Mitochondrial genetic variations in leukemia: a comprehensive overview.

Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations, and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukemia. However, these sequencing-based studies mainly focus on nuclear DNAs. Increasing evidence indicates that mitochondrial dysfunction is an important mechanism of leukemia pathogenesis, which is closely related to the mitochondrial genome variations. Here, we provide an overview of current research progress concerning mitochondrial genetic variations in leukemia, encompassing gene mutations and copy number variations. We also summarize currently accessible mitochondrial DNA (mtDNA) sequencing methods. Notably, somatic mtDNA mutations may serve as natural genetic barcodes for lineage tracing and longitudinal assessment of clonal dynamics. Collectively, these findings enhance our understanding of leukemia pathogenesis and foster the identification of novel therapeutic targets and interventions.

Sports tourism downturn: The impact of COVID-19 on Chinese tourism among urban and rural residents under epidemic.

BACKGROUND: China's sports tourism has seen significant growth since the 2008 Olympics, only to be challenged by the coronavirus disease 2019 pandemic. This study aims to assess the impact of the pandemic on China's tourism and sports tourism, which are highly interrelated. METHOD: Data and materials from 2019 to mid-2023 were systematically collected and analyzed, focusing on seasonal tourism reports published on official local networks in China. RESULTS: The study reveals a prepandemic annual tourism consumption of 6.63 trillion CNY, a 52.1% decline during the pandemic, and a postpandemic rebound exceeding pre-coronavirus disease levels. CONCLUSION: The pandemic's impact was profound, yet the resilience of China's tourism sector is evident, with a focus on the recovery's implications for sustainable growth. Despite the pandemic's disruption, China's tourism and sports tourism sectors have demonstrated resilience and potential for continued growth, warranting ongoing attention.

Immunogenicity and safety of different combinations involving a third booster dose of SARS-CoV-2 inactivated vaccine, inactivated quadrivalent influenza vaccine, and 23-valent pneumococcal polysaccharide vaccine in adults aged ≥60 years: a phase 4, randomized, open-label study.

Background: Concomitant administration of COVID-19, influenza, and pneumococcal vaccines could reduce the burden on healthcare systems. However, the immunogenicity and safety of various combinations of a third booster dose of SARS-CoV-2 inactivated vaccine (CoronaVac), inactivated quadrivalent influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23), particularly in different age groups, is still unknown. Methods: A phase 4, randomized, open-label, controlled trial was conducted in Beijing, China. 636 healthy adults were divided into two age groups (18-59 and ≥60 years) and randomized equally into three groups: CoronaVac and IIV4 followed by PPV23; CoronaVac and PPV23 followed by IIV4; or CoronaVac followed by IIV4 and PPV23, with a 28-day interval between vaccinations. Immunogenicity was evaluated by measuring antibody titers, and safety was monitored. ClinicalTrials.gov Identifier: NCT05298800. Results: Co-administration of a third dose of CoronaVac, IIV4, and PPV23 in any combination was safe. Among adults aged 18-59, co-administration with PPV23 maintained non-inferiority of antibody levels for CoronaVac and IIV4, despite a slight reduction in antibody responses. This reduction was not observed in participants ≥60 years. Furthermore, co-administration of IIV4 and PPV23 affected seroconversion rates for both vaccines. Conclusions: Co-administration of the third dose of SARS-CoV-2 inactivated vaccine with the influenza vaccine, followed by PPV23, may be optimal for adults aged 18-59. In adults ≥60, all vaccine combinations were immunogenic, suggesting a flexible vaccination approach. Since antibody measurements were taken 28 days post-vaccination, ongoing surveillance is essential to assess the longevity of the immune responses.

