A novel dual-epigenetic inhibitor enhances recombinant monoclonal antibody expression in CHO cells.

Epigenetic regulation plays a central role in the regulation of a number of cellular processes such as proliferation, differentiation, cell cycle, and apoptosis. In particular, small molecule epigenetic modulators are key elements that can effectively influence gene expression by precisely regulating the epigenetic state of cells. To identify useful small-molecule regulators that enhance the expression of recombinant proteins in Chinese hamster ovary (CHO) cells, we examined a novel dual-HDAC/LSD1 inhibitor I-4 as a supplement for recombinant CHO cells. Treatment with 2 µM I-4 was most effective in increasing monoclonal antibody production. Despite cell cycle arrest at the G1/G0 phase, which inhibits cell growth, the addition of the inhibitor at 2 µM to monoclonal antibody-expressing CHO cell cultures resulted in a 1.94-fold increase in the maximal monoclonal antibody titer and a 2.43-fold increase in specific monoclonal antibody production. In addition, I-4 significantly increased the messenger RNA levels of the monoclonal antibody and histone H3 acetylation and methylation levels. We also investigated the effect on HDAC-related isoforms and found that interference with the HDAC5 gene increased the monoclonal antibody titer by 1.64-fold. The results of this work provide an effective method of using epigenetic regulatory strategies to enhance the expression of recombinant proteins in CHO cells. KEY POINTS: • HDAC/LSD1 dual-target small molecule inhibitor can increase the expression level of recombinant monoclonal antibodies in CHO cells. • By affecting the acetylation and methylation levels of histones in CHO cells and downregulating HDAC5, the production of recombinant monoclonal antibodies increased. • It provides an effective pathway for applying epigenetic regulation strategies to enhance the expression of recombinant proteins.

Unraveling the role of ubiquitin-conjugating enzyme 5 (UBC5) in disease pathogenesis: A comprehensive review.

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.

Fucoxanthin Attenuates Angiogenesis by Blocking the VEGFR2-Mediated Signaling Pathway through Binding the Vascular Endothelial Growth Factor.

Fucoxanthin, a dietary carotenoid, is predominantly found in edible brown algae and is commonly consumed worldwide. Fucoxanthin has been shown to possess beneficial health activities such as antidiabetic, anti-inflammatory, antimutagenic, and antiobesity; however, the effects of fucoxanthin on VEGF-mediated angiogenesis and its possible binding with VEGF are unknown. Here, different lines of evidence supported the suppressive roles of fucoxanthin in VEGF-mediated angiogenesis. In human umbilical vein endothelial cells, fucoxanthin remarkedly suppressed VEGF-mediated cell proliferative, migration, and invasive abilities, as well as tube formation, without cytotoxicity. In addition, fucoxanthin inhibited the subintestinal vessel formation of zebrafish in vivo. In signaling cascades, fucoxanthin was proposed to interact with VEGF, thus attenuating VEGF's functions in activating the VEGF receptor and its related downstream signaling, i.e., phosphorylations of MEK and Erk. Fucoxanthin also significantly blocked VEGF-triggered ROS formation. Furthermore, the outcomes of applying fucoxanthin in cancer cells were identified, which included (i) inhibiting VEGF-mediated cell proliferation and migration and (ii) inhibiting NF-κB translocation via limiting MMP2 expression. These lines of investigations supported the antiangiogenic roles of fucoxanthin, as well as reviewing its signaling mechanisms, in blocking the VEGF-triggered responses. The results would benefit the potential development of fucoxanthin for the prevention and treatment of angiogenesis-related diseases.

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform.

BACKGROUND: Traditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip. METHODS: Selected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated. RESULTS: Over 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities. CONCLUSIONS: The current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.

TLR2/NF-кB signaling may control expansion and function of regulatory T cells in patients with severe fever with thrombocytopenia syndrome (SFTS).

Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified infectious ailment triggered by a new strain of bunyavirus. It is distinguished by elevated fatality rates, ranging from 12 % to 30 %. The mechanism underlying the development of severe illness caused by SFTS bunyavirus (SFTSV) is not yet fully understood. To evaluate the role of the TLR2 receptor pathway in regulating Treg function in the progression of SFTS disease and possible mechanisms, sequential serum samples from 29 patients with SFTS (15 mild, 14 severe cases) were examined. Flow cytometry was employed to scrutinize the phenotypic and functional characteristics of TLR2 expression on circulating CD4 T cells, CD8 T cells, and Tregs. In all admitted patients, the evaluation of correlations between the frequencies of the aforementioned cells and SFTS index (SFTSI) was conducted. For SFTS, the levels of TLR2 on CD4 T cells and Tregs were significantly heightened when compared to those in healthy subjects. Additionally, the expression of TLR2 on Tregs exhibited a positive correlation with Ki-67 expression in Tregs and the severity of disease. Additionally, compared with those in uninfected controls, the expression levels of NF-κB in Tregs were significantly increased. Collectively, Tregs may be activated and proliferate through the stimulation of the TLR2/NF-кB pathway in reaction to SFTSV infection.

Structural insight into binding site access and ligand recognition by human ABCB1.

ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, its mechanisms of poly-specific substrate recognition and transport remain poorly resolved. Here we present cryo-EM structures of lipid embedded human ABCB1 in its apo, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution without using stabilizing antibodies or mutations and each revealing a distinct conformation. The substrate binding site is located within one half of the molecule and, in the apo state, is obstructed by transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major differences in TM arrangement and ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Our data offer fundamental new insights into the role structural asymmetry, secondary structure breaks, and lipid interactions play in ABCB1 function and have far-reaching implications for ABCB1 inhibitor design and predicting its substrate binding profiles.

Drug release system based on a composite polycaprolactone nanofiber membrane with dual functionality of shape memory effect and antibacterial ability.

In this study, a multifunctional composite membrane based on polycaprolactone nanofibers having controlled drug release, shape memory effect, and antibacterial ability was successfully prepared by the electrospinning technique. The addition of graphene oxide (GO), zinc oxide nanoparticles (ZnO NPs), polyethylene glycol (PEG), and berberine (BBR) strongly affected the morphology, crystalline degree, melting temperature, and shape memory performance of the composite membrane, thanks to the physical crosslinking network formed by the hydrogen bonding or van der Waals interactions between the components. As a result, the recovery ratio of the composite membrane reached a higher value (76.3% ± 0.7%) than that of the PCL fiber membrane (22.8% ± 0.7%). The additional components significantly improved the wettability of the composite membrane, leading to a high amount of BBR released (42.7 wt%) during 40 hours, as well as effective antibacterial ability. Besides, the BBR release can be feasibly controlled by modulating the deformation ratio of the composite membrane, whereby the higher deformation ratio resulted in a higher BBR release. Therefore, it is suggested that the prepared composite nanofiber membrane is a potential smart material used in biomedical applications, such as wound dressing and drug release systems.

SLC25A12 inhibits Japanese encephalitis virus replication by interacting with the NS1 and enhancing the type I interferon response.

Japanese encephalitis virus (JEV) is a mosquito-borne, zoonotic orthoflavivirus causing human encephalitis and reproductive disorders in pigs. Cell-intrinsic antiviral restriction factors are the first line of defense that prevent a virus from establishing a productive infection, while the molecular mechanism of the virus-host interaction is still not fully understood. Our in vitro experiments demonstrated that the Solute Carrier Family 25 Member 12 (SLC25A12) interacted with the JEV nonstructural protein 1 (NS1) and inhibited JEV replication. Furthermore, we showed that knockdown or knockout of SLC25A12 promoted JEV replication, while overexpression of SLC25A12 repressed viral replication. Finally, we demonstrated that SLC25A12 increased IRF7 mRNA levels, which promoted IFN-ß expression and subsequently induced antiviral effects. Collectively, our study revealed that SLC25A12 interacted with NS1, inhibiting viral RNA synthesis and transcription and enhancing type I interferon induction for antiviral effects.

FXR contributes to obstructive jaundice-induced vascular hyporeactivity in mesenteric arteries by reconstituting BKCa channels.

