[Effects of Sophora japonica extract on alveolar bone mass in ovariectomized osteoporosis mice].

PURPOSE: To investigate the effect of Sophora japonica extract on alveolar bone mass in ovariectomized osteoporosis mice. METHODS: Six-week-old female non-pregnant wild-type C57BL/6J mice were randomly divided into sham operation group, ovariectomy(OVX) group and OVX+Sophora japonica extract group. Ovaries of the mice in the OVX group and the OVX+Sophora japonica extract group were removed, and the mice in the OVX+Sophora japonica extract group were treated by Sophora japonica extract at a dose of 150 mg/kg, three times a week for 4 weeks; while mice of the other two groups were given an equal volume of normal saline at the same time. Body weight was measured 3 times a week, and the micro-parameters of alveolar bone were detected by Micro-CT after 4 weeks. The data were analyzed by GraphPad Prism 9 software. RESULTS: Compared with the sham-operated group, the trabecular bone parameters of the alveolar bone in the OVX group were significantly decreased 1 month after operation (P＜0.05). One month after intervention with Sophora japonica extract, alveolar bone mineral density (BMD), trabecular number (Tb.N) and trabecular separation(Tb.Sp) in OVX mice was significantly rescued, with no significant difference compared to the sham surgery group(P＞0.05); but bone volume fraction(BV/TV) and trabecular thickness (Tb.Th) had not completely recovered to the levels of the sham-operated group(P＜0.05). CONCLUSIONS: Sophora japonica extract can effectively increase the alveolar bone mass reduced by estrogen deficiency and may be used as one of the potential drugs for the treatment of menopausal alveolar bone osteoporosis.

Aqueous Extracts of Ocimum gratissimum Sensitize Hepatocellular Carcinoma Cells to Cisplatin through BRCA1 Inhibition.

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.

Decentralized dynamic system for optimal power dispatch in wind farms based on node-dependence nature.

Meeting the power demand from the transmission system operator is an important objective for power dispatch, which introduces a power supply-demand equality constraint coupling all the wind turbines among the wind farm into the optimization problem. For a large-scale wind farm, processing the global equality constraint in a centralized or distributed framework is time-consuming and computationally complex. Here we considered the fast and localized execution issue of the power optimal dispatch problems. A completely decentralized dynamic system was designed to optimize power flow while satisfying the electricity supply constraints. A voltage optimization problem with the global power constraints was decoupled into local wind turbine controllers based on the node-dependence nature, which is an inherent characteristic of wind farms and was fitted to the power sensitivity matrix in this paper. The local optimization problem was solved iteratively using the gradient projection method, and the system converged linearly to the equilibrium point. The simulations for the case studies performed in Simulink demonstrate that the proposed method achieves a near-global optimal performance using only local measurements.

Species recognition and the divergences in the chemical and ultrasonic signals between two coexisting Rattus species.

The ability to recognize and differentiate between conspecifics and heterospecifics as well as their signals is critical for the coexistence of closely related species. In the genus Rattus, species are morphologically similar and multiple species often coexist. Here, we investigated the interspecific recognition and signal differentiation of two sympatric rat species, the brown rat (Rattus norvegicus, RN) and the Asian house rat (Rattus tanezumi, RT). In a two-way choice test, both RN and RT females showed a preference for conspecific male rats to heterospecific ones. RT females showed a significant preference for accessible urine of males of same species to those of other species, but not for the inaccessible urine. On the other hand, there were significant differences in the structural characteristics of the ultrasonic vocalization emitted by males of these two rat species. Sodium dodecyl sulphate‒polyacrylamide gel electrophoresis (SDS‒PAGE) and isoelectric focusing electrophoresis unveiled that major urinary proteins (MUPs) in voided urine were more highly expressed in RN males versus RT males. The interspecific differences of urinary volatile compounds were also discussed. In conclusion, female rats had the ability to distinguish between males of either species.

Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection of peripheral neuropathy: A cross-sectional study.

Patients with peripheral neuropathy could have damaged peripheral nerves, which leads to sensory and motor dysfunction. Diabetes, infections, and trauma are the major causes of peripheral neuropathy. Vibratory perception threshold (VPT) tools are commonly used to detect peripheral neuropathy. This study aims to determine the assessment of peripheral neuropathy through the different diagnostic tools in the community in Malaysia. A total number of 1283 participants were recruited from the seven retail pharmacies located in Selangor, Malaysia. The peripheral neuropathy test was conducted based on VPT tools on both feet using the digital biothesiometer. Following that, Neurological Symptom Score (NSS) and Neurological Disability Score (NDS) were taken from the participants to assess the neurological symptoms. Participants had an average age of 40.6 ± 12.9 years and were mostly of Chinese ethnicity (54.1%). The findings show that increasing age was associated with more severe peripheral neuropathy across the various assessment tools, but gender differences were found with the biothesiometer test and ethnicity has severity in the biothesiometer and disability scores. The sensitivity and specificity of the biothesiometer test were 0.63 and 0.84, respectively. The combined tool NSS and NDS had high specificity and a high positive predictive value, suggesting that it could be a reliable indicator of peripheral neuropathy when both scores are elevated. The findings show that the biothesiometer test, NSS, and NDS are considered screening VPT tools for diagnosing peripheral neuropathy. However, further evaluation and diagnostic testing are necessary in cases of a positive test result.

Ultrasound-guided modified dynamic needle tip positioning technique for distal radial artery catheterization: A randomized controlled trial.

INTRODUCTION: The distal radial artery presents a particular challenge for puncture and catheterization due to its diminutive size, tortuous path, and tendency to spasm, increasing the risk of procedural failure and injury. Ultrasound guidance improves success rates and reduces risk in radial artery catheterization. This study evaluates the efficacy and safety of a refined dynamic needle tip positioning technique for distal radial artery access. METHODS: One hundred twelve patients were randomized to either the modified dynamic needle tip positioning technique (MDNTP) or palpation guidance groups (palpation group), each with 56 participants. The primary outcomes were the success rate of the initial puncture and overall puncture success rate, while secondary outcomes included procedural time and complications such as puncture site hematoma and radial artery occlusion within 24 h. RESULTS: The MDNTP group exhibited superior initial puncture success (71.43% vs 46.43%, p < 0.05) and fewer puncture attempts (median 1 (1, 2) vs 2 (1, 4), p < 0.05), resulting in a higher overall puncture success rate (98.21% vs 87.50%, p = 0.028). Notably, sheath insertion times were significantly shorter (17 (12, 21) s vs 57 (32, 100) s, p = 0.001) and the Sheath insertion success rate was higher (96.43% vs 82.14%, p = 0.015) in the MDNTP group. Furthermore, the incidence of puncture site hematomas was reduced (5.36% vs 19.64%, p = 0.022), although puncture time was longer (60 (28, 116) s vs 40 (15, 79) s, p = 0.033). Despite these differences, total procedural time and the incidence of radial artery occlusion at 24 h postoperatively were comparable between the two groups. CONCLUSION: The MDNTP technique boosts the success of distal radial artery puncture and catheterization, reducing the risk of complications associated with the procedure.

LAMTOR5-AS1 Regulates Chemotherapy-induced Oxidative Stress via the miR-34a-3p/SIRT1/HNF4A Axis in Osteosarcoma Cells.

