Construction of a Cancer Stem Cell related Histone Acetylation Regulatory Genes Prognostic Model for Hepatocellular Carcinoma via Bioinformatics Analysis: Implications for Tumor Chemotherapy and Immunity.

BACKGROUND: Cancer stem cells (CSC) play an important role in the development of Liver Hepatocellular Carcinoma (LIHC). However, the regulatory mechanisms between acetylation- associated genes (HAGs) and liver cancer stem cells remain unclear. OBJECTIVE: To identify a set of histone acetylation genes (HAGs) with close associations to liver cancer stem cells (LCSCs), and to construct a prognostic model that facilitates more accurate prognosis assessments for LIHC patients. METHODS: LIHC expression data were downloaded from the public databases. Using mRNA expression- based stemness indices (mRNAsi) inferred by One-Class Logistic Regression (OCLR), Differentially Expressed Genes (DEGs) (mRNAsi-High VS. mRNAsi-Low groups) were intersected with DEGs (LIHC VS. normal samples), as well as histone acetylation-associated genes (HAGs), to obtain mRNAsi-HAGs. A risk model was constructed employing the prognostic genes, which were acquired through univariate Cox and Least Shrinkage and Selection Operator (LASSO) regression analyses. Subsequently, independent prognostic factors were identified via univariate and multivariate Cox regression analyses and then a nomogram for prediction of LIHC survival was developed. Additionally, immune infiltration and drug sensitivity analysis were performed to explore the relationships between prognostic genes and immune cells. Finally, the expressions of selected mRNAsi-HAGs were validated in the LIHC tumor sphere by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) assay and western blot analysis. RESULTS: Among 13 identified mRNAsi-HAGs, 3 prognostic genes (HDAC1, HDAC11, and HAT1) were selected to construct a risk model (mRNAsi-HAGs risk score = 0.02 * HDAC1 + 0.09 * HAT1 + 0.05 * HDAC11). T-stage, mRNAsi, and mRNAsi-HAGs risk scores were identified as independent prognostic factors to construct the nomogram, which was proved to predict the survival probability of LIHC patients effectively. We subsequently observed strongly positive correlations between mRNAsi-HAGs risk score and tumor-infiltrating T cells, B cells and macrophages/monocytes. Moreover, we found 8 drugs (Mitomycin C, IPA 3, FTI 277, Bleomycin, Tipifarnib, GSK 650394, AICAR and EHT 1864) had significant correlations with mRNAsi-HAGs risk scores. The expression of HDAC1 and HDAC11 was higher in CSC-like cells in the tumor sphere. CONCLUSION: This study constructed a mRNAsi and HAGs-related prognostic model, which has implications for potential immunotherapy and drug treatment of LIHC.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Characterization of the neural circuitry of the auditory thalamic reticular nucleus and its potential role in salicylate-induced tinnitus.

Introduction: Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The condition is believed to result from neuroplastic alterations in the auditory centers, characterized by heightened spontaneous neural activities and increased synchrony due to an imbalance between excitation and inhibition. However, the role of the thalamic reticular nucleus (TRN), a structure composed exclusively of GABAergic neurons involved in thalamocortical oscillations, in the pathogenesis of tinnitus remains largely unexplored. Methods: We induced tinnitus in mice using sodium salicylate and assessed tinnitus-like behaviors using the Gap Pre-Pulse Inhibition of the Acoustic Startle (GPIAS) paradigm. We utilized combined viral tracing techniques to identify the neural circuitry involved and employed immunofluorescence and confocal imaging to determine cell types and activated neurons. Results: Salicylate-treated mice exhibited tinnitus-like behaviors. Our tracing clearly delineated the inputs and outputs of the auditory-specific TRN. We discovered that chemogenetic activation of the auditory TRN significantly reduced the salicylate-evoked rise in c-Fos expression in the auditory cortex. Discussion: This finding posits the TRN as a potential modulatory target for tinnitus treatment. Furthermore, the mapped sensory inputs to the auditory TRN suggest possibilities for employing optogenetic or sensory stimulations to manipulate thalamocortical activities. The precise mapping of the auditory TRN-mediated neural pathways offers a promising avenue for designing targeted interventions to alleviate tinnitus symptoms.

