infrared spectroscopy (FTIR) is a time- and cost-effective approach to reveal the disease-related molecular features and variations. However, to the best of our knowledge, there is no attempts using infrared spectroscopic signatures of PB to replace BM for identifying AML. In this work, we are the first to develop a rapid and minimally invasive method to identify AML by infrared difference spectrum (IDS) of PB with only 6 characteristic wavenumbers. We dissect the leukemia-related spectroscopic signatures of three subtypes of leukemia cells (U937, HL-60, THP-1) by IDS, revealing biochemical molecular information about leukemia for the first time. Furthermore, the novel study links cellular features to complex features of blood system which demonstrates the sensitivity and specificity with IDS method. On this basis, BM and PB of AML patients and healthy controls were provided to parallel comparison. The IDS of BM and PB combined with principal component analysis method revealing that the leukemic components in BM and PB can be described by IDS peaks of PCA loadings, respectively. It is demonstrated that the leukemic IDS signatures of BM can be replaced by the leukemic IDS signatures of PB. In addition, the IDS signatures of leukemia cells are reflected in PB of AML patients with peaks of 1629, 1610, 1604, 1536, 1528 and 1404 cm-1 for the first time as well. To this end, we access the leukemic signatures of IDS peaks to compare the PB of AMLs and healthy controls. It is confirmed that the leukemic components can be detected from PB of AML and distinguished into positive (100%) and negative (100%) groups successfully by IDS classifier which is a novel and unique spectral classifier. This work demonstrates the potential use of IDS as a powerful tool to detect leukemia via PB which can release subjects' pain remarkably.

Inhibition of Resveratrol Analogs on Human and Rat 3ß-Hydroxysteroid Dehydrogenases: Structure-Activity Relationship and Docking Analysis.

Resveratrol and its analogs are phytochemicals. Human 3ß-hydroxysteroid dehydrogenase 1 (3ß-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3ß-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure-activity relationship, and docking parameters of resveratrol and its analogs on 3ß-HSD1 and rat homolog 3ß-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3ß-HSD1 was 4,4'-dihydroxystilbene (IC50, 3.68 µM) > pinostilbene (8.07 µM) > pinosylvin (10.60 µM) > lunularin (26.84 µM) > resveratrol (30.20 µM) > dihydroresveratrol (>100 µM) = oxyresveratrol (>100 µM) > dihydropinosylvin (ineffective at 100 µM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3ß-HSD1. Resveratrol and 4,4'-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 µM. Resveratrol (IC50, 32.09 µM) and pinosylvin (34.71 µM) significantly inhibited rat placental 3ß-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3ß-HSD1 and rat 3ß-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3ß-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4'-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3ß-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.

Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.

Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.

Benzophenone-type ultraviolet filters inhibit human and rat placental 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Benzophenones (BPs) are a class of chemicals found in various personal care and cosmetic products, such as sunscreens and lotions. Their usage is known to cause reproductive and hormonal health risks, but the exact mechanism of action remains unknown. In this study, we investigated the effects of BPs on human and rat placental 3ß-hydroxysteroid dehydrogenases (3ß-HSDs), which play a crucial role in the biosynthesis of steroid hormones, particularly progesterone. We tested inhibitory effects of 12 BPs, and performed structure-activity relationship (SAR) and in silico docking analysis. The potency of BPs to inhibit human 3ß-HSD1 (h3ß-HSD1) is BP-1 (IC50, 8.37 µM)>BP-2 (9.06 µM)>BP-12 (94.24 µM)>BP-7 (1160 µM) >BP-8 (1257 µM) >BP-6 (1410 µM) > other BPs (ineffective at 100 µM). The potency of BPs on rat r3ß-HSD4 is BP-1 (IC50, 4.31 µM)>BP-2 (117.3 µM)>BP-6 (669 µM) >BP-3 (820 µM)>other BPs (ineffective at 100 µM). BP-1, BP-2, and BP-12 are mixed h3ß-HSD1 inhibitors and BP-1 is a mixed r3ß-HSD4 inhibitor. LogP, lowest binding energy, and molecular weight were positively associated with IC50 for h3ß-HSD1, while LogS was negatively associated with IC50. The 4-OH substitution in the benzene ring plays a key role in enhancing the effectiveness of inhibiting h3ß-HSD1 and r3ß-HSD4, possibly through increasing water solubility and decreasing lipophilicity by forming hydrogen bonds. BP-1 and BP-2 inhibited progesterone production in human JAr cells. Docking analysis shows that 2-OH of BP-1 forms hydrogen bonds with catalytic residue Ser125 of h3ß-HSD1 and Thr125 of r3ß-HSD4. In conclusion, this study demonstrates that BP-1 and BP-2 are moderate inhibitors of h3ß-HSD1 and BP-1 is a moderate inhibitor of r3ß-HSD4. There is a significant SAR differences for 3ß-HSD homologues between BPs and distinct species-dependent inhibition of placental 3ß-HSDs.

Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses.

Intrinsic immunity is the frontline of host defense against invading pathogens. To combat viral infection, mammalian hosts deploy cell-intrinsic effectors to block viral replication prior to the onset of innate and adaptive immunity. In this study, SMCHD1 is identified as a pivotal cellular factor that restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation through a genome-wide CRISPR-Cas9 knockout screen. Genome-wide chromatin profiling revealed that SMCHD1 associates with the KSHV genome, most prominently the origin of lytic DNA replication (ORI-Lyt). SMCHD1 mutants defective in DNA binding could not bind ORI-Lyt and failed to restrict KSHV lytic replication. Moreover, SMCHD1 functioned as a pan-herpesvirus restriction factor that potently suppressed a wide range of herpesviruses, including alpha, beta, and gamma subfamilies. SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. These findings uncovered SMCHD1 as a restriction factor against herpesviruses, and this could be harnessed for the development of antiviral therapies to limit viral infection. IMPORTANCE Intrinsic immunity represents the frontline of host defense against invading pathogens. However, our understanding of cell-intrinsic antiviral effectors remains limited. In this study, we identified SMCHD1 as a cell-intrinsic restriction factor that controlled KSHV lytic reactivation. Moreover, SMCHD1 restricted the replication of a wide range of herpesviruses by targeting the origins of viral DNA replication (ORIs), and SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. This study helps us to better understand intrinsic antiviral immunity, which may be harnessed to develop new therapeutics for the treatment of herpesvirus infection and the related diseases.