The first complete genome sequence and genetic evolution analysis of bovine norovirus in Xinjiang, China.

Introduction: Viruses are among the main pathogens causing diarrhoea in calves. The current study found that bovine norovirus (BNoV) is one of the principal viruses causing diarrhoea in calves in Xinjiang, China. Material and Methods: A total of 974 calf faecal samples from six regions in Xinjiang were tested for BNoV using reverse-transcriptase PCR. The genomic characteristics of BNoV and the genetic evolution of the VP1 gene, protein three-dimensional structure characteristics and amino acid variation were analysed using bioinformatics methods. Results: Epidemiological survey results showed that the infection rate of BNoV was 19.82%, and all samples tested positive in five regions. The results of the genetic evolution analysis showed that BNoV strains from Tacheng of northern Xinjiang and Kashgar of southern Xinjiang both belonged to the GIII.2 genotype of BNoV but were not on the same cluster of evolutionary branches. Additionally, the amino acid variation of the VP1 protein was not observed to significantly affect its spatial structure. Conclusion: This study is the first to report the genetic characteristics of the BNoV complete genome sequence in Xinjiang and provides a scientific basis for BNoV vaccine development and pathogenesis research.

Ocotillol Derivatives Mitigate Retinal Ischemia-Reperfusion Injury by Regulating the Keap1/Nrf2/ARE Signaling Pathway.

Retinal ischemia-reperfusion (RIR) injury can lead to various retinal diseases. Oxidative stress is considered an important pathological event in RIR injury. Here, we designed and synthesized 34 ocotillol derivatives, then examined their antioxidant and anti-inflammatory capacities; we found that compounds 7 (C24-R) and 8 (C24-S) were most active. To enhance their water solubility, sustained release, and biocompatibility, compounds 7 and 8 were encapsulated into liposomes for in vivo activity and mechanistic studies. In vivo studies indicated that compounds 7 and 8 protected normal retinal structure and physiological function after RIR injury, reversed damage to retinal ganglion cells, and the S-configuration exhibited significantly stronger activity compared with the R-configuration. Mechanistic studies showed that compound 8 exerted a therapeutic effect on RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound 7 did not influence this pathway. We also demonstrated that differential isomerization at the C-24 position influenced protection against RIR injury.

The profile and prognostic significance of bone marrow T-cell differentiation subsets in adult AML at diagnosis.

Background: T lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the long-term protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited. Patients and methods: Fresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry. Results: CD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) (P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapse-free survival (RFS, HR [95%CI]: 5.7 (1.4-22.2), P = 0.017 and 4.8 [1.3-17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1-9.5), P = 0.029; 4.0 (1.4-11.5), P = 0.010), respectively. Conclusions: AML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes.

Triplet therapy with gilteritinib, venetoclax, and azacitidine for relapsed/refractory FLT3mut acute myeloid leukemia.

The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory (R/R) FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but the overall survival (OS) is only approximately 20 % and few patients achieve deep and/ or durable response. We retrospectively analyzed 29 R/R FLT3mut AML patients treated on triplet regimens (gilteritinib+ venetoclaxï¼»VEN] +azacitidineï¼»AZA]). Nineteen patients (65.5 %) had received prior FLT3 inhibitor therapy. The modified composite complete remission (mCRc) rate was 62.1 % (n = 18; CR, 4/29,13.8 %; CRi, 6/29, 20.7 %; MLFS, 8/29, 27.6 %). Among 18 patients achieved mCRc, FLT3-PCR negativity was 94.4 % (n=17), and flow-cytometry negativity was 77.7 % (n=14). The mCRc rate was 70 % (n=7) in 10 patients without prior FLT3 TKI exposure and 57.8 % (n=11) in 19 patients with prior FLT3 TKI exposure (P=0.52). At the end of the first cycle, the median time to ANC > 0.5× 109/L was 38 days and platelet > 50× 109/L was 31 days among responders, but 60-day mortality was 0 %. The estimated 2-year OS was 60.9 % for all R/R FLT3mut patients. The 1-year OS was 80 % and 58.8 % in patients without and with prior FLT3 TKI exposure, respectively (P=0.79). The estimated 2-year OS was 62 % in 19 (65.5 %) patients who received allo-HSCT after triplet therapy and 37 % in 10 patients who did not receive allo-HSCT (P=0.03). In conclusion, triplet therapy with gilteritinib, VEN, and AZA is effective and safe and an excellent frontline option for R/R FLT3mut AML.

A Comparative Analysis of the Immunoglobulin Repertoire in Leukemia Cells and B Cells in Chinese Acute Myeloid Leukemia by High-Throughput Sequencing.