MiR-4763-3p accelerates lipopolysaccharide-induced cardiomyocyte apoptosis and inflammatory response by targeting IL10RA.

In order to investigate miR-4763-3p and associated genes' roles in myocarditis, AC16 cell line was divided into LPS + miR-4763-3p inhibitor, LPS + NC inhibitor, LPS + miR-4763-3p inhibitor + si-IL10RA and NC groups, and Q-PCR was used to find out whether miR-4763-3p was expressed; Targetscan, Genecards, and MiRDB were used to estimate the miR-4763-3p target; Targetscan was used to display binding sites. Western blot assay was undertaken to detect Bax, Bcl-2, and IL10RA expression. Proliferation and apoptosis were processed using CCK8 and the flow cytometry assay, respectively. Migration and invasion were confirmed utilizing Transwell test. ELISA assay was processed to show the content of IL-6, IL-1ß, IL-10 and TGF-ß in the cell culture supernatant. After being exposed to LPS, cardiomyocyte cells expressed more miR-4763-3p. MiR-4763-3p inhibitor accelerated proliferation, migration and invasion behavior, while it also decreased apoptosis rate in LPS-treated cardiomyocyte cells. MiR-4763-3p inhibitor attenuated the inflammatory response by up-regulating Bax expression and down-regulating Bcl-2 level in LPS-treated cardiomyocyte cells. In cardiomyocyte cells treated with LPS, MiR-4763-3p expression was elevated. si-IL10RA The miR-4763-3p inhibitor restored its effects. MiR-4763-3p accelerates lipopolysaccharide-induced cardiomyocyte apoptosis and inflammatory response by targeting IL10RA, which might be a potential target for myocarditis.

[Human Accumulation and Toxic Effects of Microplastics：A Critical Review].

The effect of microplastics on the ecological environment and human health has become a topical issue， and research on the risks and harmful effects of MPs on human health in particular has attracted widespread attention. Due to the characteristics of small size， low degradability， and easy migration， MPs continuously migrate from the environment to the human body， and their main exposure pathways are oral ingestion， inhalation， and dermal contact， with the main exposure media being food， drinking water， dust， personal care products， etc. MPs have been detected in organs， fluids， and excreta of digestive， respiratory， cardiovascular， reproductive systems， etc. The abundance range of MPs in the human body is 0-1 206.94 particles per gram. After entering the human body， MPs can cause cytotoxicity， mitochondrial toxicity， DNA damage， cell membrane damage， and other effects on human cells and organs， leading to serious consequences such as local inflammation， ecological imbalance， metabolic disorders， etc.， in various systems. Owing to their small specific surface area， they can also adsorb pollutants such as heavy metals， organic pollutants， antibiotics， pathogens， and harmful microorganisms， causing combined toxicity and immunotoxicity. In the end， we highlighted general deficiencies in existing studies and provided directions for future research on the influence of MPs on human health.

Microglial activation in the lateral amygdala promotes anxiety-like behaviors in mice with chronic moderate noise exposure.