INTRODUCTION: Osteosarcoma (OS) drug resistance often leads to a poor prognosis. Recent evidence suggests that long non-coding RNAs play a crucial role in regulating tumor drug resistance. METHOD: This study aims to investigate the involvement of lncRNA LAMTOR5-AS1 in OS. RNA-seq and qRT-PCR were performed, and the relationship between LAMTOR5- AS1, miR-34a-3p, SIRT1, and HNF4A was determined using Dual-luciferase reporter assays and RNA immunoprecipitation assays. Gain- and loss-of-function assays were measured using CCK-8, cell proliferation, and colony formation assays. RESULT: The study found that the dysregulated LAMTOR5-AS1 acts as a competing endogenous RNA (ceRNA) and competitively protects the HNF4A mRNA 3' UTR from miR-34a-3p. In addition, in vitro functional studies showed that HNF4A can physically interact with SIRT1 to synergistically inhibit osteosarcoma drug resistance. The study found that LAMTOR5-AS1 regulates drug resistance in osteosarcoma through the miR-34a-3p/HNF4A or miR-34a-3p/SIRT1/HNF4A axis. CONCLUSION: These findings offer new insights into lncRNA-mediated drug resistance in cancer and may serve as potential biomarkers for cancer therapy.

H3K27ac acts as a molecular switch for doxorubicin-induced activation of cardiotoxic genes.

BACKGROUND: Doxorubicin (Dox) is an effective chemotherapeutic drug for various cancers, but its clinical application is limited by severe cardiotoxicity. Dox treatment can transcriptionally activate multiple cardiotoxicity-associated genes in cardiomyocytes, the mechanisms underlying this global gene activation remain poorly understood. METHODS AND RESULTS: Herein, we integrated data from animal models, CUT&Tag and RNA-seq after Dox treatment, and discovered that the level of H3K27ac (a histone modification associated with gene activation) significantly increased in cardiomyocytes following Dox treatment. C646, an inhibitor of histone acetyltransferase, reversed Dox-induced H3K27ac accumulation in cardiomyocytes, which subsequently prevented the increase of Dox-induced DNA damage and apoptosis. Furthermore, C646 alleviated cardiac dysfunction in Dox-treated mice by restoring ejection fraction and reversing fractional shortening percentages. Additionally, Dox treatment increased H3K27ac deposition at the promoters of multiple cardiotoxic genes including Bax, Fas and Bnip3, resulting in their up-regulation. Moreover, the deposition of H3K27ac at cardiotoxicity-related genes exhibited a broad feature across the genome. Based on the deposition of H3K27ac and mRNA expression levels, several potential genes that might contribute to Dox-induced cardiotoxicity were predicted. Finally, the up-regulation of H3K27ac-regulated cardiotoxic genes upon Dox treatment is conservative across species. CONCLUSIONS: Taken together, Dox-induced epigenetic modification, specifically H3K27ac, acts as a molecular switch for the activation of robust cardiotoxicity-related genes, leading to cardiomyocyte death and cardiac dysfunction. These findings provide new insights into the relationship between Dox-induced cardiotoxicity and epigenetic regulation, and identify H3K27ac as a potential target for the prevention and treatment of Dox-induced cardiotoxicity.

Progress in synthesis, modification, characterization and applications of hyperbranched polyphosphate polyesters.

Hyperbranched polyphosphate polyesters (HPPs) as a special class of hyperbranched polymers have attracted increased interest and have been intensively studied, because of peculiar structures, excellent biocompatibility, flexibility in physicochemical properties, biodegradability, water soluble, thermal stability, and mechanical properties. HPPs can be divided into phosphates as monomers and phosphates as end groups. In this article, the classification, general synthesis, modifications, and applications of HPP are reviewed. In addition, recent developments in the application of HPP are described, such as modified or functionalized by end capping and hypergrafting to improve the performances in polymer blends, coatings, flame retardant, leather. Furthermore, the modifications and application of HPPs in biomedical materials, such as drug delivery and bone regeneration were discussed. In summary, the hyperbranched polymer enlarges its application range and improves its application performance compared with conventional polymer. In the future, more new HPPs composite materials will be developed through hyperbranched technique. This review of HPPs will provide useful theoretical basis and technical support for the development of new hyperbranched polymer material.

