RESUMEN

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatory mechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)-induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1 mRNA levels were dramatically decreased and P53 mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by up-regulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1 mediated P53 expression might be identified as potential targets for the early treatment of septic AKI.

Asunto(s)

Lesión Renal Aguda , Apoptosis , Acuaporina 1 , Fibrosis , Inflamación , Sepsis , Proteína p53 Supresora de Tumor , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/etiología , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Acuaporina 1/genética , Acuaporina 1/metabolismo , Animales , Sepsis/complicaciones , Sepsis/metabolismo , Ratones , Humanos , Masculino , Ratas , Modelos Animales de Enfermedad , Riñón/patología , Riñón/metabolismo , Ratones Endogámicos C57BL , Ratas Sprague-Dawley

RESUMEN

We aimed to investigate the preventive effect of vitamin D2 on COVID-19 and the improvement of symptoms after COVID-19 infection. The study recruited 228 health care workers who tested negative PCR or antigen for COVID-19. Subjects were randomly allocated to vitamin D2 or non-intervention at a ratio 1:1. Subjects recorded PCR or antigen tests and the symptoms of COVID-19 twice a week during the follow-up visit. The concentration of serum 25-hydroxyvitamin D (25(OH)D), C-reaction protein (CRP), complement component C1q and inflammatory cytokines were measured. The rates of COVID-19 infection were 50.5% in the vitamin D2 group and 52.4% in the non-intervention group (P = 0.785). There was no difference in the COVID-19 symptoms between the two groups. The mean 25(OH)D level significantly increased from 14.1 to 31.1 ng/mL after administration (P < 0.001). The difference between the two groups was not significant for the concentrations of CRP, C1q and inflammatory cytokines on the thirtieth day of the trial. According to the second level of vitamin D, there was a 14.3% difference in positive infection rates between the vitamin D adequate (> 30 ng/mL) and deficient groups (< 20 ng/mL). Adequate vitamin D had a tendency to prevent COVID-19.Trial registration: ClinicalTrials.gov NCT05673980, dated: 12/2022.

Asunto(s)

Proteína C-Reactiva , COVID-19 , Citocinas , SARS-CoV-2 , Vitamina D , Humanos , Masculino , Vitamina D/sangre , Vitamina D/uso terapéutico , Vitamina D/análogos & derivados , Vitamina D/administración & dosificación , Femenino , COVID-19/prevención & control , COVID-19/sangre , COVID-19/epidemiología , Adulto , Persona de Mediana Edad , Citocinas/sangre , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Ergocalciferoles/uso terapéutico , Ergocalciferoles/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Complemento C1q/metabolismo

RESUMEN

The black cutworm, Agrotis ipsilon (Lepidoptera: Noctuidae), is an important agricultural pest. Phoxim is an organophosphate insecticide that has been widely used to control A. ipsilon. The extensive application of phoxim has resulted in a reduction in phoxim susceptibility in A. ipsilon. However, the molecular mechanisms underlying phoxim tolerance in A. ipsilon remain unclear. In this work, we report the involvement of AiGSTz1, a zeta class glutathione S-transferase, in phoxim tolerance in A. ipsilon. Exposure to a sublethal concentration (LC50) of phoxim dramatically upregulated the transcription level of the AiGSTz1 gene in A. ipsilon larvae, and this upregulation might be caused by phoxim-induced oxidative stress. The recombinant AiGSTz1 protein expressed in Escherichia coli was able to metabolize phoxim. Furthermore, AiGSTz1 displayed antioxidant activity to protect against oxidative stress. Knockdown of AiGSTz1 by RNA interference significantly increased the mortality rate of A. ipsilon larvae in response to phoxim. In addition, the transcription factor AiCncC can bind to the cap 'n' collar isoform C: muscle aponeurosis fibromatosis (CncC:Maf) binding site in the putative promoter of the AiGSTz1 gene. Silencing of AiCncC resulted in a dramatic downregulation of AiGSTz1. These results indicated that AiGSTz1 is involved in phoxim tolerance and is potentially regulated by AiCncC. These findings provide valuable insights into the defense mechanisms used by A. ipsilon against phoxim.