BACKGROUND: Long-term non-traumatic noise exposure, such as heavy traffic noise, can elicit emotional disorders in humans. However, the underlying neural substrate is still poorly understood. METHODS: We exposed mice to moderate white noise for 28 days to induce anxiety-like behaviors, measured by open-field, elevated plus maze, and light-dark box tests. In vivo multi-electrode recordings in awake mice were used to examine neuronal activity. Chemogenetics were used to silence specific brain regions. Viral tracing, immunofluorescence, and confocal imaging were applied to define the neural circuit and characterize the morphology of microglia. RESULTS: Exposure to moderate noise for 28 days at an 85-dB sound pressure level resulted in anxiety-like behaviors in open-field, elevated plus maze, and light-dark box tests. Viral tracing revealed that fibers projecting from the auditory cortex and auditory thalamus terminate in the lateral amygdala (LA). A noise-induced increase in spontaneous firing rates of the LA and blockade of noise-evoked anxiety-like behaviors by chemogenetic inhibition of LA glutamatergic neurons together confirmed that the LA plays a critical role in noise-induced anxiety. Noise-exposed animals were more vulnerable to anxiety induced by acute noise stressors than control mice. In addition to these behavioral abnormalities, ionized calcium-binding adaptor molecule 1 (Iba-1)-positive microglia in the LA underwent corresponding morphological modifications, including reduced process length and branching and increased soma size following noise exposure. Treatment with minocycline to suppress microglia inhibited noise-associated changes in microglial morphology, neuronal electrophysiological activity, and behavioral changes. Furthermore, microglia-mediated synaptic phagocytosis favored inhibitory synapses, which can cause an imbalance between excitation and inhibition, leading to anxiety-like behaviors. CONCLUSIONS: Our study identifies LA microglial activation as a critical mediator of noise-induced anxiety-like behaviors, leading to neuronal and behavioral changes through selective synapse phagocytosis. Our results highlight the pivotal but previously unrecognized roles of LA microglia in chronic moderate noise-induced behavioral changes.

Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome.

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

Development of a supportive care framework for breast cancer survivor's unmet needs: A modified Delphi study.

AIM: To establish a supportive care framework for addressing unmet needs among breast cancer survivors, providing practical guidance for healthcare providers to assess and manage these needs, ultimately enhancing the health outcomes and quality of life of breast cancer survivors. DESIGN: We conducted a two-round Delphi survey to gather expert opinions regarding the unmet needs supportive care framework for breast cancer survivors. METHODS: Initial framework identification and inquiry questionnaire creation was achieved via literature search and expert group discussions, which included 15 experts from nursing practice, clinical medicine, nursing management and nursing education was conducted using a Delphi survey. To establish consensus, a two-round Delphi poll was done, using criteria based on the mean (≥4.0), coefficient of variation (CV < 0.25) and percentage for entire score (≥20%). RESULTS: Experts reached a consensus, leading to six care modules, and 28 care entries: Tumour Detection Support (three care entries), Management of Complications of Antitumor Therapy (seven care entries), Healthy Lifestyle Management (five care entries), Sexual and Fertility Support (four care entries), Psychosocial Support (four care entries) and Resource and Linkage Support (five care entries). CONCLUSION: To address breast cancer survivors' unmet needs, a supportive framework was developed to actively enhance their health outcomes. However, further refinement and feasibility testing using mobile devices or artificial intelligence are required. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: This pioneering framework prioritises addressing unmet needs and equips healthcare providers to assess and manage these needs effectively, facilitating the implementation of programs aimed at improving the well-being of breast cancer survivors. REPORTING METHOD: This study was guided by a modified guideline for the Conducting and Reporting of Delphi Studies (CREDES) (Palliative Medicine, 31(8), 684, 2017). PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution. TRIAL AND PROTOCOL REGISTRATION: The Delphi study methodology does not require registration.

Maresin1 ameliorates MSU crystal-induced inflammation by upregulating Prdx5 expression.

