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Background: Immunotherapy has redefined the treatment era for metastatic non-small cell lung cancer (NSCLC); therefore, this study aimed to explore trends in survival and cardiovascular disease (CVD) mortality risk before and after the widespread adoption of immunotherapy. Methods: This research utilized information from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and the Wide-Ranging Online Data for Epidemiologic Research (CDC-WONDER) database from the Centers for Disease Control and Prevention. The study population comprised patients with metastatic NSCLC from the pre- (2011–2014) and post-immunotherapy (2016–2019) periods. Survival determinants and CVD mortality trends were analyzed using propensity score matching, Kaplan–Meier survival analyses, competing risk models, and accelerated failure time (AFT) models. Results: A total of 78,028 metastatic NSCLC patients were enrolled in the study, with significant improvements noted in overall survival (OS) and cancer-specific survival (CSS) in the later stages of immunotherapy. The AFT model analysis identified treatment modality, pathological subtype, metastatic site, and some non-medical factors as survival determinants. The interaction analyses revealed that the survival differences among certain subgroups intensified in the post-immunotherapy period. Despite the lack of significant differences in CVD mortality and subgroup composition between the two periods, CVD mortality risk remained high compared with the general U.S. population. Conclusion: Survival of patients with metastatic NSCLC has improved significantly since the introduction of immunotherapy. However, survival differences between some subpopulations continue to intensify, while CVD mortality risk also remains a key concern.

Hydroxysafflor yellow A (HSYA) possesses a variety of pharmacological activities which has been demonstrated to be effective against ischemic heart disease (IHD). This study aimed to comprehensively examine the efficacy and summarize the potential mechanisms of HSYA against IHD in animal models. We conducted electronic searches for preclinical studies on PubMed, Embase, Web of Science, Cochrane Library, CNKI, SinoMed, Wanfang, and Chinese VIP databases from inception to 31 January 2024. The CAMARADES checklist was chosen to assess the quality of evidence. STATA 14.0 software was utilized to analyze the data. The underlying mechanisms were categorized and summarized. Twenty-eight studies involving 686 rodents were included and the mean score of methodology quality was 5.04 (range from 4 to 7). Meta-analysis observed that HSYA could decrease myocardial infarction size (SMD: -2.82, 95%CI: -3.56 to -2.08, < 0.001) and reduce the levels of biomarkers of myocardial injury including cTnI (SMD: -3.82, 95%CI: -5.20 to -2.44, < 0.001) and CK-MB (SMD: -2.74, 95%CI: -3.58 to -1.91, < 0.001). HSYA displayed an improvement in cardiac function indicators including LVEF, LVSP, +dp/dt max and -dp/dt max. Furthermore, HSYA was able to reduce the levels of MDA, TNF-α and IL-6, while increasing SOD and NO levels. Mechanistically, the protective effect of HSYA in alleviating myocardial injury after ischemia may be associated with NLRP3 inflammasome, Bcl-2, Bax, caspase-3, eNOS proteins, and TLR/NF-κB, Nrf2/HO-1, JAK/STAT, PI3K/Akt, AMPK/mTOR, VEGFA pathways. This study demonstrates that HSYA exerts cardioprotective effects in decreasing infarct size, reducing myocardial enzymes and improving cardiac function, which may be mediated by anti-inflammatory, antioxidant, anti-apoptotic, regulation of autophagy, improvement of microcirculation and promotion of angiogenesis. However, the absence of safety assessment, lack of animal models of co-morbidities, and inconsistency between timing of administration and clinical practice are limitations of preclinical studies. clinicaltrials.gov, Identifier, CRD42023460790.

Background Nanomaterials have been widely used in electrochemistry, sensors, medicine among others applications, causing its inevitable environmental exposure. A raising question is the “carrier” effect due to unique surface properties of nanomaterials, which may collectively impact the bioavailability, toxicokinetic, distribution and biological effects of classic toxicants. Noteworthy, this aspect of information remains largely unexplored. Methods Here, we deliberately selected two entities to mimic this scenario. One is graphene oxide (GO), which is made in ton quantity with huge surface-area that provides hydrophilicity and π–π interaction to certain chemicals of unique structures. The other is Microcystin-LR (MCLR), a representative double-bond rich liver-toxic endotoxin widely distributed in aquatic-system. Firstly, the adsorption of GO and MCLR after meeting under environmental conditions was explored, and then we focused on the toxicological effect and related mechanism of GO-MCLR complex on human skin cutin forming cells (HaCaT cells) and normal liver cells (L02 cells). Results Abiotically, our study demonstrated that GO could effectively adsorb MCLR through hydrogen bonding and π–π interaction, the oxidation degree of GO-MCLR decreased significantly and surface defect level raised. Compared to GO or MCLR, GO-MCLR was found to induce more remarkable apoptosis and ferroptosis in both HaCaT and L02 cells. The underlying mechanism was that GO-MCLR induced stronger intracellular reactive oxygen species (ROS) and mtROS generation, followed by Fe 2+ accumulation, mitochondrial dysfunction and cytoskeletal damage. Conclusions These results suggest that the GO-MCLR complex formed by GO adsorption of MCLR may exhibit more toxic effects than the single material, which demonstrates the necessity for assessing nano-toxicant complexity. Our discovery may serve as a new toxicological paradigm in which nanomaterial mediated surface adsorption effects could impact the degree of cytotoxicity and toxicological mechanisms of classic toxins. Graphical Abstract