It is common knowledge that immunoglobulin (Ig) is produced by B lymphocytes and mainly functions as an antibody. However, it has been shown recently that myeloblasts from acute myeloid leukemia (AML) could also express Ig and that AML-Ig played a role in leukemogenesis and AML progression. The difference between Ig from myeloblasts and B cells has not been explored. Studying the characteristics of the Ig repertoire in myeloblasts and B cells will be helpful to understand the function and significance of AML-Ig. We performed 5' RACE-related PCR coupled with PacBio sequencing to analyze the Ig repertoire in myeloblasts and B cells from Chinese AML patients. Myeloblasts expressed all five classes of IgH, especially Igγ, with a high expression frequency. Compared with B-Ig in the same patient, AML-Ig showed different biased V(D)J usages and mutation patterns. In addition, the CDR3 length distribution of AML-Ig was significantly different from those of B-Ig. More importantly, mutations of AML-IgH, especially Igµ, Igα, and Igδ, were different from that of B-IgH in each AML patient, and the mutations frequently occurred at the sites of post-translational modification. AML-Ig has distinct characteristics of variable regions and mutations, which may have implications for disease monitoring and personalized therapy.

Multifunctional coating with hydrophobicity, antibacterial and flame-retardant properties on cotton fabrics by layer-by-layer self-assembly curing of phytic acid and a tyrosine-derived hyperbranched benzoxazine.

The inherent hydrophilicity and biocompatibility of cotton fabrics facilitated bacterial proliferation and safety concerns, limiting their applications. To address these issues, tyrosine-derived polyetherimide, bis(3-aminopropyl)-terminated poly(dimethylsiloxane), and paraformaldehyde were used to synthesize hyperbranched benzoxazine THB-BOZs-PDMS with potent antibacterial and antibiofilm activity. The protonated amino groups of benzoxazine facilitated electrostatic interactions with negatively charged bacteria, and hydrophobic interactions disrupted the cell membrane, leading to bacteria death. Notably, phytic acid interacts with benzoxazines through intermolecular forces, with its phosphoric acid groups facilitating the curing of benzoxazines, thereby imparting flame-retardant properties to the material. Consequently, a multifunctional coating was developed via LBL self-assembly and in-situ curing of benzoxazines and phytic acid on the fabric surfaces. The successful deposition of the coating was confirmed through compositional analysis and morphological characterization. After 4 cycles of LBL modification, the fabrics TBP + PA-CF-4 displayed outstanding antibacterial efficacy, bacterial anti-adhesion properties, and heat resistance. Furthermore, TBP + PA-CF-4 exhibited notable washing and mechanical durability, attributed to the stability conferred by in-situ cured of layers. Compared with other reported modified fabrics, TBP + PA-CF-4 displayed more comprehensive overall performances. These multifunctional fabrics provided a sustainable approach for advancing personal protective materials and public decoration, particularly suited for use in high-humidity environments or military settings.

Identification of differentially expressed tumour-related genes regulated by UHRF1-driven DNA methylation.

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator that plays critical roles in tumours. However, the DNA methylation alteration patterns driven by UHRF1 and the related differentially expressed tumour-related genes remain unclear. In this study, a UHRF1-shRNA MCF-7 cell line was constructed, and whole-genome bisulfite sequencing and RNA sequencing were performed. The DNA methylation alteration landscape was elucidated, and DNA methylation-altered regions (DMRs) were found to be distributed in both gene bodies and adjacent regions. The DMRs were annotated and categorized into 488 hypermethylated/1696 hypomethylated promoters and 1149 hypermethylated/5501 hypomethylated gene bodies. Through an integrated analysis with the RNA sequencing data, 217 methylation-regulated upregulated genes and 288 downregulated genes were identified, and these genes were primarily enriched in nervous system development and cancer signalling pathways. Further analysis revealed 21 downregulated oncogenes and 15 upregulated TSGs. We also showed that UHRF1 silencing inhibited cell proliferation and migration and suppressed tumour growth in vivo. Our study suggested that UHRF1 and the oncogenes or TSGs it regulates might serve as biomarkers and targets for breast cancer treatment.

Dissecting the Distinct Tumor Microenvironments of HRD and HRP Ovarian Cancer: Implications for Targeted Therapies to Overcome PARPi Resistance in HRD Tumors and Refractoriness in HRP Tumors.

High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRß+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRß+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors.

Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease.

BACKGROUND: As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats. METHODS: PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg- 1·wk- 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined. RESULTS: Inhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9. CONCLUSION: Inhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.

Risk prediction models for diabetic nephropathy among type 2 diabetes patients in China: a systematic review and meta-analysis.