BACKGROUND: Maresin1 (MaR1) is a potent lipid mediator that exhibits significant anti-inflammatory activity in the context of several inflammatory diseases. A previous study reported that MaR1 could suppress MSU crystal-induced peritonitis in mice. To date, the molecular mechanism by which MaR1 inhibits MSU crystal-induced inflammation remains poorly understood. METHODS: Mousebone marrow-derived macrophages (BMDMs) were pretreated with MaR1 and then stimulated with FAs (palmitic, C16:0 and stearic, C18:0) plus MSU crystals (FAs + MSUc). In vivo, the effects of MaR1 treatment or Prdx5 deficiency on MSUc induced peritonitis and arthritis mouse models were evaluated. RESULTS: The current study indicated that MaR1 effectively suppressed MSUc induced inflammation in vitro and in vivo. MaR1 reversed the decrease in Prdx5 mRNA and protein levels induced by FAs + MSUc. Further assays demonstrated that MaR1 acceleratedPrdx5 expression by regulating the Keap1-Nrf2 signaling axis. Activation of AMPK by Prdx5 improved homeostasis of the TXNIP and TRX proteins and alleviated mitochondrial fragmentation. In addition, Prdx5 overexpression inhibited the expression of CPT1A, a key enzyme for fatty acid oxidation (FAO). Prdx5 protected against defects in FA + MSUc induced FAO and the urea cycle. CONCLUSION: MaR1 treatment effectively attenuated MSUc induced inflammation by upregulating Prdx5 expression. Our study provides a new strategy by which Prdx5 may help prevent acute gout attacks.

Characterization of Anxiety-Like Behaviors and Neural Circuitry following Chronic Moderate Noise Exposure in Mice.

BACKGROUND: Commonly encountered nontraumatic, moderate noise is increasingly implicated in anxiety; however, the neural substrates underlying this process remain unclear. OBJECTIVES: We investigated the neural circuit mechanism through which chronic exposure to moderate-level noise causes anxiety-like behaviors. METHODS: Mice were exposed to chronic, moderate white noise [85 decibel (dB) sound pressure level (SPL)], 4 h/d for 4 wk to induce anxiety-like behaviors, which were assessed by open field, elevated plus maze, light-dark box, and social interaction tests. Viral tracing, immunofluorescence confocal imaging, and brain slice patch-clamp recordings were used to characterize projections from auditory brain regions to the lateral amygdala. Neuronal activities were characterized by in vivo multielectrode and fiber photometry recordings in awake mice. Optogenetics and chemogenetics were used to manipulate specific neural circuitry. RESULTS: Mice chronically (4 wk) exposed to moderate noise (85 dB SPL, 4 h/d) demonstrated greater neuronal activity in the lateral amygdala (LA), and the LA played a critical role in noise-induced anxiety-like behavior in these model mice. Viral tracing showed that the LA received monosynaptic projections from the medial geniculate body (MG) and auditory cortex (ACx). Optogenetic excitation of the MG→LA or ACx→LA circuits acutely evoked anxiety-like behaviors, whereas their chemogenetic inactivation abolished noise-induced anxiety-like behavior. Moreover, mice chronically exposed to moderate noise were more susceptible to acute stress, with more neuronal firing in the LA, even after noise withdrawal. DISCUSSION: Mice exposed to 4 wk of moderate noise (85 dB SPL, 4 h/d) demonstrated behavioral and physiological differences compared to controls. The neural circuit mechanisms involved greater excitation from glutamatergic neurons of the MG and ACx to LA neurons under chronic, moderate noise exposure, which ultimately promoted anxiety-like behaviors. Our findings support the hypothesis that nontraumatic noise pollution is a potentially serious but unrecognized public health concern. https://doi.org/10.1289/EHP12532.

Prediction of axillary lymph node metastasis in early breast cancer patients with ultrasonic videos based deep learning.

