Partial inhibition of class III PI3K VPS-34 ameliorates motor aging and prolongs health span.

Global increase of life expectancy is rarely accompanied by increased health span, calling for a greater understanding of age-associated behavioral decline. Motor independence is strongly associated with the quality of life of elderly people, yet the regulators for motor aging have not been systematically explored. Here, we designed a fast and efficient genome-wide screening assay in Caenorhabditis elegans and identified 34 consistent genes as potential regulators of motor aging. Among the top hits, we found VPS-34, the class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI(3)P), regulates motor function in aged but not young worms. It primarily functions in aged motor neurons by inhibiting PI(3)P-PI-PI(4)P conversion to reduce neurotransmission at the neuromuscular junction (NMJ). Genetic and pharmacological inhibition of VPS-34 improve neurotransmission and muscle integrity, ameliorating motor aging in both worms and mice. Thus, our genome-wide screening revealed an evolutionarily conserved, actionable target to delay motor aging and prolong health span.

Recent advances in the chemistry of isolable carbene analogues with group 13-15 elements.

Carbenes (R2C:), compounds with a divalent carbon atom containing only six valence shell electrons, have evolved into a broader class with the replacement of the carbene carbon or the RC moiety with main group elements, leading to the creation of main group carbene analogues. These analogues, mirroring the electronic structure of carbenes (a lone pair of electrons and an empty orbital), demonstrate unique reactivity. Over the last three decades, this area has seen substantial advancements, paralleling the innovations in carbene chemistry. Recent studies have revealed a spectrum of unique carbene analogues, such as monocoordinate aluminylenes, nitrenes, and bismuthinidenes, notable for their extraordinary properties and diverse reactivity, offering promising applications in small molecule activation. This review delves into the isolable main group carbene analogues that are in the forefront from 2010 and beyond, spanning elements from group 13 (B, Al, Ga, In, and Tl), group 14 (Si, Ge, Sn, and Pb) and group 15 (N, P, As, Sb, and Bi). Specifically, this review focuses on the potential amphiphilic species that possess both lone pairs of electrons and vacant orbitals. We detail their comprehensive synthesis and stabilization strategies, outlining the reactivity arising from their distinct structural characteristics.

Correction: Recent advances in the chemistry of isolable carbene analogues with group 13-15 elements.

Correction for 'Recent advances in the chemistry of isolable carbene analogues with group 13-15 elements' by Mian He et al., Chem. Soc. Rev., 2024, https://doi.org/10.1039/D3CS00784G.

Dynamic Spatial-Selective Metasurface with Multiple-Beam Interference.

The emergence of the metasurface has provided a versatile platform for the manipulation of light at the nanoscale. Recent research in metasurfaces has explored a plethora of dynamic control and switching of multifunctionalities, paving the way for innovative applications in fields such as imaging, sensing, and communication. However, current dynamic multifunctional metasurfaces face challenges in terms of functional scalability and selective activation. In this work, we introduce and experimentally demonstrate a strategy that utilizes multiple plane waves to create arbitrary periodic patterns on the metasurface, thus enabling the dynamic and arbitrary spatial-selective activation of its embedded multiplexed functionalities. Furthermore, our strategy facilitates dynamic light control through mechanical translation, as demonstrated by a high-speed, dynamically switchable beam deflection scenario. Our method effectively overcomes the limitations associated with traditional spatially multiplexing techniques, offering greater flexibility and selectivity for dynamic control in multifunctional metasurfaces.

Pioglitazone alleviates lacrimal gland impairments induced by high-fat diet by suppressing M1 polarization.