Background Carbon dot has been widely used in biomedical field as a kind of nanomaterial with low toxicity and high biocompatibility. CDs has demonstrated its unique advantages in assisted drug delivery, target diagnosis and targeted therapy with its small size and spontaneous fluorescence. However, the potential biosafety of CDs cannot be evaluated. Therefore, we focused on the study of liver, the target organ involved in CDs metabolism, to evaluate the risk of CDs in vitro. Methods and results Liver macrophage KUP5 cells and normal liver cells AML12 cells were incubated in CDs at the same concentration for 24 h to compare the different effects under the same exposure conditions. The study found that both liver cell models showed ATP metabolism disorder, membrane damage, autophagosome formation and lysosome damage, but the difference was that, KUP5 cells exhibited more serious damage than AML12 cells, suggesting that immunogenic cell type is particularly sensitive to CDs. The underlying mechanism of CDs-induced death of the two hepatocyte types were also assessed. In KUP5 cells, death was caused by inhibition of autophagic flux caused by autophagosome accumulation, this process that was reversed when autophagosome accumulation was prevented by 3-MA. AML12 cells had no such response, suggesting that the accumulation of autophagosomes caused by CDs may be specific to macrophages. Conclusion Activation of the TFEB-lysosome pathway is important in regulating autophagy and apoptosis. The dual regulation of ERK and mTOR phosphorylation upstream of TFEB influences the death outcome of AML12 cells. These findings provide a new understanding of how CDs impact different liver cells and contribute to a more complete toxicological safety evaluation of CDs.

Total plastic production is expected to reach 33 billion tons by 2050, and microplastic emissions from effluents to the environment range from 0.46 million to 140 billion tons. Microplastic distribution and toxicological effects are actually poorly known. Here we review microplastic pollution with emphasis on their environmental distribution, their aging, their analysis in the environment and living organisms, their toxicity alone or combined with other contaminants, and their mitigation techniques. We present microplastic distribution in soil, water, and the atmosphere. Microplastic aging is controlled by physical, chemical, and biological factors. Model organisms of microplastic exposure include zebrafish, earthworms, Caenorhabditis elegans, and Arabidopsis thaliana. Microplastic exposure to humans could induce gastrointestinal, pulmonary, reproductive, and cardiovascular toxicity, and neurotoxicity. We discuss the combined toxicity of microplastics with organic pollutants, heavy metals, endocrine disruptors, and antibiotics. Fourier transform infrared spectroscopy and Raman spectroscopy are currently the most commonly used techniques for microplastic analysis.

Objective Panax quinquefolius saponins (PQS) and Panax notoginseng saponins (PNS) are key bioactive compounds in Panax quinquefolius L . and Panax notoginseng , commonly used in the treatment of clinical ischemic heart disease. However, their potential in mitigating myocardial ischemia-reperfusion injury remains uncertain. This study aims to evaluate the protective effects of combined PQS and PNS administration in myocardial hypoxia/reoxygenation (H/R) injury and explore the underlying mechanisms. Methods To investigate the involvement of HIF-1α/BNIP3 mitophagy pathway in the myocardial protection conferred by PNS and PQS, we employed small interfering BNIP3 (siBNIP3) to silence key proteins of the pathway. H9C2 cells were categorized into four groups: control, H/R, H/R + PQS + PNS, and H/R + PQS + PNS+siBNIP3. Cell viability was assessed by Cell Counting Kit-8, apoptosis rates determined via flow cytometry, mitochondrial membrane potential assessed with the JC-1 fluorescent probes, intracellular reactive oxygen species detected with 2′,7′-dichlorodihydrofluorescein diacetate, mitochondrial superoxide production quantified with MitoSOX Red, and autophagic flux monitored with mRFP-GFP-LC3 adenoviral vectors. Autophagosomes and their ultrastructure were visualized through transmission electron microscopy. Moreover, mRNA and protein levels were analyzed via real-time PCR and Western blotting. Results PQS + PNS administration significantly increased cell viability, reduced apoptosis, lowered reactive oxygen species levels and mitochondrial superoxide production, mitigated mitochondrial dysfunction, and induced autophagic flux. Notably, siBNIP3 intervention did not counteract the cardioprotective effect of PQS + PNS. The PQS + PNS group showed downregulated mRNA expression of HIF-1α and BNIP3, along with reduced HIF-1α protein expression compared to the H/R group. Conclusions PQS + PNS protects against myocardial H/R injury, potentially by downregulating mitophagy through the HIF-1α/BNIP3 pathway.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated 1 . Gestational diabetes has profound and enduring effects on the long-term health of the offspring 2 , 3 . However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote 4 , is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene ( Gck ), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring. Pregestational hyperglycaemia in mothers increases the probability of glucose intolerance in the offspring, an effect controlled by TET3-dependent DNA demethylation of genes involved in insulin secretion.