Objective: To develop a deep learning (DL) model for predicting axillary lymph node (ALN) metastasis using dynamic ultrasound (US) videos in breast cancer patients. Methods: A total of 271 US videos from 271 early breast cancer patients collected from Xiang'an Hospital of Xiamen University andShantou Central Hospitabetween September 2019 and June 2021 were used as the training, validation, and internal testing set (testing set A). Additionally, an independent dataset of 49 US videos from 49 patients with breast cancer, collected from Shanghai 10th Hospital of Tongji University from July 2021 to May 2022, was used as an external testing set (testing set B). All ALN metastases were confirmed using pathological examination. Three different convolutional neural networks (CNNs) with R2 + 1D, TIN, and ResNet-3D architectures were used to build the models. The performance of the US video DL models was compared with that of US static image DL models and axillary US examination performed by ultra-sonographers. The performances of the DL models and ultra-sonographers were evaluated based on accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Additionally, gradient class activation mapping (Grad-CAM) technology was also used to enhance the interpretability of the models. Results: Among the three US video DL models, TIN showed the best performance, achieving an AUC of 0.914 (95% CI: 0.843-0.985) in predicting ALN metastasis in testing set A. The model achieved an accuracy of 85.25% (52/61), with a sensitivity of 76.19% (16/21) and a specificity of 90.00% (36/40). The AUC of the US video DL model was superior to that of the US static image DL model (0.856, 95% CI: 0.753-0.959, P<0.05). The Grad-CAM technology confirmed the heatmap of the model, which highlighted important subregions of the keyframe for ultra-sonographers' review. Conclusion: A feasible and improved DL model to predict ALN metastasis from breast cancer US video images was developed. The DL model in this study with reliable interpretability would provide an early diagnostic strategy for the appropriate management of axillary in the early breast cancer patients.

Effects of Career Adaptability and Self-Efficacy on Transition Shock Among Newly Graduated Nurses During the COVID-19 Pandemic: A Survey Conducted in China.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak has increased the work pressure of nurses worldwide, and managers must provide support and assistance for the transition period of newly graduated nurses. METHOD: A cross-sectional design was adopted to collect a sample of 318 newly graduated nurses from six hospitals in China during the COVID-19 pandemic. Data were collected using a questionnaire that consisted of a demographic questionnaire, the Transition Shock Scale (2015), the Career Adapt-Ability Scale (2012), and the General Self-Efficacy Scale (2001). RESULTS: The transition shock of newly graduated nurses was 3.77 ± 0.48 in China. Regression analysis showed that transition shock among newly graduated nurses was predicted by career adaptability, general self-efficacy, living with one's parents, and education level, which accounted for 37.7% of the variance in transition shock. CONCLUSION: Newly graduated nurses experienced a relatively high level of transition shock in China during the COVID-19 pandemic. Managers may offer continuing education to reduce the transition shock of newly graduated nurses based on the factors that affect their transition shock. [J Contin Educ Nurs. 2023;54(11):524-532.].

Distinct roles of the two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA Pol II transcription elongation.

The super elongation complex (SEC) containing P-TEFb plays a critical role in regulating transcription elongation. AFF1 and AFF4, members of the AF4/FMR2 family, act as central scaffold proteins of SEC and are associated with various human diseases. However, their precise roles in transcriptional control remain unclear. We here reveal differences in the genomic distribution patterns of AFF1 and AFF4 around transcription start sites (TSSs). AFF1 mainly binds upstream of the TSSs, while AFF4 is enriched downstream of the TSSs. Notably, disruption of AFF4 results in slow elongation and early termination in a subset of AFF4 bound active genes, whereas AFF1 deletion leads to fast elongation and transcriptional readthrough in the same gene subset. Additionally, AFF1 knockdown increases AFF4 levels at chromatin, and vice versa. In summary, these findings demonstrate that AFF1 and AFF4 function antagonistically to regulate Pol II transcription.

Clinical evidence of three traditional Chinese medicine drugs and three herbal formulas for COVID-19: A systematic review and meta-analysis of the Chinese population.