NRF2 inhibitors: Recent progress, future design and therapeutic potential.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor involved in oxidative stress response, which controls the expression of various cytoprotective genes. Recent research has indicated that constitutively activated NRF2 can enhance patients' resistance to chemotherapy drugs, resulting in unfavorable prognosis. Therefore, the development of NRF2 inhibitors has emerged as a promising approach for overcoming drug resistance in cancer treatment. However, there are limited reports and reviews focusing on NRF2 inhibitors. This review aims to provide a comprehensive analysis of the structure and regulation of the NRF2 signaling pathway, followed by a comprehensive review of reported NRF2 inhibitors. Moreover, the current design strategies and future prospects of NRF2 inhibitors will be discussed, aiming to establish a foundation for the development of more effective NRF2 inhibitors.

Effects of herbal formula on growth performance, apparent digestibility, antioxidant capacity, and rumen microbiome in fattening lambs under heat stress.

Heat stress (HS) causes severe economic losses in sheep industry worldwide. The objective of the present study was to investigate the effects of a herbal formula (HF) supplement on growth, digestibility, antioxidant capacity, and rumen microbes in fattening lambs under HS. The HF composed of four herbs was prepared based on the theory of compatibility of Chinese medicine "Jun-Chen-Zuo-Shi". Two-hundred forty 3-month weaned lambs (initial weight 36.61 ± 0.73 kg) were randomly allocated into four groups, supplemented 0% (Control), 0.5%, 1.0%, and 1.5% HF in diets. All lambs were exposed to HS conditions with 79.7 of average temperature-humidity index throughout an experimental period of 35 days. Growth performance, apparent digestibility, and antioxidant activities, involving antioxidant enzymes and heat shock proteins (HSPs), were measured at the end of trial, as well as microbial communities in bacteria and archaea. Results showed that 0.5% HF increased (P = 0.02) average daily gain by 13.80% and decreased feed-to-gain ratio (P = 0.03) by 14.68%, compared to control. With increasing HF doses, the digestibility of ether extract and acid detergent fiber demonstrated a cubical (P < 0.01) and quadratic (P = 0.03) relation, respectively; moreover, glutathione peroxidase and catalase activities demonstrated a quadratic increase (P < 0.01). Serum levels of HSP60, HSP70, and HSP90 for 0.5% HF were lower than that in control (P < 0.05). On the other hand, total volatile fatty acid, acetic acid, butyric acid, valeric acid, and isovaleric acid levels exhibited quadratic increases (P ≤ 0.01) with HF doses. From rumen microbes, the abundance and diversity of bacterial community were improved by HF supplements. Particularly for 0.5% HF group, the operational taxonomic units were the greatest among all groups. Compared to control, Prevotella abundance for HF supplements from 0.5 to 1.5% increased by 35.57 to 60.15%, and Succiniclasticum abundance demonstrated a quadratic pattern (P = 0.02) with doses. Additionally, Methanosphaera abundance in archaeal community raised by 0.2 to 3.3-folds when lambs were fed the HF additions of 0.5 to 1.5%. In summary, dietary HF supplements would contribute to alleviating HS in lambs, and our results suggest the optimal dose of 0.5% HF supplement in diet.

Chronic social isolation leads to abnormal behavior in male mice through the hippocampal METTL14 mediated epitranscriptomic RNA m6A modifications.

BACKGROUND: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior. METHODS: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool. RESULTS: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes. CONCLUSIONS: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression.

Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.

Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

Concept for power scaling by harmonic beam coaxial combination in an intra-cavity frequency doubling laser.

