Deciphering the role of cuproptosis-related lncRNAs in shaping the lung cancer immune microenvironment: A comprehensive prognostic model.

Cuproptosis plays an important role in cancer, but its role in lung cancer remains unknown. Transcriptional profiles, clinical details and mutation data were acquired from the Cancer Genome Atlas database through a variety of methods. The analysis of this publicly available data was comprehensively performed using R software along with its relevant packages, ensuring a thorough examination of the information. In this study, we conducted a detailed analysis of cuproptosis-related genes and lncRNA co-expression, identifying 129 relevant lncRNAs and establishing a prognostic model with four key lncRNAs (LINC00996, RPARP-AS1, SND1-IT1, TMPO-AS1). Utilizing data from TCGA and GEO databases, the model effectively categorized patients into high- and low-risk groups, showing significant survival differences. Correlation analysis highlighted specific relationships between individual lncRNAs and cuproptosis genes. Our survival analysis indicated a higher survival rate in the low-risk group across various cohorts. Additionally, the model's predictive accuracy was confirmed through independent prognostic analysis and ROC curve evaluations. Functional enrichment analysis revealed distinct biological pathways and immune functions between risk groups. Tumour mutation load analysis differentiated high- and low-risk groups by their mutation profiles. Drug sensitivity analysis and immune infiltration studies using the CIBERSORT algorithm further elucidated the potential treatment responses in different risk groups. This comprehensive evaluation underscores the significance of lncRNAs in cuproptosis and their potential as biomarkers for lung cancer prognosis and immune microenvironment.

Identification of the novel markers of PPAR signalling affecting immune microenvironment and immunotherapy response of lung adenocarcinoma patients.

Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.

Association of TaD14-4D, a Gene Involved in Strigolactone Signaling, with Yield Contributing Traits in Wheat.

Tillering is a crucial agronomic trait of wheat; it determines yield and plant architecture. Strigolactones (SLs) have been reported to inhibit plant branching. D14, a receptor of SLs, has been described to affect tillering in rice, yet it has seldomly been studied in wheat. In this study, three TaD14 homoeologous genes, TaD14-4A, TaD14-4B, and TaD14-4D, were identified. TaD14-4A, TaD14-4B, and TaD14-4D were constitutively expressed, and TaD14-4D had a higher expression level in most tissues. TaD14 proteins were localized in both cytoplasm and nucleus. An SNP and a 22 bp insertion/deletion (Indel) at the exon regions of TaD14-4D were detected, forming three haplotypes, namely 4D-HapI, 4D-HapII, and 4D-HapIII. Due to the frameshift mutation in the coding region of 4D-HapII, the interaction of 4D-HapII with TaMAX2 and TaD53 was blocked, which led to the blocking of SL signal transduction. Based on the two variation sites, two molecular markers, namely dCAPS-250 and Indel-747, were developed. Association analysis suggested that haplotypes of TaD14-4D were associated with effective tillering number (ETN) and thousand kernel weight (TKW) simultaneously in four environments. The favorable haplotype 4D-HapIII underwent positive selection in global wheat breeding. This study provides insights into understanding the function of natural variations of TaD14-4D and develops two useful molecular markers for wheat breeding.

Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis.

A fundamental element of acute lung injury (ALI) is the inflammatory response, which can affect the entire respiratory system, including the respiratory tract and alveoli. Berberine has gained attention because of its anti-inflammatory effects. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and endoplasmic reticulum (ER) stress are involved in lung injury. Nrf2 also acts as a protein kinase-like ER kinase (PERK) substrate in heart disease. Therefore, this study investigated the effect of berberine against lipopolysaccharide (LPS)-induced ALI and the role of the PERK-mediated Nrf2/HO-1 signaling axis. Berberine promoted Nrf2 nuclear translocation and phosphorylation in vitro. After LPS stimulation, this effect was further enhanced, whereas inflammatory factor (IL-6 and IL-8) release and reactive oxygen species generation were significantly decreased. Berberine effectively alleviated lung injury by reducing lung edema and neutrophil infiltration. Berberine also significantly reduced histopathological inflammatory changes via inhibition of ER stress and activation of Nrf2 signaling. Thapsigargin-induced ER stress and small interference RNA (siRNA)-mediated Nrf2 inhibition abrogated the protective effects of berberine in vitro, whereas siRNA-mediated suppression of ER stress and sulforaphane-induced Nrf2 activation further improved those effects. Importantly, ER stress induction led to Nrf2 activation, whereas PERK depletion partly reduced the level of Nrf2 phosphorylation and translocation in LPS-induced cells. Therefore, berberine inhibits LPS-induced ALI through the PERK-mediated Nrf2/HO-1 signaling axis.