BACKGROUND: The coronavirus disease 2019 (COVID-19) continues to spread worldwide. Integrated Chinese and Western medicine have had some successes in treating COVID-19. OBJECTIVE: This study aims to evaluate the efficacy and safety of three traditional Chinese medicine drugs and three herbal formulas (3-drugs-3-formulas) in patients with COVID-19. SEARCH STRATEGY: Relevant studies were identified from 12 electronic databases searched from their establishment to April 7, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs), non-RCTs and cohort studies that evaluated the effects of 3-drugs-3-formulas for COVID-19. The treatment group was treated with one of the 3-drugs-3-formulas plus conventional treatment. The control group was treated with conventional treatment. DATA EXTRACTION AND ANALYSIS: Two evaluators screened and selected literature independently, then extracted basic information and assessed risk of bias. The treatment outcome measures were duration of main symptoms, hospitalization time, aggravation rate and mortality. RevMan 5.4 was used to analyze the pooled results reported as mean difference (MD) with 95% confidence interval (CI) for continuous data and risk ratio (RR) with 95% CI for dichotomous data. RESULTS: Forty-one studies with a total of 13,260 participants were identified. Our analysis suggests that compared with conventional treatment, the combination of 3-drugs-3-formulas might shorten duration of fever (MD = -1.39; 95% CI: -2.19 to -0.59; P < 0.05), cough (MD = -1.57; 95% CI: -2.16 to -0.98; P < 0.05) and fatigue (MD = -1.36; 95% CI: -2.21 to -0.51; P < 0.05), decrease length of hospital stay (MD = -2.62; 95% CI -3.52 to -1.72; P < 0.05), the time for nucleic acid conversion (MD = -2.92; 95% CI: -4.26 to -1.59; P < 0.05), aggravation rate (RR = 0.49; 95% CI: 0.38 to 0.64; P < 0.05) and mortality (RR = 0.34; 95% CI: 0.19 to 0.62; P < 0.05), and increase the recovery rate of chest computerized tomography manifestations (RR = 1.22; 95% CI: 1.14 to 1.3; P < 0.05) and total effectiveness (RR = 1.24; 95% CI: 1.09 to 1.42; P < 0.05). CONCLUSION: The 3-drugs-3-formulas can play an active role in treating all stages of COVID-19. No severe adverse events related to 3-drugs-3-formulas were observed. Hence, 3-drugs-3-formulas combined with conventional therapies have effective therapeutic value for COVID-19 patients. Further long-term high-quality studies are essential to demonstrate the clinical benefits of each formula. Please cite this article as: You LZ, Dai QQ, Zhong XY, Yu DD, Cui HR, Kong YF, Zhao MZ, Zhang XY, Xu QQ, Guan ZY, Wei XX, Zhang XC, Han SJ, Liu WJ, Chen Z, Zhang XY, Zhao C, Jin YH, Shang HC. Clinical evidence of three traditional Chinese medicine drugs and three herbal formulas for COVID-19: A systematic review and meta-analysis of the Chinese population. J Integr Med. 2023; 21(5): 441-454.

Peficitinib ameliorates doxorubicin-induced cardiotoxicity by suppressing cellular senescence and enhances its antitumor activity.

Irreversible cardiotoxicity limits the clinical applications of doxorubicin (DOX). Cardiotoxicity can be detected early using clinical assessment; however, effective preventive measures are still lacking. Peficitinib (ASP015K), a JAK (Janus kinase) inhibitor, is a potent anti-inflammatory agent in autoimmune diseases. Nevertheless, little research has been conducted on anti-ageing and anti-tumour therapies. In this study, we investigated whether ASP015K could attenuate DOX-induced cardiotoxicity through its anti-ageing effects and whether it would affect the tumour treatment effect of DOX by establishing senescence, acute heart injury, and xenograft models. We observed that ASP015K could antagonise the senescence induced by various factors, including hydrogen peroxide and DOX. In addition, ASP015K treatment significantly alleviated cardiac function damage, histopathological deterioration, myocardial fibrosis, and oxidative damage in acute injury mouse models. ASP015K enhanced the sensitivity of tumour cells to DOX therapy and significantly slowed down the tumour growth rate and tumour volume in the xenograft mouse model. Therefore, ASP015K is expected to be developed as a potential cardioprotective agent to prevent or reduce the cardiotoxic side effects of anthracyclines in chemotherapy.