Objective: This study systematically reviews and meta-analyzes existing risk prediction models for diabetic kidney disease (DKD) among patients with type 2 diabetes, aiming to provide references for scholars in China to develop higher-quality risk prediction models. Methods: We searched databases including China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP Chinese Science and Technology Journal Database, Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, Embase, and the Cochrane Library for studies on the construction of DKD risk prediction models among type 2 diabetes patients, up until 28 December 2023. Two researchers independently screened the literature and extracted and evaluated information according to a data extraction form and bias risk assessment tool for prediction model studies. The area under the curve (AUC) values of the models were meta-analyzed using STATA 14.0 software. Results: A total of 32 studies were included, with 31 performing internal validation and 22 reporting calibration. The incidence rate of DKD among patients with type 2 diabetes ranged from 6.0% to 62.3%. The AUC ranged from 0.713 to 0.949, indicating the prediction models have fair to excellent prediction accuracy. The overall applicability of the included studies was good; however, there was a high overall risk of bias, mainly due to the retrospective nature of most studies, unreasonable sample sizes, and studies conducted in a single center. Meta-analysis of the models yielded a combined AUC of 0.810 (95% CI: 0.780-0.840), indicating good predictive performance. Conclusion: Research on DKD risk prediction models for patients with type 2 diabetes in China is still in its initial stages, with a high overall risk of bias and a lack of clinical application. Future efforts could focus on constructing high-performance, easy-to-use prediction models based on interpretable machine learning methods and applying them in clinical settings. Registration: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a recognized guideline for such research. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024498015.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Comprehensive machine learning-based integration develops a novel prognostic model for glioblastoma.

In this study, we developed a new prognostic model for glioblastoma (GBM) based on an integrated machine learning algorithm. We used univariate Cox regression analysis to identify prognostic genes by combining six GBM cohorts. Based on the prognostic genes, 10 machine learning algorithms were integrated into 117 algorithm combinations, and the artificial intelligence prognostic signature (AIPS) with the greatest average C-index was chosen. The AIPS was compared with 10 previously published models by univariate Cox analysis and the C-index. We compared the differences in prognosis, tumor immune microenvironment (TIME), and immunotherapy sensitivity between the high and low AIPS score groups. The AIPS based on the random survival forest algorithm with the highest average C-index (0.868) was selected. Compared with the previous 10 prognostic models, our AIPS has the highest C-index. The AIPS was closely linked to the clinical features of GBM. We discovered that patients in the low score group had improved prognoses, a more active TIME, and were more sensitive to immunotherapy. Finally, we verified the expression of several key genes by western blotting and immunohistochemistry. We identified an ideal prognostic signature for GBM, which might provide new insights into stratified treatment approaches for GBM patients.

Multi-Dimensional Fragmentomics Enables Early and Accurate Detection of Colorectal Cancer.

Colorectal cancer (CRC) is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage CRC detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 CRC patients and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish CRC patients from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 CRC patients and 119 controls) and a prospective cohort of 242 participants (129 CRC patients and 113 controls). The ensemble stacked model showed remarkable discriminatory power between CRC patients and controls, outperforming all base models and achieving a high area under the ROC curve (AUC) of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting CRC in the validation cohort, with sensitivity increasing as cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early CRC detection and broad patient benefit.

A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

ABL1-mediated phosphorylation promotes FOXM1-related tumorigenicity by Increasing FOXM1 stability.

The transcription factor FOXM1, which plays critical roles in cell cycle progression and tumorigenesis, is highly expressed in rapidly proliferating cells and various tumor tissues, and high FOXM1 expression is related to a poor prognosis. However, the mechanism responsible for FOXM1 dysregulation is not fully understood. Here, we show that ABL1, a nonreceptor tyrosine kinase, contributes to the high expression of FOXM1 and FOXM1-dependent tumor development. Mechanistically, ABL1 directly binds FOXM1 and mediates FOXM1 phosphorylation at multiple tyrosine (Y) residues. Among these phospho-Y sites, pY575 is indispensable for FOXM1 stability as phosphorylation at this site protects FOXM1 from ubiquitin-proteasomal degradation. The interaction of FOXM1 with CDH1, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which is responsible for FOXM1 degradation, is significantly inhibited by Y575 phosphorylation. The phospho-deficient FOXM1(Y575F) mutant exhibited increased ubiquitination, a shortened half-life, and consequently a substantially decreased abundance. Compared to wild-type cells, a homozygous Cr-Y575F cell line expressing endogenous FOXM1(Y575F) that was generated by CRISPR/Cas9 showed obviously delayed mitosis progression, impeded colony formation and inhibited xenotransplanted tumor growth. Overall, our study demonstrates that ABL1 kinase is involved in high FOXM1 expression, providing clear evidence that ABL1 may act as a therapeutic target for the treatment of tumors with high FOXM1 expression.