A high-fat diet (HFD) contributes to the pathogenesis of various inflammatory and metabolic diseases. Previous research confirms that under HFD conditions, the extraorbital lacrimal glands (ELGs) can be impaired, with significant infiltration of pro-inflammatory macrophages (Mps). However, the relationship between HFD and Mps polarization in the ELGs remains unexplored. We first identified and validated the differential expression of PPAR-γ in murine ELGs fed ND and HFD through RNA sequencing. Tear secretion was measured using the Schirmer test. Lipid droplet deposition within the ELGs was observed through Oil Red O staining and transmission electron microscopy. Mps phenotypes were determined through quantitative RT-PCR, immunofluorescence, and flow cytometric analysis. An in vitro high-fat culture system for Mps was established using palmitic acid (PA), with supernatants collected for co-culture with lacrimal gland acinar cells. Gene expression was determined through ELISA, immunofluorescence, immunohistochemistry, quantitative RT-PCR, and Western blot analysis. Pioglitazone reduced M1-predominant infiltration induced by HFD by increasing PPAR-γ levels in ELGs, thereby alleviating lipid deposition and enhancing tear secretion. In vitro tests indicated that PPAR-γ agonist shifted Mps from M1-predominant to M2-predominant phenotype in PA-induced Mps, reducing lipid synthesis in LGACs and promoting lipid catabolism, thus alleviating lipid metabolic disorders within ELGs. Conversely, the PPAR-γ antagonist induced opposite effects. In summary, the lacrimal gland is highly sensitive to high-fat and lipid metabolic disorders. Downregulation of PPAR-γ expression in ELGs induces Mps polarization toward predominantly M1 phenotype, leading to lipid metabolic disorder and inflammatory responses via the NF-κb/ERK/JNK/P38 pathway.

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma.

BACKGROUND: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. METHODS: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. RESULTS: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. CONCLUSIONS: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

Risks of digestive diseases in long COVID: evidence from a population-based cohort study.

BACKGROUND: In the post-pandemic era, a wide range of COVID-19 sequelae is of growing health concern. However, the risks of digestive diseases in long COVID have not been comprehensively understood. To investigate the long-term risk of digestive diseases among COVID patients. METHODS: In this large-scale retrospective cohort study with up to 2.6 years follow-up (median follow-up: 0.7 years), the COVID-19 group (n = 112,311), the contemporary comparison group (n = 359,671) and the historical comparison group (n = 370,979) predated the COVID-19 outbreak were built using UK Biobank database. Each digestive outcome was defined as the diagnosis 30 days or more after the onset of COVID-19 infection or the index date. Hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting. RESULTS: Compared with the contemporary comparison group, patients with previous COVID-19 infection had higher risks of digestive diseases, including gastrointestinal (GI) dysfunction (HR 1.38 (95% CI 1.26 to 1.51)); peptic ulcer disease (HR 1.23 (1.00 to 1.52)); gastroesophageal reflux disease (GERD) (HR 1.41 (1.30 to 1.53)); gallbladder disease (HR 1.21 (1.06 to 1.38)); severe liver disease (HR 1.35 (1.03 to 1.76)); non-alcoholic liver disease (HR 1.27 (1.09 to 1.47)); and pancreatic disease (HR 1.36 (1.11 to 1.66)). The risks of GERD were increased stepwise with the severity of the acute phase of COVID-19 infection. Even after 1-year follow-up, GERD (HR 1.64 (1.30 to 2.07)) and GI dysfunction (HR 1.35 (1.04 to 1.75)) continued to pose risks to COVID-19 patients. Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of pancreatic diseases (HR 2.57 (1.23 to 5.38)). The results were consistent when the historical cohort was used as the comparison group. CONCLUSIONS: Our study provides insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing digestive diseases. The risks exhibited a stepwise escalation with the severity of COVID-19, were noted in cases of reinfection, and persisted even after 1-year follow-up. This highlights the need to understand the varying risks of digestive outcomes in COVID-19 patients over time, particularly those who experienced reinfection, and develop appropriate follow-up strategies.

Blended BA.5 infection within 8 days after a boosted bivalent mRNA vaccination strengthens and lengthens the host immunity.