Artesunate alleviates 5-fluorouracil-induced intestinal damage by suppressing cellular senescence and enhances its antitumor activity.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent diagnosed malignancies and one of the leading causes of cancer-related deaths worldwide. 5-Fluorouracil (5-FU) and its combination regimen are commonly used as primary chemotherapeutic agents for advanced CRC. Intestinal mucositis is one of the most frequent side effects of 5-FU. Artesunate (Arte) is derived from the wormwood plant Artemisia annua. Arte is not only effective against malaria but also diabetes, atherosclerosis, inflammation, and other conditions. The mechanism by which 5-FU damages the intestinal tract is unclear, and there is no standard treatment for diarrhea caused by 5-FU. Therefore, it is critical to discover novel and promising therapeutic drugs for 5-FU side effect treatment. METHODS: The morphology and expression of genes and proteins associated with the aging of HUVECs, HIECs, and intestinal tissues were compared to the those of the control group. The cell lines and tissues were evaluated by SA-ß-Gal staining, Western blotting, and RT‒qPCR. HIEC and HCT116 cell viability was assessed in vitro by a CCK-8 assay and in vivo by a subcutaneous tumor mouse assay. Tumor cell proliferation and apoptosis was evaluated by immunohistochemistry. RESULTS: Here, we report that Arte alleviates the adverse side effects caused by 5-FU in intestinal tissue, and that 5-FU-induced intestinal damage is associated with drug-induced chemical inflammation and an increase in the proportion of senescent cells. Arte decreases the ratio of SA-ß-Gal-positive cells and downregulated the expression of aging-related proteins (p53, p16) and aging-related genes (p53, p21). Mechanistically, Arte relieves intestinal injury by inhibiting mTOR expression, which is associated with the regulation of aging. Moreover, Arte suppresses the p38MAPK and NF-κB signaling pathways, which are related to inflammation regulation. In addition, the combined therapy of Arte plus 5-FU significantly decreases cancer cell viability in vitro. Arte and 5-FU synergistically reduce the growth of colorectal cancer (CRC) xenografts in vivo. CONCLUSIONS: Overall, our findings point to the crucial treatment effect of Arte on inflammation, intestinal cell senescence, and CRC cell proliferation and offer a new option for CRC treatment.

Structural, Electronic and Optical Properties of Some New Trilayer Van de Waals Heterostructures.

Constructing two-dimensional (2D) van der Waals (vdW) heterostructures is an effective strategy for tuning and improving the characters of 2D-material-based devices. Four trilayer vdW heterostructures, BP/BP/MoS2, BlueP/BlueP/MoS2, BP/graphene/MoS2 and BlueP/graphene/MoS2, were designed and simulated using the first-principles calculation. Structural stabilities were confirmed for all these heterostructures, indicating their feasibility in fabrication. BP/BP/MoS2 and BlueP/BlueP/MoS2 lowered the bandgaps further, making them suitable for a greater range of applications, with respect to the bilayers BP/MoS2 and BlueP/MoS2, respectively. Their absorption coefficients were remarkably improved in a wide spectrum, suggesting the better performance of photodetectors working in a wide spectrum from mid-wave (short-wave) infrared to violet. In contrast, the bandgaps in BP/graphene/MoS2 and BlueP/graphene/MoS2 were mostly enlarged, with a specific opening of the graphene bandgap in BP/graphene/MoS2, 0.051 eV, which is much larger than usual and beneficial for optoelectronic applications. Accompanying these bandgap increases, BP/graphene/MoS2 and BlueP/graphene/MoS2 exhibit absorption enhancement in the whole infrared, visible to deep ultraviolet or solar blind ultraviolet ranges, implying that these asymmetrically graphene-sandwiched heterostructures are more suitable as graphene-based 2D optoelectronic devices. The proposed 2D trilayer vdW heterostructures are prospective new optoelectronic devices, possessing higher performance than currently available devices.