Asunto(s)

Glutatión Transferasa , Proteínas de Insectos , Insecticidas , Mariposas Nocturnas , Compuestos Organotiofosforados , Factores de Transcripción , Animales , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Compuestos Organotiofosforados/farmacología , Compuestos Organotiofosforados/toxicidad , Insecticidas/farmacología , Insecticidas/toxicidad , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/genética , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Larva/efectos de los fármacos , Resistencia a los Insecticidas/genética , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Itaconate serves as an immune-specific metabolite that regulates gene transcription and metabolism in both host and pathogens. S-itaconation is a post-translational modification that regulates immune response; however, its antimicrobial mechanism under the physiological condition remains unclear. Here, we apply a bioorthogonal itaconate probe to perform global profiling of S-itaconation in living pathogens, including S. Typhimurium, S. aureus, and P. aeruginosa. Some functional enzymes are covalently modified by itaconate, including those involved in the de novo purine biosynthesis pathway. Further biochemical studies demonstrate that itaconate suppresses this specific pathway to limit Salmonella growth by inhibiting the initiator purF to lower de novo purine biosynthesis and simultaneously targeting the guaABC cluster to block the salvage route. Our chemoproteomic study provides a global portrait of S-itaconation in multiple pathogens and offers a valuable resource for finding susceptible targets to combat drug-resistant pathogens in the future.

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Linggui-Zhugan (LGZG) comprises four herbs and is a classic formula in traditional Chinese medicine. There is strong clinical evidence of its pleiotropic effects in the prevention of diabetes and its related complications. Although several classes of drugs are currently available for clinical management of diabetic kidney disease (DKD), tight glycemic and/or hypertension control may not prevent disease progression. This study evaluated the therapeutic effect of the ethnopharmacological agent LGZG on DKD. AIM OF THE STUDY: This study aimed to investigate the effects of LGZG formula with standard quality control on experimental DKD and its related metabolic disorders in animal model. Meanwhile, the present study aimed to investigate regulatory effects of LGZG on renal proteinase 3 (PR3) to reveal mechanisms underlying renoprotective benefits of LGZG. MATERIALS AND METHODS: LGZG decoction was fingerprinted by high-performance liquid chromatography for quality control. An experimental model of DKD was induced in C57 BL/6J mice by a combination of high-fat diet feeding, uninephrectomy, and intraperitoneal injection of streptozocin. The LGZG decoction was administrated by daily oral gavage. RESULTS: Treatment with LGZG formula significantly attenuated DKD-like traits (including severe albuminuria, mesangial matrix expansion, and podocyte loss) and metabolic dysfunction (disordered body composition and dyslipidemia) in mice. RNA sequencing data revealed a close association of LGZG treatment with marked modulation of signaling pathways related to podocyte injury and cell apoptosis. Mechanistically, LGZG suppressed the DKD-triggered increase in renal PR3 and podocyte apoptosis. In-vitro incubation of mouse immortalized podocytes with LGZG-medicated serum attenuated PR3-mediated apoptosis. CONCLUSION: Our data demonstrated that the LGZG formula protected against DKD in mice and was closely associated with its inhibitory effects on PR3-mediated podocyte apoptosis.

Asunto(s)

Apoptosis , Nefropatías Diabéticas , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Podocitos , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Nefropatías Diabéticas/patología , Podocitos/efectos de los fármacos , Podocitos/patología , Apoptosis/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Masculino , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones

RESUMEN

This study aimed to explore the impact of dietary supplementation of Poria cocos polysaccharide (PCP) on the lipopolysaccharide(LPS)-induced intestinal inflammation, morphology, and barrier damage in broilers. A total of 240 1-day-old male Arbor Acre broilers were randomly divided into 4 groups in a 2 × 2 factorial design comprising PCP supplementation (0 or 2 g/kg PCP from d 1 to 23) and LPS challenge (intraperitoneal injection of 1.5 mg/kg body weight of LPS or the same volume of sterile saline at d 22). Our results showed that compared to the non-LPS-treated groups, the treated birds showed a decrease in the ADG, VH, V/C, and the expression of ZO-1, occludin, claudin 1, and mucin2 in the duodenum and jejunum (P < 0.05). However, dietary PCP supplementation significantly mitigated these effects (P < 0.05) except for mucin2 in the duodenum. Furthermore, LPS treatment increased the levels of sIgA and upregulated the mRNA abundances of IL-1ß, IL-6, TNF-α, IFN-γ, TLR-4, and MyD88 both in the duodenal and jejunal mucosa (P < 0.05). Whereas, PCP supplementation significantly reversed the LPS-induced effects on these genes (P < 0.05) except for the TLR-4 and MyD88. However, LPS did not impact the expression of anti-inflammatory IL-10 in the duodenal and jejunal mucosa (P > 0.05). Briefly, this study implied that dietary PCP supplementation could ameliorate intestinal inflammation and mucosal damage of LPS-challenged broilers, improving broiler performance.

RESUMEN

Histone lysine demethylase (KDM), AlkB homolog (ALKBH), and Ten-Eleven Translocation (TET) proteins are members of the 2-Oxoglutarate (2OG) and ferrous iron-dependent oxygenases, each of which harbors a catalytic domain centered on a double-stranded ß-helix whose topology restricts the regions directly involved in substrate binding. However, they have different catalytic functions, and the deeply structural biological reasons are not yet clear. In this review, the catalytic domain features of the three protein families are summarized from both sequence and structural perspectives. The construction of the phylogenetic tree and comparison of the structure show ten relatively conserved ß-sheets and three key regions with substantial structural differences. We summarize the relationship between three key regions of remarkable differences and the substrate compatibility of the three protein families. This review facilitates research into substrate-selective inhibition and bioengineering by providing new insights into the catalytic domains of KDM, ALKBH, and TET proteins.

Asunto(s)

Dominio Catalítico , Ácidos Cetoglutáricos , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/química , Humanos , Modelos Moleculares , Filogenia , Especificidad por Sustrato , Hierro/química , Hierro/metabolismo , Animales , Histona Demetilasas/química , Histona Demetilasas/metabolismo , Secuencia de Aminoácidos

RESUMEN

Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo, is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging-related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically-based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging-related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.

Asunto(s)

Envejecimiento , Amlodipino , Pueblo Asiatico , Citocromo P-450 CYP3A , Modelos Biológicos , Humanos , Amlodipino/farmacocinética , Anciano , Citocromo P-450 CYP3A/metabolismo , Masculino , Femenino , Envejecimiento/metabolismo , Anciano de 80 o más Años , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , China , Persona de Mediana Edad , Factores de Edad , Hígado/metabolismo , Hígado/enzimología , Anciano Frágil , Bloqueadores de los Canales de Calcio/farmacocinética , Pueblos del Este de Asia

RESUMEN

Rhizoctonia solani is a fungal pathogen that causes significant losses in agricultural production. Because of its rapid transmission and broad host range, the exploration of genes involved in defense responses to the infection of R. solani has become an important task. Here, we performed a time-course RNA-Seq experiment to explore crucial genes or pathways involved in host responses to R. solani AG3-TB infection at 6, 12, 24, 36, 48, and 72 hours post inoculation (hpi). GO and KEGG enrichment analysis revealed that most DEGs were enriched in the basal metabolism pathways, including carbohydrate metabolic processes and the biosynthesis of amino acids. Moreover, catalase (CAT) and superoxide dismutase (SOD) were up-regulated, and transcription factors (TFs) such as WRKY, AP2, and MYB were increased significantly compared to the control (0 hpi). Silencing of WRKY70 and catalase-3 exhibited elevated susceptibility to the fungal infection. To summarize, the TFs WRKY70 and WRKY75, genes involved in jasmonic acid (JA), salicylic acid (SA), and brassinosteroids (BR) signaling pathways, and defense-related enzymes may play crucial roles in the host responses to R. solani AG3-TB infection.