The impact of SARS-CoV-2 infection shortly after vaccination on vaccine-induced immunity is unknown, which is also one of the concerns for some vaccinees during the pandemic. Here, based on a cohort of individuals who encountered BA.5 infection within 8 days after receiving the fourth dose of a bivalent mRNA vaccine, preceded by three doses of inactivated vaccines, we show that booster mRNA vaccination provided 48% protection efficacy against symptomatic infections. At Day 7 postvaccination, the level of neutralizing antibodies (Nabs) against WT and BA.5 strains in the uninfected group trended higher than those in the symptomatic infection group. Moreover, there were greater variations in Nabs levels and a significant decrease in virus-specific CD4+ T cell response observed in the symptomatic infection group. However, symptomatic BA.5 infection significantly increased Nab levels against XBB.1.9.1 and BA.5 (symptomatic > asymptomatic > uninfected group) at Day 10 and resulted in a more gradual decrease in Nabs against BA.5 compared to the uninfected group at Day 90. Our data suggest that BA.5 infection might hinder the early generation of Nabs and the recall of the CD4+ T cell response but strengthens the Nab and virus-specific T cell response in the later phase. Our data confirmed that infection can enhance host immunity regardless of the short interval between vaccination and infection and alleviate concerns about infections shortly after vaccination, which provides valuable guidance for developing future vaccine administration strategies.

The neutrophil-to-lymphocyte ratio is associated with all-cause and cardiovascular mortality among individuals with hypertension.

BACKGROUND: Identifying reliable prognostic markers is crucial for the effective management of hypertension. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential inflammatory marker linked to cardiovascular outcomes. This study aims to investigate the association of NLR with all-cause and cardiovascular mortality among patients with hypertension. METHODS: This study analyzed data from 3067 hypertensive adults in the National Health and Nutritional Examination Surveys (NHANES) from 2009 to 2014. Mortality details were obtained from the National Death Index (NDI). Restricted cubic spline (RCS) was deployed to visualize the association of the NLR with mortality risk. Weighted Cox proportional hazards models were employed to assess the independent association of NLR with mortality risk. Time-dependent receiver operating characteristic curve (ROC) analysis was conducted to access the predictive ability of NLR for survival. Mediation analysis was used to explore the indirect impact of NLR on mortality mediated through eGFR. RESULTS: Over a median 92.0-months follow-up, 538 deaths occurred, including 114 cardiovascular deaths. RCS analysis revealed a positive association between NLR and both all-cause and cardiovascular mortality. Participants were stratified into higher (> 3.5) and lower (≤ 3.5) NLR groups. Weighted Cox proportional hazards models demonstrated that individuals with higher NLR had a significantly increased risk of all-cause (HR 1.96, 95% confidence interval (CI) 1.52-2.52, p < 0.0001) and cardiovascular mortality (HR 2.33, 95% CI 1.54-3.51, p < 0.0001). Stratified and interaction analysis confirmed the stability of the core results. Notably, eGFR partially mediated the association between NLR and both all-cause and cardiovascular mortality by a 5.4% and 4.7% proportion, respectively. Additionally, the areas under the curve (AUC) of the 3-, 5- and 10- year survival was 0.68, 0.65 and 0.64 for all-cause mortality and 0.68, 0.70 and 0.69 for cardiovascular mortality, respectively. CONCLUSION: Elevated NLR independently confers an increased risk for both all-cause and cardiovascular mortality in individuals with hypertension.

Survival outcomes and treatment experience of 124 patients with primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a rare malignancy of the central nervous system with high invasiveness. There is little consensus on the treatment of PCNSL. This study retrospectively studied data from PCNSL patients in a single center to summarize treatment experience and explore prognostic factors. METHODS: Survival curves were drawn using the Kaplan-Meier method and prognostic factors were analyzed using Cox's hazards model. RESULTS: In multivariate analysis, cerebrospinal fluid lactic acid dehydrogenase (CSF LDH; p = 0.005 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.014 and p = 0.038), and completion of four cycles of induction therapy (p < 0.001and p < 0.001) were significant and independent predictors of overall survival (OS) and progression-free survival (PFS), respectively. CONCLUSION: On the basis of this study, we propose that PCNSL patients should receive early induction therapy with sufficient cycles. Subsequent consolidation therapy can prevent relapses and improve survival. In patients with PCNSL, the independent prognostic factors for OS and PFS were CSF LDH level, NLR, and full cycles of induction therapy.

Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

PURPOSE: Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1)2) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [68Ga]Ga-labeled (TMVP1)2. METHODS: In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N', N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]Ga-NOTA-(TMVP1)2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30-45 min after intravenous injection of [68Ga]Ga-NOTA-(TMVP1)2. RESULTS: Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]Ga-NOTA-(TMVP1)2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1)2 reduced the enrichment of [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]Ga-NOTA-(TMVP1)2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]Ga-NOTA-(TMVP1)2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. CONCLUSION: The favorable characterizations of [68Ga]Ga-NOTA-(TMVP1)2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. TRIAL REGISTRATION: ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

Anaerolentibacter hominis gen. nov. sp. nov., Diplocloster hominis sp. nov. and Pilosibacter fragilis gen. nov. sp. nov., isolated from human faeces.

Three Gram-positive, obligately anaerobic bacterial strains, namely CSJ-1T, CSJ-3T, and CSJ-4T, were isolated from faeces of healthy persons. They were characterized through a combination of whole-genome sequencing, phenotypic traits, and metabolomic analysis. The genome sizes of CSJ-1T, CSJ-4T, and CSJ-3T were 3.3, 3.8, and 6.1 Mbp, with DNA G+C contents of 47.2, 48.3, and 48.8 mol%, respectively. Strain CSJ-3T was identified as representing a novel species, Diplocloster hominis (type strain CSJ-3T=CGMCC 1.18033T=JCM 36512T) of the genus Diplocloster. The 16S rRNA gene sequence similarity and whole genome average nucleotide identity (gANI) of CSJ-4T to its closest related species, Diplocloster modestus ASD 4241T, were 98.3 and 91.4 %, respectively. Comparative analysis of 16S rRNA gene sequences showed 91.6 % similarity between CSJ-1T and its closest phylogenetic neighbour, Catenibacillus scindens DSM 106146T, and 93.3 % similarity between CSJ-4T and its closest relative strain, Clostridium fessum SNUG30386T. Based on the polyphasic taxonomic results, we proposed two novel genera and three novel species. Strain CSJ-1T was identified as representing a novel species of novel genus, Anaerolentibacter hominis gen. nov. sp. nov. (type strain CSJ-1T=CGMCC 1.18046T=JCM 36511T) of the family Lachnospiraceae, and strain CSJ-4T was identified as representing a novel species of novel genus Pilosibacter fragilis gen. nov. sp. nov. (type strain CSJ-4T=CGMCC 1.18026T= JCM 36513T) of the family Clostridiaceae.

A Nanoconfined FeCo2O4-Embedded Ceramic Membrane Regulates Electron Transfer in Peroxymonosulfate Activation to Selectively Generate Singlet Oxygen for Water Decontamination.

Peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs), as a promising technology for water decontamination, are constrained by low reaction kinetics due to limited reaction selectivity and mass transfer. Herein, we designed a nanoconfined FeCo2O4-embedded ceramic membrane (FeCo2O4-CM) under flow-through pattern for PMS activation. Confining PMS and FeCo2O4 within nanochannels (3.0-4.7 nm) enhanced adsorption interactions (-7.84 eV vs -2.20 eV), thus boosting mass transfer. Nanoconfinement effect regulated electron transfer pathways from PMS to FeCo2O4-CM by modulating the active site transformation to ≡Co(III) in nanoconfined FeCo2O4-CM, enabling selectively generating 1O2. The primary role of 1O2 in the nanoconfined system was confirmed by kinetic solvent isotope experiments and indicative anthracene endoperoxide (DPAO2). The system enabled 100% removal of atrazine (ATZ) within a hydraulic retention time of 2.124 ms, demonstrating a rate constant over 5 orders of magnitude higher than the nonconfined system (3.50 × 103 s-1 vs 0.42 min-1). It also exhibited strong resilience to pH variations (3.3-9.0) and coexisting substances, demonstrating excellent stability indicated by consistent 100% ATZ removal for 14 days. This study sheds light on regulating electron transfer pathways to selectively generate 1O2 through the nanoconfinement effect, boosting the practical application of PMS-based AOPs in environmental remediation and potentially applying them to various other AOPs.

SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 µmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.

Tumor targeting peptide TMTP1 modified Antigen capture Nano-vaccine combined with chemotherapy and PD-L1 blockade effectively inhibits growth of ovarian cancer.

The mortality of ovarian cancer (OC) has long been the highest among gynecological malignancies. Although OC is considered to be an immunogenic tumor, the effect of immunotherapy is not satisfactory. The immunosuppressive microenvironment is one reason for this, and the absence of recognized effective antigens for vaccines is another. Chemotherapy, as one of the most commonly used treatment for OC, can produce chemotherapy-associated antigens (CAAs) during treatment and show the effect of in situ vaccine. Herein, we designed an antigen capture nano-vaccine NP-TP1@M-M with tumor targeting peptide TMTP1 and dendritic cell (DC) receptor mannose assembled on the surface and adjuvant monophosphoryl lipid A (MPLA) encapsulated in the core of poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles. PLGA itself possessed the ability of antigen capture. TMTP1 was a tumor-homing peptide screened by our research team, which held extensive and excellent tumor targeting ability. After these modifications, NP-TP1@M-M could capture and enrich more tumor-specific antigens after chemotherapy, stimulate DC maturation, activate the adaptive immunity and combined with immune checkpoint blockade to maximize the release of the body's immune potential, providing an eutherapeutic strategy for the treatment of OC.

Regulation of GSTu1-mediated insecticide resistance in Plutella xylostella by miRNA and lncRNA.

The evolution of resistance to insecticides is well known to be closely associated with the overexpression of detoxifying enzymes. Although the role of glutathione S-transferase (GST) genes in insecticide resistance has been widely reported, the underlying regulatory mechanisms are poorly understood. Here, one GST gene (GSTu1) and its antisense transcript (lnc-GSTu1-AS) were identified and cloned, and both of them were upregulated in several chlorantraniliprole-resistant Plutella xylostella populations. GSTu1 was confirmed to be involved in chlorantraniliprole resistance by direct degradation of this insecticide. Furthermore, we demonstrated that lnc-GSTu1-AS interacted with GSTu1 by forming an RNA duplex, which masked the binding site of miR-8525-5p at the GSTu1-3'UTR. In summary, we revealed that lnc-GSTu1-AS maintained the mRNA stability of GSTu1 by preventing its degradation that could have been induced by miR-8525-5p and thus increased the resistance of P. xylostella to chlorantraniliprole. Our findings reveal a new noncoding RNA-mediated pathway that regulates the expression of detoxifying enzymes in insecticide-resistant insects and offer opportunities for the further understanding of the mechanisms of insecticide and drug resistance.

[Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions].

The group standard Guidelines for construction of traditional Chinese medicine(TCM) pharmacovigilance system in medical institutions, managed by Chinese Association of Chinese Medicine and led by the Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Sciences and Dongfang Hospital of Beijing University of Chinese Medicine, was announced on National Group Standard Information Platform on January 16, 2024, with the standard number T/CACM 1563. 2-2024. According to EU pharmacovigilance regulations and the second-level guidance principles of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), the unique characteristics of TCM were fully considered, and the relevant systems and procedures for constructing TCM pharmacovigilance systems in medical institutions were clearly defined. This included establishing TCM pharmacovigilance information platforms, arranging staff, formulating various regulations, and monitoring adverse reactions of TCM(including TCM decoction pieces, granules, Chinese patent medicines, in-hospital preparations, and pre-marketed Chinese patent medicines). It aimed to develop a TCM pharmacovigilance system in medical institutions that was tailored to the characteristics of TCM. The system could be appropriately adjusted according to the scope of practice and actual circumstances of medical institutions at different levels. This will enhance the implementation of TCM pharmacovigilance work and safeguard medication safety. The group standard underwent multiple rounds of consultations with internal and external experts and has ultimately evolved into a guiding document applicable to medical institutions and related entities engaged in pharmacovigilance activities.

[Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines].

Oral Chinese patent medicine is the essence of effective prescriptions created and summarized by Chinese medical scientists through thousands of years of medical practice. It is portable and convenient, with an obvious curative effect and other characteristics. However, at present, oral Chinese patent medicine is rich in dosage forms, various in types, complex in mechanism of action, and broad in clinical positioning. In clinical application, there are often cases of drug use without reference to instructions,repeated drug use, and prolonged drug use, which highlights safety problems such as adverse reactions and hepatorenal toxicity. Oral Chinese patent medicine pharmacovigilance is facing challenges. World Health Organization(WHO) has issued the WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) has issued the ICH E2 pharmacovigilance guidelines. The United States has issued the Pharmacovigilance management standards and pharmacoepidemiological assessment guidelines, and the European Union has issued the Guidelines on good pharmacovigilance practices. Japan, South Korea, and other countries in the Asia Pacific region have established their own pharmacovigilance systems, but currently, there are no pharmacovigilance guidelines related to oral Chinese patent medicine in China. Therefore, experts from many disciplines and fields in China were invited to jointly develop the Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines, which aims to develop pharmacovigilance guidelines for clinical application that are consistent with China's national conditions and highlight the characteristics of oral Chinese patent medicine, and provide guidance for clinically safe and rational drug application in medical institutions.

[Pharmacovigilance guidelines of Chinese patent medicines].

Drug administration law of the People's Republic of China(2019 revised edition), which came into effect on December 1, 2019, proposed that " the state shall establish a pharmacovigilance system". Pharmacovigilance work of Chinese patent medicines is more difficult, and it is necessary to carry out Pharmacovigilance activities that are in line with the characteristics of Chinese patent medicines. Pharmacovigilance guidelines of Chinese patent medicines(T/CACM 1563. 1-2024), based on the principles of Drug Administration Law of the People's Republic of China(2019 revised edition) and Pharmacovigilance quality management standards(No. 65 of 2021) of the National Medical Products Administration, draws on the EU Pharmacovigilance regulation and the secondary guidelines of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), and it is drafted in accordance with the provisions of Guidelines for standardization work part 1: structure and drafting rules of standardization documents(GB/T1. 1-2020) based on the characteristics of Chinese patent medicines. It serves as a general document for a series of pharmacovigilance guidelines of Chinese patent medicines, such as Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions(T/CACM 1563. 2-2024), Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines(T/CACM 1563. 3-2024), Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections(T/CACM 1563. 4-2024), Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use(T/CACM 1563. 5-2024), and Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration(T/CACM 1563. 6-2024), including four major elements of pharmacovigilance monitoring and reporting of Chinese patent medicines, signal identification, risk evaluation, and risk control, as well as pharmacovigilance activities for Chinese patent medicines, ensuring the safety of public drug use.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration].

The group standard Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration was released on January 16, 2024, on the national group standards information platform by the Institute of Basic Research in Clinical Medicine of China Academy of Chinese Medical Sciences and School and Hospital of Stomatology of Peking University, under the centralized management by the China Association of Chinese Medicine. The standard number is T/CACM 1563.6-2024. It aims to propose key elements and specify technical methods for safety monitoring and reporting, signal identification, risk assessment, and risk control based on the Drug administration law of the People's Republic of China(revised in 2019), which establishes normative pharmacovigilance guideline of Chinese patent medicine for mucosal administration that is in line with the characteristics of traditional Chinese Medicine(TCM) based on the pharmacovigilance content for clinical application of Chinese patent medicine for mucosal administration. The group standard has been discussed by internal and external experts through multiple rounds of consultation. It serves as a guiding document for stakeholders involved in pharmacovigilance activities, including pharmaceutical license holders, drug manufacturers, medical institutions, research institutes, and pharmaceutical trading enterprises.