Heat shock factor C2a serves as a proactive mechanism for heat protection in developing grains in wheat via an ABA-mediated regulatory pathway.

High temperature at grain filling can severely reduce wheat yield. Heat shock factors (Hsfs) are central regulators in heat acclimation. This study investigated the role of TaHsfC2a, a member of the monocot-specific HsfC2 subclass, in the regulation of heat protection genes in Triticum aestivum. Three TaHsfC2a homoeologous genes were highly expressed in wheat grains during grain filling and showed only transient up-regulation in the leaves by heat stress but were markedly up-regulated by drought and abscisic acid (ABA) treatment. Overexpression of TaHsfC2a-B in transgenic wheat resulted in up-regulation of a suite of heat protection genes (e.g. TaHSP70d and TaGalSyn). Most TaHsfC2a-B target genes were heat, drought and ABA inducible. Transactivation analysis of two representative targets (TaHSP70d and TaGalSyn) showed that TaHsfC2a-B activated expression of reporters driven by these target promoters. Promoter mutagenesis analyses revealed that heat shock element is responsible for transactivation by TaHsfC2a-B and heat/drought induction. TaHsfC2a-B-overexpressing wheat showed improved thermotolerance but not dehydration tolerance. Most TaHsfC2a-B target genes were co-up-regulated in developing grains with TaHsfC2a genes. These data suggest that TaHsfC2a-B is a transcriptional activator of heat protection genes and serves as a proactive mechanism for heat protection in developing wheat grains via the ABA-mediated regulatory pathway.

Epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan, China during 2017-2022.

Background: Wuhan is located in the hinterland of China, in the east of Hubei Province, at the intersection of the Yangtze River and Hanshui River. It is a national historical and cultural city, an important industrial, scientific, and educational base, and a key transportation hub. There are many schools in Wuhan, with nearly a thousand of all kinds. The number of students is ~2.2 million, accounting for nearly one-fifth of the resident population; college or university students account for ~60% of the total student population. The geographical location of these colleges is relatively concentrated, and the population density is relatively high, making it prone to tuberculosis cluster epidemic. Objective: This study analyzed the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan, China, during 2017-2022 to provide the basis for the scientific development of tuberculosis prevention and control strategies and measures in schools. Methods: This study adopted the methods of descriptive epidemiology to analyze the epidemic characteristics of tuberculosis aggregation in schools in Wuhan from January 2017 to December 2022, collecting the relevant data on tuberculosis prevention and control in all kinds of schools in the city using Questionnaire Star, an application of the China network questionnaire survey, and analyze the influencing factors of tuberculosis aggregation by using multifactor logistic regression analysis. Results: From 2017 to 2022, 54 outbreaks of pulmonary tuberculosis aggregation in schools were reported in Wuhan, which involved 37 different schools, including 32 colleges or universities and five senior high schools; 176 cases were reported, among which 73 were positive for pathogens and 18 were rifampicin or izoniazid resistant. The median duration of a single cluster epidemic was 46 (26,368) days. Universities were more prone to cluster outbreaks than middle schools (χ2 = 105.160, P = 0.001), and the incidence rate among male students was higher than that of female students in cluster epidemics (χ2 = 12.970, P = 0.001). The multivariate logistic regression analysis results showed that boarding in school (OR = 7.60) is the risk factor for a tuberculosis cluster epidemic in schools. The small number of students (OR = 0.50), the location of the school in the city (OR = 0.60), carry out physical examinations for freshmen (OR = 0.44), carry out illness absence and cause tracking (OR = 0.05), dormitories and classrooms are regularly ventilated with open windows (OR = 0.16), strict implement the management of sick student's suspension from school (OR = 0.36), and seeking timely medical consultation (OR = 0.32) were the protective factors for a tuberculosis cluster epidemic in schools. Conclusion: We successfully identified the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan. The results revealed the influence and status of various factors and indicated ways for schools to improve their TB prevention and control measures in their daily activities. These measures can effectively help curb the cluster epidemic of tuberculosis in schools.