Asunto(s)

Resistencia a la Enfermedad , Regulación de la Expresión Génica de las Plantas , Enfermedades de las Plantas , Rhizoctonia , Factores de Transcripción , Rhizoctonia/fisiología , Rhizoctonia/patogenicidad , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Resistencia a la Enfermedad/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Oxilipinas/metabolismo , Ciclopentanos/metabolismo , Ácido Salicílico/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transducción de Señal/genética , Interacciones Huésped-Patógeno/genética

RESUMEN

BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.

Asunto(s)

Conservadores de la Densidad Ósea , Difosfonatos , Imidazoles , Dolor de la Región Lumbar , Osteoporosis Posmenopáusica , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Femenino , Osteoporosis Posmenopáusica/tratamiento farmacológico , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Anciano , Difosfonatos/uso terapéutico , Difosfonatos/efectos adversos , Difosfonatos/administración & dosificación , Resultado del Tratamiento , Dolor de la Región Lumbar/tratamiento farmacológico , Persona de Mediana Edad , Imidazoles/uso terapéutico , Imidazoles/efectos adversos , Imidazoles/administración & dosificación , Dimensión del Dolor , Densidad Ósea/efectos de los fármacos , Alendronato/uso terapéutico , Alendronato/efectos adversos , Alendronato/administración & dosificación

RESUMEN

BACKGROUND AND OBJECTIVES: Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. METHODS: In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. RESULTS: The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an Emax function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. CONCLUSIONS: No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks.

Asunto(s)

Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Inyecciones Subcutáneas , Femenino , Masculino , Persona de Mediana Edad , Adulto , Antígeno B7-H1/antagonistas & inhibidores , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética

RESUMEN

BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. METHODS AND RESULTS: Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac ß-adrenergic receptor (ß-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to ß1- and ß2-AR, but not to D1-dopamine receptor. These interactions were blocked by ß1- and ß2-AR blockers. Molecular docking and MST assay of ß-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both ß-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on ß-ARs. CONCLUSION: Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric ß-AR agonist, leading to cardiac ß-AR hyperactivity, thus contributing to PASC-CVS.

Asunto(s)

COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Glicoproteína de la Espiga del Coronavirus/metabolismo , COVID-19/complicaciones , COVID-19/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Síndrome Post Agudo de COVID-19 , Anciano , Simulación del Acoplamiento Molecular , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Agonistas Adrenérgicos beta/uso terapéutico

RESUMEN

The process of carbohydrate metabolism and genetic information transfer is an important part of the study on the effects of the external environment on microbial growth and development. As one of the most significant environmental parameters, pH has an important effect on mycelial growth. In this study, the effects of environmental pH on the growth and nutrient composition of Aspergillus niger (A. niger) filaments were determined. The pH values of the medium were 5, 7, and 9, respectively, and the molecular mechanism was further investigated by transcriptomics and metabolomics methods. The results showed that pH 5 and 9 significantly inhibited filament growth and polysaccharide accumulation of A. niger. Further, the mycelium biomass of A. niger and the crude polysaccharide content was higher when the medium's pH was 7. The DEGs related to ribosome biogenesis were the most abundant, and the downregulated expression of genes encoding XRN1, RRM, and RIO1 affected protein translation, modification, and carbohydrate metabolism in fungi. The dynamic changes of pargyline and choline were in response to the oxidative metabolism of A. niger SICU-33. The ribophorin_I enzymes and DL-lactate may be important substances related to pH changes during carbohydrate metabolism of A.niger SICU-33. The results of this study provide useful transcriptomic and metabolomic information for further analyzing the bioinformatic characteristics of A. niger and improving the application in ecological agricultural fermentation.