OBJECTIVE: Vascular hyporeactivity increases with the incidence of obstructive jaundice (OJ). Evidence suggests that OJ activates the farnesoid X receptor (FXR) as well as the large-conductance Ca2+-activated K+ (BKCa or MaxiK) channel. This study was designed to explore the role of the FXR in vascular hyporesponsiveness induced by cholestasis. METHODS: The OJ model rats were constructed by bile duct ligation (BDL) and treated with an FXR agonist or antagonist. Vasoconstriction of the mesenteric arteries (MAs) was assessed in vitro. Whole-cell patch clamp recordings were used to investigate BKCa channel function. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect mRNA and protein levels. RESULTS: A significant increase in vascular tone and responsiveness to norepinephrine (NE) was observed after the MaxiK channel blocker (IbTX) was administered. This effect was pronounced in BDL animals and can be mimicked by the FXR agonist GW4064 and inhibited by the FXR antagonist Z-guggulsterone (Z-Gu). GW4064 has a similar effect as cholestasis in promoting MaxiK currents in isolated arterial smooth muscle cells (ASMCs), while Z-Gu blunted this effect. The mRNA and protein expression of FXR and MaxiK-ß1, but not MaxiK-α, were significantly increased in the BDL group in comparison to the sham. Furthermore, activation or inhibition of FXR promoted or inhibited the mRNA and protein expression of the MaxiK-ß1 subunit, respectively. CONCLUSION: Activation of FXR enhances the capability of the MaxiK channel to regulate vascular tone and leads to vascular hyporesponsiveness in the MAs of BDL rats, which may be mediated by the nonparallel upregulation of MaxiK-α and MaxiK-ß1 subunit expression.

A novel AP2/ERF transcription factor, NtERF10, positively regulates plant height in tobacco.

Ethylene response factors have been shown to be involved in the effects of plant developmental processes and to regulate stress tolerance. The aim of this study was to recognize the regulatory mechanisms of ethylene response factors on tobacco plant height. In this study, a gene-edited mutant (ERF10-KO) and wild type (WT) were utilized as experimental materials. Transcriptome and metabolome analyses were used to investigate the regulatory mechanism of NtERF10 gene editing on plant height in tobacco. Here, through the analysis of differentially expressed genes (DEGs), 2051 genes were upregulated and 1965 genes were downregulated. We characterized the different ERF10-KO and WT plant heights and identified key genes for photosynthesis, the plant hormone signal transduction pathway and the terpene biosynthesis pathway. NtERF10 was found to affect the growth and development of tobacco by regulating the expression levels of the PSAA, PSBA, GLY17 and GGP3 genes. Amino acid metabolism was analyzed by combining analyses of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs). In addition, we found that members of the bHLH, NAC, MYB, and WRKY transcription factor families have vital roles in regulating plant height. This study not only provides important insights into the positive regulation of the ethylene response factor NtERF10 on plant height during plant growth and development but also provides new research ideas for tobacco molecular breeding.

Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor.

Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

Metabolomic profiles and differential metabolites of volatile components in Citrus aurantium Changshan-huyou pericarp during different growth and development stages.

Citrus fruits possess a distinctive aroma and flavor, with Citrus aurantium Changshan-huyou (CACH) standing out due to their considerable edible and medicinal value. However, the volatile components (VOCs) in the CACH pericarp (CP) remain underexplored. In this study, gas chromatography-mass spectrometry (GC-MS) was utilized to qualitatively analyze VOCs in 27 CP samples across different growth stages. A total of 544 VOCs were identified, including 91 terpenoids. The types, quantities and distributions of VOCs were conducted. Detailed discussions on the major terpenoids in CP were also presented. A metabolomics approach combining multivariate statistical analysis with univariate analysis was employed for screening the differential metabolites. The study provides comprehensive insights into the VOCs in CP and citrus plants. Moreover, it delivers the first in-depth analysis of differential metabolites in CP throughout the entire CACH growth and development process, laying a foundation for ongoing research and development of the VOCs in CP.

Rules of acupoint selection in treatment of cancer-related insomnia with acupuncture and moxibustion based on data mining technology. / åŸºäºŽæ•°æ®æŒ–æŽ˜æŠ€æœ¯æŽ¢æžé’ˆç¸æ²»ç–—è‚¿ç˜¤ç›¸å ³æ€§å¤±çœ çš„é€‰ç©´è§„å¾‹.