Can the new adipokine asprosin be a metabolic troublemaker for cardiovascular diseases? A state-of-the-art review.

Adipokines play a significant role in cardiometabolic diseases. Asprosin, a newly discovered adipokine, was first identified as a glucose-raising protein hormone. Asprosin also stimulates appetite and regulates glucose and lipid metabolism. Its identified receptors so far include Olfr734 and Ptprd. Clinical studies have found that asprosin may be associated with cardiometabolic diseases. Asprosin may have diagnostic and therapeutic potential in obesity, diabetes, metabolic syndrome and atherosclerotic cardiovascular diseases. Herein, the structure, receptors, and functions of asprosin and its relationship with cardiometabolic diseases are summarized based on recent findings.

Wheat WRKY genes TaWRKY2 and TaWRKY19 regulate abiotic stress tolerance in transgenic Arabidopsis plants.

WRKY-type transcription factors are involved in multiple aspects of plant growth, development and stress response. WRKY genes have been found to be responsive to abiotic stresses; however, their roles in abiotic stress tolerance are largely unknown especially in crops. Here, we identified stress-responsive WRKY genes from wheat (Triticum aestivum L.) and studied their functions in stress tolerance. Forty-three putative TaWRKY genes were identified and two multiple stress-induced genes, TaWRKY2 and TaWRKY19, were further characterized. TaWRKY2 and TaWRKY19 are nuclear proteins, and displayed specific binding to typical cis-element W box. Transgenic Arabidopsis plants overexpressing TaWRKY2 exhibited salt and drought tolerance compared with controls. Overexpression of TaWRKY19 conferred tolerance to salt, drought and freezing stresses in transgenic plants. TaWRKY2 enhanced expressions of STZ and RD29B, and bound to their promoters. TaWRKY19 activated expressions of DREB2A, RD29A, RD29B and Cor6.6, and bound to DREB2A and Cor6.6 promoters. The two TaWRKY proteins may regulate the downstream genes through direct binding to the gene promoter or via indirect mechanism. Manipulation of TaWRKY2 and TaWRKY19 in wheat or other crops should improve their performance under various abiotic stress conditions.

[Construction of strains for bioconversion of steroid key intermediates and intelligent industrial production].

Steroidal hormone pharmaceuticals are the second largest class of medicines after antibiotics. At present, the initial materials of the steroidal industry have shifted from sapogenins, which were extracted from plants of the genus Dioscore to phytosterols. As a byproduct of soybean oil production, phytosterols are readily available and of low prices. Androstenedione (AD), androstadiendione (ADD), 9α-hydroxy-androstenedione (9α-OH-AD) and a series of key intermediates used in the synthesis of steroidal pharmaceuticals can be produced from phytosterols by microbial transformation. Nevertheless, due to the long metabolic pathways, the byproducts and the complex regulation, traditional microbial screening, mutagenizing methods and the oil-water biphasic transformation systems are no longer suitable for current industrial production. A new generation strains for the production of key steroidal pharmaceutical intermediates have been constructed and an intelligent production process has been jointly developed by us and Zhejiang Xianju Junye Pharmaceutical Co. Ltd.. Taking these products and processes as an example, this article reviews the improvement of strains for the production of steroidal pharmaceutical intermediates and the development of biotransformation process on an industrial scale. With the development of synthetic biology, it is expected to develop a new generation of intermediates which are more suitable for the synthesis of steroidal medicines. Moreover, de novo biosynthesis the steroidal active pharmaceutical ingredients from glucose is also expected. The application of these new-generation strains constructed by biotechnology (BT) in modern factories based on informatization and intelligent technology (IT) will be more efficient and greener, and create remarkable social and economic values.