Costunolide Inhibits Chronic Kidney Disease Development by Attenuating IKKß/NF-κB Pathway.

Background: Chronic kidney disease (CKD) is a significant worldwide health concern that leads to high mortality rates. The bioactive substance costunolide (CTD) has demonstrated several pharmacological effects and holds promise as a CKD treatment. This study aims to investigate the impact of CTD on CKD and delve into its mechanisms of action. Methods: Unilateral ureteral obstruction (UUO) methods and renal fibrosis mice models were created. Various concentrations of CTD were injected into UUO mice models to investigate the therapeutic effects of CTD on renal fibrosis of mice. Then, renal morphology, pathological changes, and the expression of genes related to fibrosis, inflammation and ferroptosis were analysed. RNA sequencing was utilized to identify the main biological processes and pathways involved in renal injury. Finally, both overexpression and inhibition of IKKß were studied to examine their respective effects on fibrosis and inflammation in both in vitro and in vivo models. Results: CTD treatment was found to significantly alleviate fibrosis, inflammation and ferroptosis in UUO-induced renal fibrosis mice models. The results of RNA sequencing suggested that the IKKß acted as key regulatory factor in renal injury and the expression of IKKß was increased in vitro and in vivo renal fibrosis model. Functionally, down-regulated IKKß expression inhibits ferroptosis, inflammatory cytokine production and collagen deposition. Conversely, IKKß overexpression exacerbates progressive renal fibrosis. Mechanistically, CTD alleviated renal fibrosis and inflammation by inhibiting the expression of IKKß and attenuating IKKß/NF-κB pathway. Conclusion: This study demonstrates that CTD could mitigate renal fibrosis, ferroptosis and inflammation in CKD by modulating the IKKß/NF-κB pathway, which indicates targeting IKKß has an enormous potential for treating CKD.

Dynamic changes in γδT cells and bone resorption markers after zoledronic acid in multiple myeloma: A prospective study.

We conducted a prospective evaluation for the dynamic change of γδT cells in peripheral blood (PB) and N-telopeptide of type I collagen in urine (uNTX) of patients diagnosed with multiple myeloma (MM) who underwent their initial treatment with zoledronic acid (ZOA; Zobonic®, TTY, Taiwan). Between March 2012 and November 2015, a total of 35 patients were enrolled, including 25 newly diagnosed MM (NDMM) patients. The percentage of γδT cells in PB was assessed at 20 days prior to the first ZOA infusion, then at day 8, day 64, and day 85 after the infusion. Simultaneously, uNTX levels were measured as well. Thirty-three patients who had received at least one dose of ZOA were included in subsequent analysis. We identified three dynamic change patterns for γδT cells: fluctuated pattern, continuously increasing pattern, and continuously decreasing pattern. Among NDMM patients, those exhibiting a continuously increasing pattern showed a significantly shorter overall survival compared to those with the other two patterns combined (4.7 months vs. 92.9 months, p = 0.037). For uNTX, which levels significantly decreased following ZOA treatment. In conclusion, our findings reveal three distinct dynamic change patterns for γδT cells after ZOA initiation, with continuously increasing pattern being associated with a poor prognosis. These findings prompt further inquiry into the role of γδT cells in MM patients and support the suppressive nature of γδT cells and their associated tumor microenvironment.