OBJECTIVES: To analyze the rules of acupoint selection in treatment of cancer-related insomnia with acupuncture and moxibustion by data mining technology. METHODS: The articles of cancer-related insomnia treated with acupuncture and moxibustion were searched from CNKI, Wanfang, VIP, SinoMed, PubMed, WOS, Cochrane, and Embase databases, from the inception of each database to January 5, 2024. The prescription database of acupuncture and moxibustion for cancer-related insomnia was established. The descriptive analysis was conducted on the use frequency, meridian tropism and distribution of acupoints. Using SPSS Modeler 18.0 Apriori algorithm, the association rules of acupoint prescriptions were analyzed. With Cytoscape3.9.1 software used, the complex network diagram was plotted, and the cluster analysis of high-frequency acupoints was performed by SPSS26.0 software. RESULTS: Forty-one articles were included, and 67 prescriptions were extracted with 89 acupoints involved, and the total use frequency was 447 times. The top 4 acupoints of the high use frequency were Baihui (GV20), Sanyinjiao (SP6), Shenmen (HT7) and Shenting (GV24). The included meridians were the governor vessel, the spleen meridian, the bladder meridian, the conception vessel, the heart meridian and the stomach meridian. The selected acupoints were mostly distributed on the head, the neck and and the upper and lower limbs. The special acupoints of the high use frequency included the five-Shu points, the crossing points and yuan-primordial points. Regarding acupoint combination, GV24, SP6, HT7, and GV20 were highly correlated. The three effective clusters were categorized among the top 12 acupoints of the high use frequency. CONCLUSIONS: In treatment of cancer-related insomnia with acupuncture and moxibustion, the principle focuses on supporting the healthy qi, eliminating pathogens, regulating yin and yang, promoting the circulation of the governor vessel for regulating the spirit, and tranquilizing the mind. The core acupoint prescription may includes GV24, SP6, HT7 and GV20；combined with Zusanli (ST36) and Yintang (GV4+) to enhance the therapeutic effect.

Population genetic diversity and structure of Tephritis angustipennis and Campiglossa loewiana (Diptera: Tephritidae) based on COI DNA barcodes in the three-river source region, China.

Tephritis angustipennis (Diptera: Tephritidae) and Campiglossa loewiana (Diptera: Tephritidae) are phytophagous pests in China. Their damage has significantly impacted the collection and cultivation of germplasm resources of native Asteraceae plants. However, the genetic characteristics and structure of their population are unclear. This study focused on the highly damaging species of T. angustipennis and C. loewiana collected from the three-river source region (TRSR). We amplified the mitochondrial cytochrome C oxidase subunit I (mtCOI) gene sequences of these pests collected from this area and compared them with COI sequences from GenBank. We also analyzed their genetic diversity and structure. In T. angustipennis, 5 haplotypes were identified from 5 geographic locations; the genetic differentiation between France population FRPY (from Nylandia, Uusimaa) and China populations GLJZ (from Dehe Longwa Village, Maqin County), GLDR (from Zhique Village, Dari County), and GLMQ (from Rijin Village, Maqin County) was the strongest. GLJZ exhibited strong genetic differentiation from GLDR and GLMQ, with relatively low gene flow. For C. loewiana, 11 haplotypes were identified from 5 geographic locations; the genetic differentiation between the Chinese population GLMQ-YY (from Yangyu Forest Farm, Maqin County) and Finnish population FDNL (from Nylandia, Uusimaa) was the strongest, with relatively low gene flow, possibly due to geographical barriers in the Qinghai-Tibet plateau. Only 1 haplotype was identified across GLDR, GLMQ, and GLBM. High gene flow between distant locations indicates that human activities or wind dispersal may facilitate the dispersal of fruit flies and across different geographic. Geostatistical analysis suggested a recent population expansion of these 2 species in TRSR. Our findings provide technical references for identifying pests in the TRSR region and theoretical support for managing resistance, monitoring pest occurrences, analyzing environmental adaptability, and formulating biological control strategies for Tephritidae pests on Asteraceae plants.

Immunogenic cell death inducers for cancer therapy: An emerging focus on natural products.