The Effects of Heat Treatment on Microstructure and Mechanical Properties of Selective Laser Melting 6061 Aluminum Alloy.

Selective laser melting technology can be used for forming curved panels of 6061 aluminum alloy thermal shield devices for the International Thermonuclear Experimental Reactor (ITER), in order to make the formed parts with better performance. This study proposes different heat treatment processes, including annealed treatment at 300 °C for 2 h, solution treatment at 535 °C and then aging at 175 °C over 2 h, to control the mechanical behavior of the 6061 aluminum alloy samples prepared by selective laser melting (SLM). The mechanical properties such as ductility, tensile strength, and hardness of SLM 6061 aluminum alloy were investigated, and the microstructure of the samples was analyzed. The eutectic silicon skeleton shape disappeared after annealing treatment at 300 °C for 2 h. The tensile strength decreased by 22.86% (from 315 MPa to 243 MPa of the deposited state samples), and the elongation increased from 2.01% to 6.89%. Moreover, the hardness reduced from 120.07 HV0.2 to 89.6 HV0.2. After solution aging, the unique microstructure of SLM disappeared. Furthermore, the precipitation of massive Si particles on the α-Al matrix increased, and a trace amount of the Mg2Si(ß) phase was generated. Compared with the deposited samples, the tensile strength decreased by 12.06%, while the hardness of specimens was 118.8 HV0.2. However, the elongation showed a remarkable increase of 297% (from 2.01% to 7.97%). Therefore, solution aging can critically improve the plasticity without losing significant tensile stress in the SLM 6061 aluminum alloy. This study proposes the use of SLM 6061 aluminum alloy for the thermal shields on the ITER and provides a reference for choosing a reasonable heat-treatment method for the optimal performance of the SLM 6061 aluminum alloy.

Transmission of multidrug-resistant Mycobacterium tuberculosis in Wuhan, China: A retrospective molecular epidemiological study.

ABSTRACT: How multidrug-resistant tuberculosis (MDR-TB) spreads and expands in Wuhan population is not clear. The study aimed to determine the transmission patterns of MDR-TB in Wuhan city, China, including 149 patients with MDR-TB.Tuberculosis isolates were genotyped by deletion-targeted multiplex polymerase chain reaction, mycobacterial interspersed repetitive unit-variable number tandem repeat typing, and sequencing of drug resistance-associated genes. The risk factors of genomic-clustering were analyzed with logistic regression. The genomic-clustering patients were deeply investigated.The analysis identified 111 unique and 11 clustered genotypes (38 isolates). The clustering rate was 25.50% and the minimum estimate proportion of recent transmission was 18.12%. Two clusters (5 isolates) shared the same mutation, the remain 9 clusters (33 isolates) had different mutation. Logistic regression showed that older than 60 years (adjusted OR 2.360, 95% CI:1.052-5.292) was an independent factor associated with the genomic-clustering of MDR-TB. Among the 38 genomic-clustering cases, 14 cases had epidemiological transmission links. The most common type of transmission link was social contact.The local transmission of MDR-TB in Wuhan was really an issue. The elderly population might be the high-risk groups for transmission of MDR-TB, and the community or public transportation might be the main transmission places.

Efficacy of Alprostadil in Preventing Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis.