Spatiotemporal analysis of microstructure, sensory attributes, and full-spectrum metabolomes reveals the relationship between bitterness and nootkatone in Alpinia oxyphylla miquel fruit peel and seeds.

The Alpinia oxyphylla fruit (AOF) is a popular condiment and traditional Chinese medicine in Asia, known for its neuroprotective compound nootkatone. However, there has not been a comprehensive study of its flavor or the relationship between sensory and bioactive compounds. To address this issue, we examined AOF's microstructure, flavor, and metabolomic profiles during fruit maturation. The key markers used to distinguish samples included fruit expansion, testa pigmentation, aril liquefaction, oil cell expansion, peel spiciness, aril sweetness, and seed bitterness. A full-spectrum metabolomic analysis, combining a nontargeted metabolomics approach for volatile compounds and a widely targeted metabolomics approach for nonvolatile compounds, identified 1,448 metabolites, including 1,410 differentially accumulated metabolites (DAMs). Notably, 31 DAMs, including nootkatone, were associated with spicy peel, sweet aril, and bitter seeds. Correlational analysis indicated that bitterness intensity is an easy-to-use biomarker for nootkatone content in seeds. KEGG enrichment analysis linked peel spiciness to phenylpropanoid and capsaicin biosynthesis, seed bitterness to terpenoid (especially nootkatone) biosynthesis, and aril sweetness to starch and sucrose metabolism. This investigation advances the understanding of AOF's complex flavor chemistry and underlying bioactive principle, encapsulating the essence of the adage: "no bitterness, no intelligence" within the realm of phytochemistry.

The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies.

Integrated Metabolomics and Transcriptomics Analyses of the Biosynthesis of Arbutin and 6'-O-Caffeoylarbutin in Vaccinium dunalianum Cell Suspension Cultures Fed with Hydroquinone.

Arbutin and 6'-O-caffeoylarbutin (CA) from Vaccinium dunalianum Wight are known for their ability to inhibit melanin synthesis. To boost the production of arbutin and CA, precursor feeding with hydroquinone (HQ) was studied in V. dunalianum suspension cells. The effect of HQ on the biosynthesis of arbutin and CA in the suspension cells was investigated using high-performance liquid chromatography (HPLC), and possible molecular mechanisms were analyzed using metabolomics and transcriptomics analyses. HPLC analysis only showed that the addition of HQ significantly enhanced arbutin synthesis in cells, peaking at 15.52 ± 0.28 mg·g-1 after 0.5 mmol·L-1 HQ treatment for 12 h. Subsequently, metabolomics identified 78 differential expression metabolites (DEMs), of which arbutin and CA were significantly up-regulated metabolites. Moreover, transcriptomics found a total of 10,628 differential expression genes (DEGs). The integrated transcriptomics and metabolomics revealed that HQ significantly enhanced the expression of two arbutin synthase (AS) genes (Unigene0063512 and Unigene0063513), boosting arbutin synthesis. Additionally, it is speculated that CA was generated from arbutin and 3,4,5-tricaffeoylquinic acid catalyzed by caffeoyl transferase, with Unigene0044545, Unigene0043539, and Unigene0017356 as potentially associated genes with CA synthesis. These findings indicate that the precursor feeding strategy offers a promising approach for the mass production of arbutin and CA in V. dunalianum suspension cells and provides new insights for CA biosynthesis in V. dunalianum.

Enhancing CO2 fixation by microalgae in a Photobioreactor: Molecular mechanisms with exogenous carbonic anhydrase.

Microalgae biotechnology holds great potential for mitigating CO2 emissions, yet faces challenges in commercialization due to suboptimal photosynthetic efficiency. This study presents an innovative approach to improve CO2 mass transfer efficiency in microalgae using carbonic anhydrase (CA) in an internal LED flexible air-lift photobioreactor. Optimal conditions initial inoculation with 3.55 × 106 cells/mL and 20 % CO2 concentration, complemented by white LED lighting in Chlorella sp. CA regulated intracellular composition, enhancing chlorophyll, lipid, and protein contents. Metabolomics revealed elevated malic and succinic acids, associated with increased Ribulose 1,5-bisphosphate carboxylase oxygenase (RuBisCO) and Acetoacetyl coenzyme A (Acetyl-CoA) activities, facilitating efficient carbon fixation. CA also mitigated cellular oxidative stress by reducing reactive oxygen species (ROS). Furthermore, CA improved extracellular electron acceptor with currents surpassed CK. This CA-based microalgae biotechnology provides a foundation for future commercial applications, addressing CO2 emissions.