BACKGROUND: Immunogenic cell death (ICD) is a specific form of regulated cell death induced by a variety of stressors. During ICD, the dying cancer cells release damage-associated molecular patterns (DAMPs), which promote dendritic cell maturation and tumor antigen presentation, subsequently triggering a T-cell-mediated anti-tumor immune response. In recent years, a growing number of studies have demonstrated the potential of natural products to induce ICD and enhance tumor cell immunogenicity. Moreover, there is an increasing interest in identifying new ICD inducers from natural products. PURPOSE: This study aimed to emphasize the potential of natural products and their derivatives as ICD inducers to promote research on using natural products in cancer therapy and provide ideas for future novel immunotherapies based on ICD induction. METHOD: This review included a thorough search of the PubMed, Web of Science, Scopus, and Google Scholar databases to identify natural products with ICD-inducing capabilities. A comprehensive search for clinical trials on natural ICD inducers was also conducted using ClinicalTrials.gov, as well as the approved patents using the Espacenet and CNKI Patent Database. RESULTS: Natural compounds that induce ICD can be categorized into several groups, such as polyphenols, flavonoids, terpenoids, and alkaloids. Natural products can induce the release of DAMPs by triggering endoplasmic reticulum stress, activation of autophagy-related pathways, and reactive oxygen species generation, etc. Ultimately, they activate anti-tumor immune response and improve the efficacy of cancer treatments. CONCLUSION: A growing number of ICD inducers from natural products with promising anti-cancer potential have been identified. The detailed information presented in this review will contribute to the further development of natural ICD inducers and cancer treatment strategies based on ICD-induced responses.

Polyphenols as Potential Antioxidants for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD. Polyphenols are antioxidant compounds that can inhibit ROS production, which can scavenge free radicals, reduce hydrogen peroxide production, and inhibit lipid oxidation in nucleus pulposus (NP) cells and IDD animal models. In this review, we discussed the antioxidant effects of polyphenols and their regulatory role in different molecular pathways associated with the pathogenesis of IDD, as well as the limitations and future prospects of polyphenols as a potential treatment of IDD.

ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.

Suppression of neuroinflammation using small molecule compounds targeting the key pathways in microglial inflammation has attracted great interest. Recently, increasing attention has been gained to the role of the second bromodomain (BD2) of the bromodomain and extra-terminal (BET) proteins, while its effect and molecular mechanism on microglial inflammation has not yet been explored. In this study, we evaluated the therapeutic effects of ABBV-744, a BD2 high selective BET inhibitor, on lipopolysaccharide (LPS)-induced microglial inflammation in vitro and in vivo, and explored the key pathways by which ABBV-744 regulated microglia-mediated neuroinflammation. We found that pretreatment of ABBV-744 concentration-dependently inhibited the expression of LPS-induced inflammatory mediators/enzymes including NO, TNF-α, IL-1ß, IL-6, iNOS, and COX-2 in BV-2 microglial cells. These effects were validated in LPS-treated primary microglial cells. Furthermore, we observed that administration of ABBV-744 significantly alleviated LPS-induced activation of microglia and transcriptional levels of pro-inflammatory factors TNF-α and IL-1ß in mouse hippocampus and cortex. RNA-Sequencing (RNA-seq) analysis revealed that ABBV-744 induced 508 differentially expressed genes (DEGs) in LPS-stimulated BV-2 cells, and gene enrichment and gene expression network analysis verified its regulation on activated microglial genes and inflammatory pathways. We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation.

Epidemiological characteristics of tuberculosis incidence and its macro-influence factors in Chinese mainland during 2014-2021.