This study aimed to determine the efficacy of alprostadil in preventing contrast-induced nephropathy (CIN). Eligible studies were searched using the keywords through the databases of PubMed, Cochrane, Embase, China Biological Medicine Database, China National Knowledge Infrastructure, and Vanfun. Quality evaluation of the included studies was conducted according to international evidence evaluation and recommended Grades of Recommendations Assessment, Development, and Evaluation standards. We included 29 studies with 5623 patients. Compared with hydration, 10 µg/d alprostadil or 20 µg/d alprostadil plus hydration significantly decreased the incidence of CIN. Compared with hydration, alprostadil plus hydration significantly reduced serum creatinine and blood urea nitrogen at 24, 48, and 72 hours and 7 days after coronary angiography (CAG). Alprostadil (20 µg/d) plus hydration significantly decreased serum cystatin versus hydration at 24, 48, and 72 hours after CAG. Compared with hydration, alprostadil plus hydration significantly increased glomerular filtration rate at 24 and 72 hours after CAG. Alprostadil plus hydration significantly decreased neutrophil gelatinase-associated lipocalin levels compared to hydration at 24, 48, and 72 hours after CAG. Alprostadil plus hydration significantly decreased urine macroglobulin versus hydration at 24 and 48 hours after CAG.

The Role of Major Transcription Factors in Solanaceous Food Crops under Different Stress Conditions: Current and Future Perspectives.

Plant growth, development, and productivity are adversely affected by environmental stresses such as drought (osmotic stress), soil salinity, cold, oxidative stress, irradiation, and diverse diseases. These impacts are of increasing concern in light of climate change. Noticeably, plants have developed their adaptive mechanism to respond to environmental stresses by transcriptional activation of stress-responsive genes. Among the known transcription factors, DoF, WRKY, MYB, NAC, bZIP, ERF, ARF and HSF are those widely associated with abiotic and biotic stress response in plants. Genome-wide identification and characterization analyses of these transcription factors have been almost completed in major solanaceous food crops, emphasizing these transcription factor families which have much potential for the improvement of yield, stress tolerance, reducing marginal land and increase the water use efficiency of solanaceous crops in arid and semi-arid areas where plant demand more water. Most importantly, transcription factors are proteins that play a key role in improving crop yield under water-deficient areas and a place where the severity of pathogen is very high to withstand the ongoing climate change. Therefore, this review highlights the role of major transcription factors in solanaceous crops, current and future perspectives in improving the crop traits towards abiotic and biotic stress tolerance and beyond. We have tried to accentuate the importance of using genome editing molecular technologies like CRISPR/Cas9, Virus-induced gene silencing and some other methods to improve the plant potential in giving yield under unfavorable environmental conditions.

Clinical efficacy of glucocorticoid on the treatment of patients with COVID-19 pneumonia: A single-center experience.

The aim of the present study was to identify the clinical efficacy of glucocorticoid therapy on the treatment of patients with Coronavirus Disease 2019 (COVID-19) pneumonia. Clinical and laboratory parameters were collected from 308 patients with COVID-19 pneumonia from the fever clinic of Wuhan Pulmonary Hospital (Wuhan City, Hubei Province, China) between January 14, 2020 and February 9, 2020, of which 216 patients received low-dose (equivalent of methylprednisolone 0.75-1.5 mg/kg/d) glucocorticoid treatment. The effect of glucocorticoid on imaging progress, adverse events, nucleic acid results and the outcomes were investigated. Lymphocyte count and C-reactive protein (CRP) significantly differed between the glucocorticoid therapy and non-glucocorticoid therapy groups. Compared with the non-glucocorticoid therapy group, glucocorticoid therapy did not significantly influence the clinical course of COVID-19 pneumonia, including imaging progress and the time duration for negative transformation of nucleic acid. Glucocorticoid therapy did not significantly influence the outcomes nor the adverse events of COVID-19 pneumonia. For the treatment of COVID-19 pneumonia, systemic and in-depth investigation is needed to determine the timing and dosage of glucocorticoids needed to inhibit overwhelming inflammatory response and not the protective immune response to COVID-19 pneumonia.

Shortening the sgRNA-DNA interface enables SpCas9 and eSpCas9(1.1) to nick the target DNA strand.

