p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis.

Cancer cells exhibit altered and usually increased metabolic processes to meet their high biogenetic demands1,2. Under these conditions, ammonia is concomitantly produced by the increased metabolic processing. However, it is unclear how tumour cells dispose of excess ammonia and what outcomes might be caused by the accumulation of ammonia. Here we report that the tumour suppressor p53, the most frequently mutated gene in human tumours, regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1, OTC and ARG1, p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumour growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC, thereby inhibiting the biosynthesis of polyamine and cell proliferation. Together, these findings link p53 to ureagenesis and ammonia metabolism, and further reveal a role for ammonia in controlling polyamine biosynthesis and cell proliferation.

Publisher Correction: p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis.

In Fig. 1c of this Letter, the labels p53+/+ and p53-/- were inadvertently swapped. The original figure has been corrected online.

Oral microbiome diversity and diet quality in relation to mortality.

AIM: To examine the independent and joint associations of oral microbiome diversity and diet quality with risks of all-cause and cause-specific mortality. MATERIALS AND METHODS: We included 7,055 eligible adults from the U.S. National Health and Nutrition Examination Survey (NHANES). Oral microbiome diversity was measured with α-diversity, including the Simpson Index, observed amplicon sequence variants (ASVs), Faith's phylogenetic diversity, and Shannon-Weiner index. Dietary quality was assessed using the Healthy Eating Index-2015 (HEI-2015). Cox proportional hazard models were used to assess the corresponding associations. RESULTS: During a mean follow-up of 9.0 years, we documented 382 all-cause deaths. We observed independent associations of oral microbiome diversity indices and dietary quality with all-cause mortality (hazard ratio [HR] = 0.63; 95% confidence interval [CI]: 0.49-0.82 for observed ASVs; HR = 0.68, 95% CI: 0.52-0.89 for HEI-2015). Jointly, participants with the highest tertiles of both oral microbiome diversity (in Simpson index) and HEI-2015 had the lowest hazard of mortality (HR = 0.37, 95% CI: 0.23-0.60). In addition, higher oral microbiome diversity was associated with lower risks of deaths from cardiometabolic disease and cancer. CONCLUSIONS: Higher oral microbiome α-diversity and diet quality were independently associated with lower risk of mortality.

Associations of the Mediterranean-DASH Intervention for Neurodegenerative Delay diet with brain structural markers and their changes.

INTRODUCTION: The associations of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet with brain structural changes are unclear. METHODS: Among 26,466 UK Biobank participants, a 15-point MIND score was calculated from 24-hour diet recalls from 2009 to 2012. We assessed its associations with 17 magnetic-resonance-derived brain volumetric markers and their longitudinal changes and explored whether genetic factors modify the associations. RESULTS: Higher MIND adherence was associated with larger volumes of thalamus, putamen, pallidum, hippocampus, and accumbens (beta per 3-unit increment ranging from 0.024 to 0.033) and lower white matter hyperintensities (P-trends < 0.05), regardless of genetic predispositions of Alzheimer's disease. MIND score was not associated with their longitudinal changes (P > 0.05) over a median of 2.2 years among participants with repeated imaging assessments (N = 2963), but was associated with slower atrophy in putamen (beta: 0.026, P-trend = 0.044) and pallidum (beta: 0.030, P-trend = 0.033) among APOE Îµ4 non-carriers (N = 654). DISCUSSION: The MIND diet showed beneficial associations with certain brain imaging markers, and its associations with long-term brain structural changes warrants future investigation. HIGHLIGHTS: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet was significantly associated with higher volumes and larger gray matter volumes in certain brain regions in UK adults, and the associations were not modified by genetic factors. No significant associations were observed between MIND diet and longitudinal changes in the investigated brain structural markers over a median of 2.2 years. Higher MIND score was significantly associated with slower atrophy in the putamen and pallidum among APOE Îµ4 non-carriers.

Tomato defence against Meloidogyne incognita by jasmonic acid-mediated fine-tuning of kaempferol homeostasis.

Jasmonic acid (JA) is involved in the modulation of defence and growth activities in plants. The best-characterized growth-defence trade-offs stem from antagonistic crosstalk among hormones. In this study, we first confirmed that JA negatively regulates root-knot nematode (RKN) susceptibility via the root exudates (REs) of tomato plants. Omics and toxicological analyses implied that kaempferol, a type of flavonol, from REs has a negative effect on RKN infection. We demonstrated that SlMYB57 negatively regulated kaempferol contents in tomato roots, whereas SlMYB108/112 had the opposite effect. We revealed that JA fine-tuned the homeostasis of kaempferol via SlMYB-mediated transcriptional regulation and the interaction between SlJAZs and SlMYBs, thus ensuring a balance between lateral root (LR) development and RKN susceptibility. Overall, this work provides novel insights into JA-modulated LR development and RKN susceptibility mechanisms and elucidates a trade-off model mediated by JA in plants encountering stress.

Hectogram-scale synthesis of [Aib8 , Arg34 ]-GLP-1 (7-37) by liquid-phase fragment condensation.