RESUMEN

Oxidative stress is a universal interpretation for the toxicity mechanism of nanoplastics to microalgae. However, there is a lack of deeper insight into the regulation mechanism in microalgae response to oxidative stress, thus affecting the prevention and control for nanoplastics hazard. The integrated analysis of transcriptomics and metabolomics was employed to investigate the mechanism for the oxidative stress response of Chlorella pyrenoidosa to nanoplastics and subsequently lock the according core pathways and driver genes induced. Results indicated that the linoleic acid metabolism, glycine (Gly)-serine (Ser)-threonine (Thr) metabolism, and arginine and proline metabolism pathways of C. pyrenoidosa were collectively involved in oxidative stress. The analysis of linoleic acid metabolism suggested that nanoplastics prompted algal cells to secrete more allelochemicals, thereby leading to destroy the immune system of cells. Gly-Ser-Thr metabolism and arginine and proline metabolism pathways were core pathways involved in algal regulation of cell membrane function and antioxidant system. Key genes, such as LOX2.3, SHM1, TRPA1, and proC1, are drivers of regulating the oxidative stress of algae cells. This investigation lays the foundation for future applications of gene editing technology to limit the hazards of nanoplastics on aquatic organism.

Asunto(s)

Chlorella , Metabolómica , Estrés Oxidativo , Transcriptoma , Chlorella/genética , Chlorella/metabolismo , Chlorella/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Microalgas/genética , Microalgas/efectos de los fármacos , Microalgas/metabolismo

RESUMEN

Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC0-48h) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC0-24h values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure-response relationship in pregnant women, which indicated that the fetal AUC0-48h of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.

RESUMEN

In this study, the growth characteristics of microalgae cultured with different carbon sources were analyzed, and the flocculation characteristics under the influence of carbon sources were evaluated using three typical flocculants. The results showed that the organic carbon sources could significantly increase the content of extracellular proteins in microalgae. Specifically, the extracellular protein concentrations of microalgae cultured with pure BG-11, ethanol, sodium acetate and glucose were 18.2 29.2, 97.3, and 34.7 mg/g, respectively. During the flocculation process, microalgae cultured with sodium acetate exhibited a weak response to the flocculant because of excessive extracellular proteins inhibited flocculation. In addition, the flocculation efficiency was also less than 50.0% cultured with sodium acetate in all pH test ranges when alum and chitosan were used as flocculants. It could be inferred that the flocculant initially happened to charge neutralization with the negatively charged proteins in the solution and then bridged the charges with the microalgae. These findings provide insights into the effects of different carbon sources on microalgal flocculation, promising organic integration of microalgae wastewater treatment and harvesting.

Asunto(s)

Carbono , Chlorella , Floculación , Microalgas , Chlorella/crecimiento & desarrollo , Carbono/química , Microalgas/crecimiento & desarrollo , Quitosano/química , Acetato de Sodio/química , Aguas Residuales/química , Glucosa , Concentración de Iones de Hidrógeno , Etanol/química , Eliminación de Residuos Líquidos/métodos

RESUMEN

OBJECTIVE: Given the high prevalence of hypertension among Chinese adults, this population is at a significantly increased risk of severe COVID-19 complications. The purpose of this study is to assess the willingness of Chinese hypertensive adults to receive the COVID-19 vaccine and to identify the diverse factors that shape their vaccination decisions. METHODS: Sampling was conducted utilizing multistage stratified random sampling, and ultimately, a total of 886 adult hypertensive patients from Luzhou City in Southwest China were included in this study. The questionnaire design was based on the Theory of Planned Behaviour and was used to investigate their willingness to be vaccinated with COVID-19. Structural equation modeling was employed for data analysis. RESULTS: The results showed that 75.6% of hypertensive individuals were willing to receive COVID-19 vaccination. The structural equation modeling revealed that Subjective Norms (path coefficient = 0.361, CR = 8.049, P < 0.001) and Attitudes (path coefficient = 0.253, CR = 4.447, P < 0.001) had positive effects on vaccination willingness, while Perceived Behavioral Control (path coefficient=-0.004, CR=-0.127, P = 0.899) had no significant impact on Behavioral Attitudes. Mediation analysis indicated that Knowledge (indirect path coefficient = 0.032, LLCI = 0.014, ULCI = 0.058), Risk Perception (indirect path coefficient = 0.077, LLCI = 0.038, ULCI = 0.124), and Subjective Norms (indirect path coefficient = 0.044, LLCI = 0.019, ULCI = 0.087) significantly influenced vaccination willingness through Attitudes as a mediating factor. CONCLUSION: The willingness of hypertensive individuals to receive the COVID-19 vaccination is not satisfactory. The Theory of Planned Behavior provides valuable insights into understanding their vaccination intentions. Efforts should be concentrated on enhancing the subjective norms, attitudes, and knowledge about vaccination of hypertensive patients.