The length of the sgRNA-DNA complementary sequence is a key factor influencing the cleavage activity of Streptococcus pyogenes Cas9 (SpCas9) and its variants. The detailed mechanism remains unknown. Here, based on in vitro cleavage assays and base editing analysis, we demonstrate that reducing the length of this complementary region can confer nickase activity on SpCas9 and eSpCas9(1.1). We also show that these nicks are made on the target DNA strand. These properties encouraged us to develop a dual-functional system that simultaneously carries out double-strand DNA cleavage and C-to-T base conversions at separate targets. This system provides a novel tool for achieving trait stacking in plants.

Genome-wide Identification of WRKY transcription factor family members in sorghum (Sorghum bicolor (L.) moench).

WRKY transcription factors regulate diverse biological processes in plants, including abiotic and biotic stress responses, and constitute one of the largest transcription factor families in higher plants. Although the past decade has seen significant progress towards identifying and functionally characterizing WRKY genes in diverse species, little is known about the WRKY family in sorghum (Sorghum bicolor (L.) moench). Here we report the comprehensive identification of 94 putative WRKY transcription factors (SbWRKYs). The SbWRKYs were divided into three groups (I, II, and III), with those in group II further classified into five subgroups (IIa-IIe), based on their conserved domains and zinc finger motif types. WRKYs from the model plant Arabidopsis (Arabidopsis thaliana) were used for the phylogenetic analysis of all SbWRKY genes. Motif analysis showed that all SbWRKYs contained either one or two WRKY domains and that SbWRKYs within the same group had similar motif compositions. SbWRKY genes were located on all 10 sorghum chromosomes, and some gene clusters and two tandem duplications were detected. SbWRKY gene structure analysis showed that they contained 0-7 introns, with most SbWRKY genes consisting of two introns and three exons. Gene ontology (GO) annotation functionally categorized SbWRKYs under cellular components, molecular functions and biological processes. A cis-element analysis showed that all SbWRKYs contain at least one stress response-related cis-element. We exploited publicly available microarray datasets to analyze the expression profiles of 78 SbWRKY genes at different growth stages and in different tissues. The induction of SbWRKYs by different abiotic stresses hinted at their potential involvement in stress responses. qRT-PCR analysis revealed different expression patterns for SbWRKYs during drought stress. Functionally characterized WRKY genes in Arabidopsis and other species will provide clues for the functional characterization of putative orthologs in sorghum. Thus, the present study delivers a solid foundation for future functional studies of SbWRKY genes and their roles in the response to critical stresses such as drought.

Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy.

Mitochondrial unfolding protein response (UPRmt) effectively resists the pathological cardiac hypertrophy and improves the mitochondrial function. However, the specific activation mechanism and drugs that can effectively activate UPRmt in the cardiac muscle are yet to be elucidated. The aim of this study was to determine the regulation role of UPRmt on preventing pathological cardiac hypertrophy by tetrahydrocurcumin (THC) and explore its underlying molecular mechanism. Male C57BL/6J wild-type (WT) mice were divided into a control group and subjected to sham treatment for 4 weeks, and a test group which was subjected to transverse aortic constriction (TAC) surgery. Animals in the control and test group were orally administered THC (50 mg/kg) for 4 weeks after TAC procedure; an equivalent amount of saline was orally administered in the control sham-treated group and the TAC group. Subsequently, oxidative stress and UPRmt markers were assessed in these mice, and cardiac hypertrophy, fibrosis, and cardiac function were tested. Small interfering RNA (siRNA) targeting proliferator-activated receptor-gamma coactivator (PGC)-1α and activating transcription factor 5 (ATF5) were used to determine the UPRmt activation mechanism. THC supplement partly upregulated UPRmt effectors and inhibited TAC-induced oxidative stress compared with TAC-operated WT mice, thereby substantially attenuating contractile dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, PGC-1α knockdown blunted the UPRmt activation and the cardioprotective role of THC. The interaction between PGC-1α and ATF5 was tested in neonatal rat cardiac myocytes under normal conditions. The results showed that PGC-1α was an upstream effector of ATF5 and partly activated UPRmt. In vitro, phenylephrine- (PE-) induced cardiomyocyte hypertrophy caused ATF5 upregulating rather than downregulating corresponding to the downregulation of PGC-1α. The PGC-1α/ATF5 axis mediated the UPRmt activation and stress-resistance role of THC in vitro. Collectively, the present study provides the first evidence that PGC-1 and ATF5 can form a signaling axis to partly activate UPRmt that mediates the cardioprotective role of THC in pathological cardiac hypertrophy.