BACKGROUND: Tuberculosis (TB) remains a pressing public health issue, posing a significant threat to individuals' well-being and lives. This study delves into the TB incidence in Chinese mainland during 2014-2021, aiming to gain deeper insights into their epidemiological characteristics and explore macro-level factors to enhance control and prevention. METHODS: TB incidence data in Chinese mainland from 2014 to 2021 were sourced from the National Notifiable Disease Reporting System (NNDRS). A two-stage distributed lag nonlinear model (DLNM) was constructed to evaluate the lag and non-linearity of daily average temperature (℃, Atemp), average relative humidity (%, ARH), average wind speed (m/s, AWS), sunshine duration (h, SD) and precipitation (mm, PRE) on the TB incidence. A spatial panel data model was used to assess the impact of demographic, medical and health resource, and economic factors on TB incidence. RESULTS: A total of 6,587,439 TB cases were reported in Chinese mainland during 2014-2021, with an average annual incidence rate of 59.17/100,000. The TB incidence decreased from 67.05/100,000 in 2014 to 46.40/100,000 in 2021, notably declining from 2018 to 2021 (APC = -8.87%, 95% CI: -11.97, -6.85%). TB incidence rates were higher among males, farmers, and individuals aged 65 years and older. Spatiotemporal analysis revealed a significant cluster in Xinjiang, Qinghai, and Xizang from March 2017 to June 2019 (RR = 3.94, P < 0.001). From 2014 to 2021, the proportion of etiologically confirmed cases increased from 31.31% to 56.98%, and the time interval from TB onset to diagnosis shortened from 26 days (IQR: 10-56 days) to 19 days (IQR: 7-44 days). Specific meteorological conditions, including low temperature (< 16.69℃), high relative humidity (> 71.73%), low sunshine duration (< 6.18 h) increased the risk of TB incidence, while extreme low wind speed (< 2.79 m/s) decreased the risk. The spatial Durbin model showed positive associations between TB incidence rates and sex ratio (ß = 1.98), number of beds in medical and health institutions per 10,000 population (ß = 0.90), and total health expenses (ß = 0.55). There were negative associations between TB incidence rates and population (ß = -1.14), population density (ß = -0.19), urbanization rate (ß = -0.62), number of medical and health institutions (ß = -0.23), and number of health technicians per 10,000 population (ß = -0.70). CONCLUSIONS: Significant progress has been made in TB control and prevention in China, but challenges persist among some populations and areas. Varied relationships were observed between TB incidence and factors from meteorological, demographic, medical and health resource, and economic aspects. These findings underscore the importance of ongoing efforts to strengthen TB control and implement digital/intelligent surveillance for early risk detection and comprehensive interventions.

Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

Destroyed lung contributes to the recurrence of hemoptysis after bronchial artery embolization in patients with post-tuberculosis bronchiectasis.

BACKGROUND: Bronchiectasis has high rates of hemoptysis and recurrent hemoptysis, which is inconsistent among various etiologies. Idiopathic bronchiectasis and post-tuberculous bronchiectasis are two important etiologies in China, but the differences in clinical features and risk factors of recurrent hemoptysis have not been elucidated. METHODS: Patients hospitalized for idiopathic bronchiectasis or post-tuberculosis bronchiectasis were included. Patients were followed up for at least 24 months post-BAE. Demographic characteristics and clinical data were collected and analyzed between idiopathic bronchiectasis and post-tuberculosis bronchiectasis. Based on the outcomes of recurrent severe hemoptysis in patients with post-tuberculosis bronchiectasis, Cox regression models were used to identify risk factors for recurrence. RESULTS: Among 417 patients including 352 idiopathic bronchiectasis and 65 post-tuberculous bronchiectasis, 209 (50.1%) were females. Compared with the idiopathic group, the proportion of patients with female (54.5% vs. 26.2%, p < 0.001), with sputum (79.5% vs. 36.9%, p < 0.001), isolation of Pseudomonas aeruginosa (28.7% vs. 7.7%, p < 0.001), and the number of bronchiectatic lobes≥ 3(98.3% vs 50.8%, p < 0.001) were lower, and the proportion of destroyed lung (4.5% vs. 26.6%, p < 0.001) and recurrence of severe hemoptysis (22.4% vs. 41.5%, p = 0.001) were higher in the post-tuberculous group. Among patients with post-tuberculosis bronchiectasis, destroyed lung [HR: 3.2(1.1,9.1), p = 0.026] and abnormal esophageal proper artery [HR: 2.8(1.1,7.0), p = 0.032] were two independent risk factors for the recurrence of hemoptysis. CONCLUSIONS: The recurrence rate of severe hemoptysis in patients with post-tuberculous bronchiectasis receiving BAE is high, and the proper esophageal artery should be actively evaluated and standardized treatment should be given.