A new method of harmonic beam coaxial combination (HBCC) from two intra-cavity frequency doubling branches was demonstrated. Firstly, two identical nanosecond (ns) 532 nm green lasers with high power and good beam quality were created. Each green laser was constructed of an intra-cavity frequency doubling branch based on a laser diode (LD) end-pumped acousto-optical (AO) Q-switched 1064 nm Nd:YVO4 laser in a LiB3O5 (LBO) nonlinear crystal. Each branch generated about 45 W green output at a 50 kHz pulse repetition rate (PRR) with diffraction limited beam quality. The first green beam was injected into the LBO crystal in the second branch, and the pulses from the two branches did not exist simultaneously. Then, the HBCC was performed. Consequently, an 83 W combined green output power at 532 nm was obtained with a combination efficiency of 92.2%. The PRR of the HBCC pulse was doubled to be 100 kHz, with a pulse width of about 22 ns, corresponding to a single pulse energy of 0.83 mJ and a peak power of 37.73 kW. The combined beam quality factor was measured to be M x2 = 1.80 in the x direction and M y2 = 1.71 in the y direction, respectively. Moreover, many more beams could also be combined with this method for further scaling the green power.

The prevalence, diagnostic accuracy and genotype-phenotype correlation of GNAS mutations in fibrous dysplasia: a meta-analysis.

Background: There is inconsistent evidence regarding the accuracy of GNAS mutations identification for the diagnosis of FD/MAS. This study was performed to estimate the prevalence and diagnostic accuracy of GNAS mutations detection and to preliminarily investigate the genotype-phenotype correlation in FD patients. Methods: Five electronic databases were searched from 1995 to 2024 using search terms related to GNAS and fibrous dysplasia. Observational studies of FD patients undergoing GNAS mutation detection in FD were included. Results: A total of 878 FD patients were included. The pooled prevalence of GNAS mutations in FD based on the random effects model was 74% (95% CI = 64%-83%). Regarding diagnostic accuracy, a sensitivity of 0.83 (95% CI, 0.65-0.96), specificity of 0.99 (95% CI, 0.98-1.00) and the area under the receiver operating characteristic curve of 98.38% were found. Additionally, meta-analysis and Fisher's test showed the GNAS mutation types were significantly associated with FD types (OR = 3.51, 95% CI = 1.05 to 11.72; p < 0.05). Conclusion: A high detection rate of GNAS mutations occurred in FD, and its detection is reliable for diagnosing FD. Additionally, GNAS mutation type was types were significantly associated with FD type. Systematic Review Registration: Identifier CRD42024553469.

Precision Control of Amphoteric Doping in Cu x Bi2Se3 Nanoplates.

Copper-doped Bi2Se3 (Cu x Bi2Se3) is of considerable interest for tailoring its electronic properties and inducing exotic charge correlations while retaining the unique Dirac surface states. However, the copper dopants in Cu x Bi2Se3 display complex electronic behaviors and may function as either electron donors or acceptors depending on their concentration and atomic sites within the Bi2Se3 crystal lattice. Thus, a precise understanding and control of the doping concentration and sites is of both fundamental and practical significance. Herein, we report a solution-based one-pot synthesis of Cu x Bi2Se3 nanoplates with systematically tunable Cu doping concentrations and doping sites. Our studies reveal a gradual evolution from intercalative sites to substitutional sites with increasing Cu concentrations. The Cu atoms at intercalative sites function as electron donors while those at the substitutional sites function as electron acceptors, producing distinct effects on the electronic properties of the resulting materials. We further show that Cu0.18Bi2Se3 exhibits superconducting behavior, which is not present in Bi2Se3, highlighting the essential role of Cu doping in tailoring exotic quantum properties. This study establishes an efficient methodology for precise synthesis of Cu x Bi2Se3 with tailored doping concentrations, doping sites, and electronic properties.

Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression.

Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer. Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression. Nevertheless, the mechanistic role of epigenetic dysregulation in the tumor microenvironment is not fully understood. Here, we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor microenvironment and recent research advances in cancer epigenetic drugs. In addition, we discussed the great potential of epigenetic combination therapies in the clinical treatment of cancer. However, there are still some challenges in the field of cancer epigenetics, such as epigenetic tumor heterogeneity, epigenetic drug heterogeneity, and crosstalk between epigenetics, proteomics, metabolomics, and other omics, which may be the focus and difficulty of cancer treatment in the future. In conclusion, epigenetic modifications in the tumor microenvironment are essential for future epigenetic drug development and the comprehensive treatment of cancer. Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.