Prevalence and Factor Associated with Anti-N-Methyl-D-Aspartate Receptor Encephalitis Among Patients with Medical Conditions: A Systematic Review and Meta-Analysis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune encephalitis due to immune production of anti-NMDAR antibodies against the NR1 subunit of the NMDA receptor which is present throughout the central nervous system. This condition had been reported to be prevalent in patients with certain medical conditions; however so far, there have been limited systematic reviews and meta-analyses on the prevalence and factors associated. OBJECTIVE: This study was to determine the prevalence and factors associated with anti-NMDAR encephalitis among affected patients. MATERIAL AND METHODS: The protocol of this study has been registered (2019: CRD42019142002) with the International Prospective Register of Systematic Reviews (PROSPERO). The primary outcome was the incidence or prevalence of anti-NMDAR encephalitis and secondary outcomes were factors associated with anti-NMDAR encephalitis. RESULTS: There were 11 studies and a total of 873 million patients taken from high-risk populations across 11 countries that were included in the primary analysis. The overall pooled prevalence of anti-NMDAR encephalitis among patients with medical conditions was 7.0% (95% CI = 4.4, 9.6). Those with first episode of psychosis or schizophrenia were at a higher risk of developing anti-NMDAR encephalitis with an odds ratio of 5.976 (95% CI = 1.122, 31.825). CONCLUSION: We found that almost one-tenth of patients with medical conditions had anti-NMDAR encephalitis; particularly those with first episode of psychosis or schizophrenia were among the high-risk medical conditions.

Flexible and Disposable Hafnium Nitride Extended Gates Fabricated by Low-Temperature High-Power Impulse Magnetron Sputtering.

To obtain a high-performance extended gate field-effect transistor for pH detection, hafnium nitride (HfN) was first fabricated on an indium tin oxide on polyethylene terephthalate (ITO/PET) substrate using a high-power impulse magnetron sputter system (HiPIMS) in this study. It can be easily applied in biomedical diagnostic and environmental monitoring applications with the advantages of flexible, disposable, cost-effective, and reliable components. Various duty cycle conditions in HiPIMSs were designed to investigate the corresponding sensing performance and material properties including surface morphology and composition. As the duty cycle increased, the grain size of HfN increased. Additionally, X-ray photoelectron spectroscopy (XPS) analysis illustrated the presence of HfOxNy on the deposited HfN surface. Both behaviors could result in a better pH sensing performance based on the theory of the site-binding model. Subsequently, HfN with a 15% duty cycle exhibited excellent pH sensitivity and linearity, with values of 59.3 mV/pH and 99.8%, respectively; its hysteresis width and drift coefficient were -1 mV and 0.5 mV/h, respectively. Furthermore, this pH-sensing performance remained stable even after 2000 repeated bending cycles. These results indicate the potential and feasibility of this HiPIMS-deposited HfN for future wearable chemical applications.

One-step approach to fabricating amphoteric polymer fatliquors for chrome-free tanned leather eco-manufacturing.

The leather manufacturing industry is increasingly embracing chrome-free tanning methods to promote environmental sustainability. However, the transition to chrome-free tanning systems presents a notable obstacle: the incompatibility of traditional anionic wet finishing materials with chrome-free tanned leather due to differences in surface electrical behavior. Herein, an amphoteric polymer, referred to P(AA-co-DMAEMA-co-DA), was synthesized through a simple one-step free radical copolymerization using acrylic acid (AA), dimethylaminoethyl methacrylate (DMAEMA), and dodecyl acrylate (DA). Notably, the isoelectric point of P(AA-co-DMAEMA-co-DA) is 7.7, which contributes to improving the leather's positive electric property and enhancing the binding between the amphoteric polymer fatliquors (APF) and collagen fiber. The APF achieves a remarkable absorption rate of 96.2% and a dyeing uptake rate of 94.3% for anionic dyes, resulting in a uniformly bright surface color of the dyed leather and further significantly reducing the dye usage. Overall, the comprehensive properties of APF align with the electrical origins of organic chrome-free tanning leather, exhibiting a pronounced fatliquoring effect while reducing the dye content in the waste liquor. This contribution holds promise for advancing chrome-free tanning technology toward greener environmental practices.

Multicolor Tuning of Perylene Diimides Dyes for Targeted Organelle Imaging In Vivo.