The Raspy crickets are an interesting group of nocturnal animals that bear femoral-abdominal stridulation and spin silk from the mouthparts. Gryllacridid classification is the subject of ongoing discussion. Here, we present the first mitogenomic sequences for three Ocellarnaca taxa: O. braueri (15,597 bp), O. fuscotessellata (15,607 bp), and O. emeiensis (16,510 bp). Three mitochondrial genomes exhibited the conventional metazoan gene and conserved the characteristic gene order across Gryllacrididae species. Evolutionary selection analyses showed that atp8 was the least evolutionarily constrained mitochondrial gene, whereas cox1 was the most conserved across lineages. The three Ocellarnaca species harbored 5–8 mitochondrial DNA sequence repeats (mtSSRs), falling within the 1–8 range detected in all analyzed Gryllacrididae species. Magnigryllacris and Ocellarnaca exhibited higher mtSSR counts than related genera sharing analogous male abdominal apex morphology. Phylogenomic analyses of 35 mitogenomes from 21 Gryllacrididae species supported Ocellarnaca as monophyletic and a sister to Magnigryllacris (bootstrap = 100%), with O. fuscotessellata resolved as sister to the clade (O. sp. + (O. emeiensis + O. braueri)). This study expands the mitogenomic resources for Ocellarnaca, which will facilitate further resolution of phylogenetic reconstruction within this genus and across Gryllacrididae genera.

In China, Anostostomatidae is represented by a single tribe, Anabropsini; two genera; and 33 species. Although extensive research has been conducted on Anabropsini, the monophyly of this tribe within Anostostomatidae remains unverified. Furthermore, the phylogenetic relationships within Anabropsis remain under debate. To address these gaps, we sequenced and annotated the mitochondrial genomes of five Anabropsini species to investigate their mitochondrial characteristics and phylogenetic positions and clarify the relationships among Anabropsis subgenera. The total mitochondrial length of the five species ranged from 15,985 bp to 16,423 bp and contained 13 protein-coding genes, 22 tRNAs, 2 rRNAs, and 1 control region. A grouped analysis of selection pressure on Anabropsis revealed that the Ka/Ks values for alate and apterous forms are not significantly different, suggesting that using wing length alone as the basis for dividing subgenera within Anabropsis may be unreliable. Tertiary structure modeling of proteins showed that the variable sites were concentrated in α-helix regions. Phylogenetic trees were reconstructed using the Bayesian inference and maximum likelihood methods and were based on two better datasets, namely, PCG123 (all codon positions of the PCGs) and PCG123 + 2R (all codon positions of PCGs, 12SrRNA, and 16SrRNA). The results indicate that the Chinese Anabropsini is paraphyletic, whereas Anabropsis is monophyletic, with a stable subgeneric topology.

Background: Lonchodidae is the largest family within the order Phasmatodea, and although many studies have been conducted on this family, the monophyly of the family has not been established. Methods: Eight mitogenomes from Lonchodidae, including the first complete mitogenomes of four genera, were sequenced and annotated to explore their features and phylogenetic relationships. Results: The total length ranged from 15,942–18,021 bp, and the mitogenome consisted of 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and a control region (CR). atp8 had the highest A + T content in Lonchodidae, except for Neohirasea stephanus and Asceles clavatus, in which the highest A + T contents were detected in nad6. The phylogenetic trees were reconstructed via Bayesian inference (BI) and maximum likelihood (ML) based on the PCG123 and PCG12 datasets. As the phylogenetic trees show, Necrosciinae is recognized as monophyletic, but the monophyly of Lonchodinae has not been supported. Gene deletion and rearrangement have occurred mainly in Lonchodidae and Aschiphasmatidae. The most common reason for gene rearrangements was tandem duplication random loss (TDRL), but trnI of Stheneboea repudiosa inverted into the CR. In addition, genes within the same family or genus share related sequences and conserved gene blocks. Conclusions: we expanded the mitochondrial genomic data for this family, thereby establishing a foundational dataset for future studies.