Group Theory on Quasisymmetry and Protected Near Degeneracy.

In solid state systems, group representation theory is powerful in characterizing the behavior of quasiparticles, notably the energy degeneracy. While conventional group theory is effective in answering yes-or-no questions related to symmetry breaking, its application to determining the magnitude of energy splitting resulting from symmetry lowering is limited. Here, we propose a theory on quasisymmetry and near degeneracy, thereby expanding the applicability of group theory to address questions regarding large-or-small energy splitting. Defined within the degenerate subspace of an unperturbed Hamiltonian, quasisymmetries form an enlarged symmetry group eliminating the first-order splitting. This framework ensures that the magnitude of splitting arises as a second-order effect of symmetry-lowering perturbations, such as external fields and spin-orbit coupling. We systematically tabulate the quasisymmetry groups within 32 crystallographic point groups and find all the possible unitary quasisymmetry group structures regarding double degeneracy. Applying our theory to the realistic material AgLa, we predict a "quasi-Dirac semimetal" phase characterized by two tiny-gap band anticrossings.

PERK inhibitor (ISRIB) improves depression-like behavior by inhibitions of HPA-axis over-activation in mice exposed to chronic restraint stress.

Stressful life event is closely associated with depression, thus strategies that blunt or prevent the negative effect stress on the brain might benefits for the treatment of depression. Although previous study showed the role of protein kinase R (PKR)-like ER kinase (PERK) in inflammation related depression, its involvement in the neuropathology of chronic stress induced depression is still unknown. We tried to explore whether block the PERK pathway would alleviate the animals' depression-like behavior induced by chronic restraint stress (CRS) and investigate the underlying mechanism. The CRS-exposed mice exhibited depression-like behavior, including anhedonia in the sucrose preference test (SPT), and increased immobility time in tail suspension test (TST) and forced swim test (FST). ISRIB administration for 2 weeks significantly improved the depression-like behavior in male mice exposed to CRS, which was manifested by markedly increasing the sucrose preference and reducing the immobility time in the FST and TST. However, we observed that exposure to the same dose of ISRIB in CRS female mice only showed improved anhedonia-like deficits,leaving unaltered improvement in the FST and TST. Mechanically, we found that ISRIB reversed the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, indicating decreased levels of serum corticosterone, reduced hippocampal glucocorticoidreceptor (GR) expression and expression of FosB in hypothalamic paraventricularnucleus (PVN), which was accompanied by preserved hippocampal neurogenesis. The present findings further expand the potential role of ER stress in depression and provide important details for a therapeutic path forward for PERK inhibitors in mood disorders.

Causal association between plasma metabolites and neurodegenerative diseases.

BACKGROUND: Establishing causal relationships between metabolic biomarkers and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is a challenge faced by observational studies. In this study, our aim was to investigate the causal associations between plasma metabolites and neurodegenerative diseases using Mendelian Randomization (MR) methods. METHODS: We utilized genetic associations with 1400 plasma metabolic traits as exposures. We used large-scale genome-wide association study (GWAS) summary statistics for AD and PD as our discovery datasets. For validation, we performed repeated analyses using different GWAS datasets. The main statistical method employed was inverse variance-weighted (IVW). We also conducted enrichment pathway analysis for IVW-identified metabolites. RESULTS: In the discovered dataset, there are a total of 69 metabolites (36 negatively, 33 positively) potentially associated with AD, and 47 metabolites (24 negatively， 23 positively) potentially associated with PD. Among these, 4 significant metabolites overlap with significant metabolites (PIVW < 0.05)in the validation dataset for AD, and 1 metabolite overlaps with significant metabolites in the validation dataset for PD. Three metabolites serve as common potential metabolic markers for both AD and PD, including Tryptophan betaine, Palmitoleoylcarnitine (C16:1), and X-23655 levels. Further pathway enrichment analysis suggests that the SLC-mediated transmembrane transport pathway, involving tryptophan betaine and carnitine metabolites, may represent potential intervention targets for treating AD and PD. CONCLUSION: This study offers novel insights into the causal effects of plasma metabolites on degenerative diseases through the integration of genomics and metabolomics. The identification of metabolites and metabolic pathways linked to AD and PD enhances our comprehension of the underlying biological mechanisms and presents promising targets for future therapeutic interventions in AD and PD.