Network pharmacology and molecular docking prediction, combined with experimental validation to explore the potential mechanism of Qishen Yiqi pills against HF-related cognitive dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Qishen Yiqi Pills (QSYQ) is a classical herbal formula for treating heart failure (HF) and has potential efficacy in improving cognitive function. The latter is one of the most common complications in patients with HF. However, there is no study on treating HF-related cognitive dysfunction by QSYQ. AIMS OF THE STUDY: The study aims to investigate the effect and mechanism of QSYQ on treating post-HF cognitive dysfunction based on network pharmacology and experimental validation. MATERIALS AND METHODS: Network pharmacology analysis and molecular docking was used to explore endogenous targets of QSYQ in treating cognitive impairment. Ligation of the anterior descending branch of the left coronary artery and sleep deprivation (SD) were used to induce HF-related cognitive dysfunction in rats. The efficacy and potential signal targets of QSYQ were then verified by functional evaluation, pathological staining, and molecular biology experiments. RESULTS: 384 common targets were identified by intersecting QSYQ 'compound targets' and 'cognitive dysfunction' disease targets. KEGG analysis showed these targets were enriched to the cAMP signal, and four marks responsible for regulating the cAMP signal were successfully docked with core compounds of QSYQ. Animal experiments demonstrated that QSYQ significantly ameliorated cardiac function and cognitive function in rats suffering from HF and SD, inhibited the reduction of cAMP and BDNF content, reversed the upregulation of PDE4 and downregulation of CREB, suppressed the loss of neurons, and restored the expression of synaptic protein PSD95 in the hippocampus. CONCLUSION: This study clarified that QSYQ could improve HF-related cognitive dysfunction by modulating cAMP-CREB-BDNF signals. It provides a rich basis for the potential mechanism of QSYQ in the treatment of heart failure with cognitive dysfunction.

Artesunate ameliorates irinotecan-induced intestinal injury by suppressing cellular senescence and significantly enhances anti-tumor activity.

Irinotecan (CPT-11) is a topoisomerase I inhibitor that was approved for cancer treatment in 1994. To date, this natural product derivative remains the world's leading antitumor drug. However, the clinical application of irinotecan is limited due to its side effects, the most troubling of which is intestinal toxicity. In addition, irinotecan has certain toxicity to cells and even causes cellular senescence. Committed to developing alternatives to prevent these adverse reactions, we evaluated the activity of artesunate, which has never been tested in this regard despite its biological potential. Irinotecan accelerated the process of aging in vivo and in vitro, and we found that this was mainly caused by activating mTOR signaling targets. Artesunate inhibited the activity of mTOR, thereby alleviating the aging process. Our study found that artesunate treatment improved irinotecan-induced intestinal inflammation by reducing the levels of TNF-α, IL1, and IL6; reducing inflammatory infiltration of the colonic ileum in mice; and preventing irinotecan-induced intestinal damage by reducing weight loss and improving intestinal length. In addition, in mouse xenograft tumor models, artesunate and irinotecan significantly inhibited tumor growth in mice.

Unified ICH quantification and prognosis prediction in NCCT images using a multi-task interpretable network.

With the recent development of deep learning, the regression, classification, and segmentation tasks of Computer-Aided Diagnosis (CAD) using Non-Contrast head Computed Tomography (NCCT) for spontaneous IntraCerebral Hematoma (ICH) have become popular in the field of emergency medicine. However, a few challenges such as time-consuming of ICH volume manual evaluation, excessive cost demanding patient-level predictions, and the requirement for high performance in both accuracy and interpretability remain. This paper proposes a multi-task framework consisting of upstream and downstream components to overcome these challenges. In the upstream, a weight-shared module is trained as a robust feature extractor that captures global features by performing multi-tasks (regression and classification). In the downstream, two heads are used for two different tasks (regression and classification). The final experimental results show that the multi-task framework has better performance than single-task framework. And it also reflects its good interpretability in the heatmap generated by Gradient-weighted Class Activation Mapping (Grad-CAM), which is a widely used model interpretation method, and will be presented in subsequent sections.