Asunto(s)

Vacunas contra la COVID-19 , COVID-19 , Hipertensión , Intención , SARS-CoV-2 , Vacunación , Humanos , Hipertensión/epidemiología , Hipertensión/psicología , COVID-19/prevención & control , COVID-19/epidemiología , COVID-19/psicología , Masculino , Femenino , China/epidemiología , Persona de Mediana Edad , Vacunas contra la COVID-19/administración & dosificación , Vacunación/psicología , Vacunación/estadística & datos numéricos , Adulto , Encuestas y Cuestionarios , Análisis de Clases Latentes , Anciano , Conocimientos, Actitudes y Práctica en Salud , Aceptación de la Atención de Salud/psicología , Aceptación de la Atención de Salud/estadística & datos numéricos , Estudios Transversales , Pueblos del Este de Asia

RESUMEN

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.

Asunto(s)

Ferroptosis , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Succinatos , Animales , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Ferroptosis/efectos de los fármacos , Ratones , Succinatos/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Humanos , Carboxiliasas/metabolismo , Carboxiliasas/genética , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Ratones Endogámicos C57BL , Masculino , Ratones Transgénicos , Modelos Animales de Enfermedad , Hidroliasas

RESUMEN

More than one hundred studies have used the mainland Chinese version of the MATRICS Consensus Cognitive Battery (MCCB) to assess cognition in schizophrenia, but the results of these studies, the quality of the reports, and the strength of the evidence provided in the reports have not been systematically assessed. We identified 114 studies from English-language and Chinese-language databases that used the Chinese MCCB to assess cognition in combined samples of 7394 healthy controls (HC), 392 individuals with clinical high risk for psychosis (CHR-P), 4922 with first-episode schizophrenia (FES), 1549 with chronic schizophrenia (CS), and 2925 with schizophrenia of unspecified duration. The mean difference (MD) of the composite MCCB T-score (-13.72) and T-scores of each of the seven cognitive domains assessed by MCCB (-14.27 to -7.92) were significantly lower in individuals with schizophrenia than in controls. Meta-analysis identified significantly greater cognitive impairment in FES and CS than in CHR-P in six of the seven domains and significantly greater impairment in CS than FES in the reasoning and problem-solving domain (i.e., executive functioning). The only significant covariate of overall cognitive functioning in individuals with schizophrenia was a negative association with the severity of psychotic symptoms. These results confirm the construct validity of the mainland Chinese version of MCCB. However, there were significant limitations in the strength of the evidence provided about CHR-P (small pooled sample sizes) and the social cognition domain (inconsistency of results across studies), and the quality of many reports (particularly those published in Chinese) was rated 'poor' due to failure to report sample size calculations, matching procedures or methods of handling missing data. Moreover, almost all studies were cross-sectional studies limited to persons under 60 with at least nine years of education, so longitudinal studies of under-educated, older individuals with schizophrenia are needed.

RESUMEN

Topological photonic crystals (PCs) provide an effective method for controlling how light propagates and concentrates through their topological states. However, it remains unclear whether topological states can be obtained by combining two different two-dimensional (2D) PCs with topological non-trivial states. In this Letter, two types of 2D Penrose-square (P-S) PCs are proposed. These PCs can generate topological edge states (TESs) and topological corner states (TCSs) within the low-frequency part of the bandgap. Moreover, by combining these two non-trivial PCs, a total of two groups of TESs and four groups of TCSs can be generated in both the high-frequency and low-frequency parts of the common bandgap. To the best of our knowledge, the two proposed P-S PCs offer a new platform for investigating topological photonics and related devices, providing novel approaches and perspectives for generating topological states in 2D PCs.