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. METHODS: Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. RESULTS: Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-L-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. CONCLUSIONS: Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

The FUSE binding protein is a cellular factor required for efficient replication of hepatitis C virus.

Hepatitis C virus (HCV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma and one of the primary indications for liver transplantation. The molecular mechanisms underlying the actions of host factors in HCV replication remain poorly defined. FUSE (far upstream element of the c-myc proto-oncogene) binding protein (FBP) is a cellular factor that we have identified as a binder of HCV 3' nontranslated region (3'NTR). Mapping of the binding site showed that FBP specifically interacts with the poly(U) tract within the poly(U/UC) region of the 3'NTR. Silencing of FBP expression by small interfering RNA in cells carrying HCV subgenomic replicons severely reduced viral replication, while overexpression of FBP significantly enhanced viral replication. We confirmed these observations by an in vitro HCV replication assay in the cell-free replicative lysate, which suggested that there is a direct correlation between the cellular FBP level and HCV replication. FBP immunoprecipitation coprecipitated HCV nonstructural protein 5A (NS5A), indicating that FBP interacts with HCV NS5A, which is known to function as a link between HCV translation and replication. Although FBP is mainly localized in the nucleus, we found that in MH14 cells a significant level of this protein is colocalized with NS5A in the cytosol, a site of HCV replication. While the mechanism of FBP involvement in HCV replication is yet to be delineated, our findings suggest that it may be an important regulatory component that is essential for efficient replication of HCV.

Chromosomal location of traits associated with wheat seedling water and phosphorus use efficiency under different water and phosphorus stresses.

The objective of this study was to locate chromosomes for improving water and phosphorus-deficiency tolerance of wheat at the seedling stage. A set of Chinese Spring-Egyptian Red wheat substitution lines and their parent Chinese Spring (recipient) and Egyptian Red (donor) cultivars were measured to determine the chromosomal locations of genes controlling water use efficiency (WUE) and phosphorus use efficiency (PUE) under different water and phosphorus conditions. The results underlined that chromosomes 1A, 7A, 7B, and 3A showed higher leaf water use efficiency (WUE(l) = Pn/Tr; Pn = photosynthetic rate; Tr = transpiration rate) under W-P (Hoagland solution with 1/2P), -W-P (Hoagland solution with 1/2P and 10% PEG). Chromosomes 7A, 3D, 2B, 3B, and 4B may carry genes for positive effects on individual plant water use efficiency (WUE(p) = biomass/TWC; TWC = total water consumption) under WP (Hoagland solution), W-P and -W-P treatment. Chromosomes 7A and 7D carry genes for PUE enhancement under WP, -WP (Hoagland solution with 10% PEG) and W-P treatment. Chromosome 7A possibly has genes for controlling WUE and PUE simultaneously, which indicates that WUE and PUE may share the same genetic background. Phenotypic and genetic analysis of the investigated traits showed that photosynthetic rate (Pn) and transpiration rate (Tr), Tr and WUE(l) showed significant positive and negative correlations under WP, W-P, -WP and -W-P, W-P, -WP treatments, respectively. Dry mass (DM), WUE(P), PUT (phosphorus uptake) all showed significant positive correlation under WP, W-P and -WP treatment. PUE and phosphorus uptake (PUT = P uptake per plant) showed significant negative correlation under the four treatments. The results might provide useful information for improving WUE and PUE in wheat genetics.