Vaccarin alleviates septic cardiomyopathy by potentiating NLRP3 palmitoylation and inactivation.

BACKGROUND: Sepsis often leads to significant morbidity and mortality due to severe myocardial injury. As is known, the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome crucially contributes to septic cardiomyopathy (SCM) by facilitating the secretion of interleukin (IL)-1ß and IL-18. The removal of palmitoyl groups from NLRP3 is a crucial step in the activation of the NLRP3 inflammasome. Thus, the potential inhibitors that regulate the palmitoylation and inactivation of NLRP3 may significantly diminish sepsis-induced cardiac dysfunction. PURPOSE: The present study sought to explore the effects of the prospective flavonoid compounds targeting NLRP3 on SCM and to elucidate the associated underlying mechanisms. STUDY DESIGN: The palmitoylation and activation of NLRP3 were detected in H9c2 cells and C57BL/6 J mice. METHODS/RESULTS: Echocardiography, histological staining, western blotting, co-immunoprecipitation, qPCR, ELISA and network pharmacology were used to assess the impact of vaccarin (VAC) on SCM in mice subjected to lipopolysaccharide (LPS) injection. From the collection of 74 compounds, we identified that VAC had the strongest capability to suppress NLRP3 luciferase report gene activity in cardiomyocytes, and the anti-inflammatory characteristics of VAC were further ascertained by the network pharmacology. Exposure of LPS triggered apoptosis, inflammation, oxidative stress, mitochondrial disorder in cardiomyocytes. The detrimental alterations were significantly reversed upon VAC treatment in both septic mice and H9c2 cells exposed to LPS. In vivo experiments demonstrated that VAC treatment alleviated septic myocardial injury, indicated by enhanced cardiac function parameters, preserved cardiac structure, and reduced inflammation/oxidative response. Mechanistically, VAC induced NLRP3 palmitoylation to inactivate NLRP3 inflammasome by acting on zDHHC12. In support, the NLRP3 agonist ATP and the acylation inhibitor 2-bromopalmitate (2-BP) prevented the effects of VAC. CONCLUSION: Our findings suggest that VAC holds promise in protecting against SCM by mitigating cardiac oxidative stress and inflammation via priming NLRP3 palmitoylation and inactivation. These results lay the solid basis for further assessment of the therapeutic potential of VAC against SCM.

Dietary Supplementation with Naringin Improves Systemic Metabolic Status and Alleviates Oxidative Stress in Transition Cows via Modulating Adipose Tissue Function: A Lipid Perspective.