The adjustment of the emission wavelengths and cell permeability of the perylene diimides (PDI) for multicolor cell imaging is a great challenge. Herein, based on a bay-region substituent engineering strategy, multicolor perylene diimides (MCPDI) were rationally designed and synthesized by introducing azetidine substituents on the bay region of PDIs. With the fine-tuned electron-donating ability of the azetidine substituents, these MCPDI showed high brightness, orange, red, and near infrared (NIR) fluorescence along with Stokes shifts increasing from 35 to 110 nm. Interestingly, azetidine substituents distorted to the plane of the MCPDI dyes, and the twist angle of monosubstituted MCPDI was larger than that of disubstituted MCPDI, which might efficiently decrease their π-π stacking. Moreover, all of these MCPDI dyes were cell-permeable and selectively stained various organelles for multicolor imaging of multiple organelles in living cells. Two-color imaging of lipid droplets (LDs) and other organelles stained with MCPDI dyes was performed to reveal the interaction between the LDs and other organelles in living cells. Furthermore, a NIR-emitting MCPDI dye with a mitochondria-targeted characteristic was successfully applied for tumor-specific imaging. The facile synthesis, excellent stability, high brightness, tunable fluorescence emission, and Stokes shifts make these MCPDI promising fluorescent probes for biological applications.

Development and Validation of a Biparametric MRI Deep Learning Radiomics Model with Clinical Characteristics for Predicting Perineural Invasion in Patients with Prostate Cancer.

RATIONALE AND OBJECTIVES: Perineural invasion (PNI) is an important prognostic biomarker for prostate cancer (PCa). This study aimed to develop and validate a predictive model integrating biparametric MRI-based deep learning radiomics and clinical characteristics for the non-invasive prediction of PNI in patients with PCa. MATERIALS AND METHODS: In this prospective study, 557 PCa patients who underwent preoperative MRI and radical prostatectomy were recruited and randomly divided into the training and the validation cohorts at a ratio of 7:3. Clinical model for predicting PNI was constructed by univariate and multivariate regression analyses on various clinical indicators, followed by logistic regression. Radiomics and deep learning methods were used to develop different MRI-based radiomics and deep learning models. Subsequently, the clinical, radiomics, and deep learning signatures were combined to develop the integrated deep learning-radiomics-clinical model (DLRC). The performance of the models was assessed by plotting the receiver operating characteristic (ROC) curves and precision-recall (PR) curves, as well as calculating the area under the ROC and PR curves (ROC-AUC and PR-AUC). The calibration curve and decision curve were used to evaluate the model's goodness of fit and clinical benefit. RESULTS: The DLRC model demonstrated the highest performance in both the training and the validation cohorts, with ROC-AUCs of 0.914 and 0.848, respectively, and PR-AUCs of 0.948 and 0.926, respectively. The DLRC model showed good calibration and clinical benefit in both cohorts. CONCLUSION: The DLRC model, which integrated clinical, radiomics, and deep learning signatures, can serve as a robust tool for predicting PNI in patients with PCa, thus aiding in developing effective treatment strategies.

Penetrative Ionic Organic Molecular Cage Nanozyme for the Targeted Treatment of Keratomycosis.

Keratomycosis, caused by pathogenic fungi, is an intractable blinding eye disease. Corneal penetration is an essential requirement for conventional antifungal medications to address keratomycosis. Due to the distinctive anatomical and physiological structure of the cornea, the therapeutic efficacy is hampered by the inadequate penetration capacity. Despite the emergence of diverse antifungal drug delivery systems and advanced antifungal nanomaterials, it has remained challenging to achieve corneal penetration over the past decade. This study fabricates a penetrative ionic organic molecular cage-based nanozyme (OMCzyme) for treating keratomycosis. The synthesis of OMCzyme involved two steps. Initially, the ionic OMC is synthesized by a [2+3] cycloimination reaction of triformylphloroglucinol and 2,3-diaminopropionic acid. Subsequently, OMCzyme is fabricated by coordination of Fe2⁺ with carboxyl anions and phenolic hydroxyls in the organic cage, and further deposition of silver nanoparticles on the surface of OMC-Fe complex. The as-prepared OMCzyme demonstrates excellent water dispersion, peroxidase-like activity, in vitro and in vivo biocompatibility, and corneal penetration. Notably, the nanozyme displays targeted antifungal activity, effectively combating Fusarium solani with negligible cytotoxicity toward human corneal epithelial cells. The hybrid mimic is further demonstrated to be effective in treating keratomycosis in mice, indicating the potential of OMCzyme for curing fungal infectious diseases.