Dairy cows face metabolic challenges around the time of calving, leading to a negative energy balance and various postpartum health issues. Adipose tissue is crucial for cows during this period, as it regulates energy metabolism and supports immune function. Naringin, one of the main flavonoids in citrus fruit and their byproducts, is a potent antioxidant and anti-inflammatory phytoconstituent. The study aimed to evaluate the effects of supplemental naringin on performance, systemic inflammation, oxidative status, and adipose tissue metabolic status. A total of 36 multiparous Holstein cows (from ~21 d prepartum through 35 d postpartum) were provided a basal control (CON) diet or a CON diet containing naringin (NAR) at 30 g/d per cow. Supplemental NAR increased the yield of raw milk and milk protein, without affecting dry matter intake. Cows fed NAR showed significantly lower levels (p < 0.05) of serum non-esterified fatty acid (NEFA), C-reactive protein, IL-1ß, IL-6, malonaldehyde, lipopolysaccharide (LPS), aspartate aminotransferase, and alanine aminotransferase, but increased (p < 0.05) glutathione peroxidase activity relative to those fed CON. Supplemental NAR increased (p < 0.05) adipose tissue adiponectin abundance, decreased inflammatory responses, and reduced oxidative stress. Lipidomic analysis showed that cows fed NAR had lower concentrations of ceramide species (p < 0.05) in the serum and adipose tissue than did the CON-fed cows. Adipose tissue proteomics showed that proteins related to lipolysis, ceramide biosynthesis, inflammation, and heat stress were downregulated (p < 0.05), while those related to glycerophospholipid biosynthesis and the extracellular matrix were upregulated (p < 0.05). Feeding NAR to cows may reduce the accumulation of ceramide by lowering serum levels of NEFA and LPS and increasing adiponectin expression, thereby decreasing inflammation and oxidative stress in adipose tissue, ultimately improving their systemic metabolic status. Including NAR in periparturient cows' diets improves lactational performance, reduces excessive lipolysis in adipose tissue, and decreases systemic and adipose tissue inflammation and oxidative stress. Integrating lipidomic and proteomic data revealed that reduced ceramide and increased glycerophospholipids may alleviate metabolic dysregulations in adipose tissue, which in turn benefits systemic metabolic status.

Comparative Metabolome and Transcriptome Analyses Reveal Differential Enrichment of Metabolites with Age in Panax notoginseng Roots.

Panax notoginseng is a perennial plant well known for its versatile medicinal properties, including hepatoprotective, antioxidant, anti-inflammatory, anti-tumor, estrogen-like, and antidepressant characteristics. It has been reported that plant age affects the quality of P. notoginseng. This study aimed to explore the differential metabolome and transcriptome of 2-year (PN2) and 3-year-old (PN3) P. notoginseng plant root samples. Principal component analysis of metabolome and transcriptome data revealed major differences between the two groups (PN2 vs. PN3). A total of 1813 metabolites and 28,587 genes were detected in this study, of which 255 metabolites and 3141 genes were found to be differential (p < 0.05) between PN2 vs. PN3, respectively. Among differential metabolites and genes, 155 metabolites and 1217 genes were up-regulated, while 100 metabolites and 1924 genes were down-regulated. The KEGG pathway analysis revealed differentially enriched metabolites belonging to class lipids ("13S-hydroperoxy-9Z, 11E-octadecadionic acid", "9S-hydroxy-10E, 12Z-octadecadionic acid", "9S-oxo-10E, 12Z-octadecadionic acid", and "9,10,13-trihydroxy-11-octadecadionic acid"), nucleotides and derivatives (guanine and cytidine), and phenolic acids (chlorogenic acid) were found to be enriched (p < 0.05) in PN3 compared to PN2. Further, these differentially enriched metabolites were found to be significantly (p < 0.05) regulated via linoleic acid metabolism, nucleotide metabolism, plant hormone signal transduction, and arachidonic acid metabolism pathways. Furthermore, the transcriptome analysis showed the up-regulation of key genes MAT, DMAS, SDH, gallate 1-beta-glucosyltransferase, and beta-D-glucosidase in various plants' secondary metabolic pathways and SAUR, GID1, PP2C, ETR, CTR1, EBF1/2, and ERF1/2 genes observed in phytohormone signal transduction pathway that is involved in plant growth and development, and protection against the various stressors. This study concluded that the roots of a 3-year-old P. notoginseng plant have better metabolome and transcriptome profiles compared to a 2-year-old plant with importantly enriched metabolites and genes in pathways related to metabolism, plant hormone signal transduction, and various biological processes. These findings provide insights into the plant's dynamic biochemical and molecular changes during its growth that have several implications regarding its therapeutic use.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.