The involvement of circulating miR-146a and miR-27a in patients with atherosclerotic cardiovascular disease after SARS-CoV-2 infection.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is a group of clinical diseases based on pathology of atherosclerosis that is the leading cause of mortality worldwide. There is a bidirectional interaction between ASCVD and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alterations in circulating miRNAs levels are involved in the development of ASCVD in patients infected with SARS-CoV-2, however, the correlation between ASCVD co-infection with SARS-CoV-2 and alterations of cardiac-specific miRNAs is not well understood. HYPOTHESIS: The circulating miR-146a and miR-27a are involved in bidirectional interactions between ASCVD and SARS-CoV-2 infections. METHODS: Circulating miR-146a and miR-27a levels were measured in serum and PBMCs deriving from ASCVD patients and controls after SARS-CoV-2 infection by qRT-PCR analysis. The levels of neutralizing antibodies-resistant SARS-CoV-2 in human serum was determined by competitive magnetic particle chemiluminescence method. Interleukin (IL)-6 levels were detected by automatic biochemical analyzer using electrochemiluminescence. RESULTS: Significant downregulation of circulating miR-146a and upregulation of miR-27a in ASCVD patients after infection with SARS-CoV-2 compared with controls were observed, among which the alterations were more evident in ASCVD patients comorbid with hyperlipidemia and diabetes mellitus. Consistently, correlation analysis revealed that serum miR-146a and miR-27a levels were associated with the levels of lipids and glucose, inflammatory response, and immune function in ASCVD patients. Remarkably, SARS-CoV-2 S protein RBD stimulation of PBMCs derived from both ASCVD and controls significantly downregulated miR-146a, upregulated miR-27a expression levels, and promoted IL-6 release in vitro. CONCLUSIONS: The circulating miR-146a and miR-27a are involved in metabolism, inflammation, and immune levels in patients with ASCVD after SARS-CoV-2 infection, laying the foundation for the development of strategies to prevent the risk of SARS-CoV-2 infection in ASCVD patients.

CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells.

BACKGROUND: Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown. METHODS: Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. RESULTS: CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9-Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth. CONCLUSIONS: We propose a novel regulatory paradigm in which the activation of CDK7/CDK9-Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.

Tannic acids and proanthocyanidins in tea inhibit SARS-CoV-2 variants infection.

The COVID-19 pandemic has caused hundreds million cases and millions death as well as continues to infect human life in the world since late of 2019. The breakthrough infection caused from mutation of SARS-CoV-2 is rising even the vaccinated population has been increasing. Currently, the severe threat posed by SARS-CoV-2 has been alleviated worldwide, and the situation has transitioned to coexisting with the virus. The dietary food with antiviral activities may improve to prevent virus infection for living with COVID-19 pandemic. Teas containing enriched phenolic ingredients such as tannins have been reported to be antitumor agents as well as be good inhibitors for coronavirus. This study developed a highly sensitive and selective ultra-high performance liquid chromatography-high resolution mass spectrometric method for quantification of tannic acids, a hydrolysable tannin, and proanthocyanidins, a condense tannin, in teas with different levels of fermentation. The in vitro pseudoviral particles (Vpp) infection assay was used to evaluate the inhibition activities of various teas. The results of current research demonstrate that the tannins in teas are effective inhibitors against infection of SARS-CoV-2 and its variants.