Based on small-scale synthesis (0.3 g), a 100-g scale-up synthesis of crude [Aib8 , Arg34 ]-glucagon-like peptide-1 (GLP-1) (7-37) was completed. The crude [Aib8 , Arg34 ]-GLP-1 (7-37) was purified using a dynamic axial compression column 200 (DAC-200). Approximately 61 g of [Aib8 , Arg34 ]-GLP-1 (7-37) with a purity of >99% was obtained through one-step reverse-phase chromatography. The purification yield was approximately 92%. The yield from the total reaction was approximately 60%. In summary, we developed an economical and environmentally friendly route to the synthesis and purification of crude [Aib8 , Arg34 ]-GLP-1 (7-37), laying a foundation for subsequent industrial production.

PEGylated hyaluronic acid-coated liposome for enhanced in vivo efficacy of sorafenib via active tumor cell targeting and prolonged systemic exposure.

This study aimed to design an effective formulation for enhancing the tumor-targeted delivery of sorafenib. Three sorafenib-loaded liposomal formulations including uncoated liposome (SF-Lip), hyaluronic acid-coated liposome (HA-SF-Lip), and PEGylated hyaluronic acid-coated liposome (PEG-HA-SF-Lip) were developed with narrow size distribution and high encapsulation efficiency. The cellular uptake and cytotoxicity of HA-SF-Lip and PEG-HA-SF-Lip were greater than those of SF-Lip in MDA-MB-231 cells overexpressing CD44, whereas there were no significant differences in MCF-7 cells with low CD44 expression, indicating the CD44-mediated cellular uptake of coated liposomes. In comparison with sorafenib solution, PEG-HA-SF-Lip increased the systemic exposure and plasma half-life in rats by 3-fold and 2-fold, respectively. Consistently, PEG-HA-SF-Lip was the most effective for tumor growth inhibition through CD44 targeting in the MDA-MB-231 tumor xenograft mouse model. Taken together, the present study suggests that PEG-HA-SF-Lip might be effective for the tumor-targeted delivery of sorafenib with enhanced systemic exposure and longer blood circulation.

Modeling "Two-Hit" Severe Pneumonia in Mice: Pathological Characteristics and Mechanistic Studies.

Severe pneumonia is one of the most common critical diseases in clinical practice. Existing models for severe pneumonia have limitations, leading to limited clinical translation. In this study, a two-hit severe pneumonia mouse model was established by inducing primary pneumonia through intratracheal instillation of 800 µg lipopolysaccharide (LPS), followed by intraperitoneal injection of 10 mg/kg LPS. The effectiveness of various inflammatory indicators and the lung tissue damage during the time course of this model were confirmed and evaluated. At 3 h post two-hit, the IL-6, TNF-α levels in peripheral blood and bronchoalveolar lavage fluid (BALF), and the white blood cells, neutrophils, and lymphocytes in BALF notably exhibited the most pronounced elevation. At 12 h post two-hit, the white blood cells and neutrophils in peripheral blood significantly increased, accompanied by notable alterations in splenic immune cells and worsened pulmonary histopathological damage. Transcriptomics of lung tissue, microbiota analysis of lung and gut, as well as plasma metabolomics analyses further indicated changes in transcriptional profiles, microbial composition, and metabolites due to the two-hit modeling. These results validate that the two-hit model mimics the clinical presentation of severe pneumonia and serves as a robust experimental tool for studying the pathogenesis of severe pneumonia and developing and assessing treatment strategies.

Tetrastigma hemsleyanum polysaccharide combined with doxorubicin promote ferroptosis and immune function in triple-negative breast cancer.

The absence of effective therapeutic targets poses considerable obstacles to the treatment of triple-negative breast cancer (TNBC). This study aimed to explore the function and mechanism of polysaccharides derived from the aerial parts of Tetrastigma hemsleyanum (THP) for the treatment of TNBC. THP exerts notable anti-TNBC effects when used alone, and its combination with Doxorubicin (DOX) effectively augments the sensitivity of TNBC cells to DOX. Through RNA sequencing, Fe2+ assays, western blotting, and transmission electron microscopy, THP was identified as a natural inducer of ferroptosis and ferritinophagy through the xCT/GSH/GPX4 and Nrf2/NCOA4/FTH1 pathways. Further research revealed that the THP branched-chain hexose directly binds to the xCT protein to inhibit its expression and promotes ferroptosis. In vivo experiments confirmed the role of THP in inducing ferroptosis and showed that THP improves the tumor microenvironment and immune function by increasing the ratio of CD4+ and CD8+ T cells to regulatory T cells and modulating cytokine levels. As demonstrated by electrocardiography, blood chemistry, and histological analyses, THP alleviates organ toxicity caused by DOX. Overall, these results suggest that THP has significant clinical potential as a natural macromolecular drug and may provide a safe and effective treatment strategy for TNBC when combined with DOX.

Bioresorbable Multilayer Organic-Inorganic Films for Bioelectronic Systems.

Bioresorbable electronic devices as temporary biomedical implants represent an emerging class of technology relevant to a range of patient conditions currently addressed with technologies that require surgical explantation after a desired period of use. Obtaining reliable performance and favorable degradation behavior demands materials that can serve as biofluid barriers in encapsulating structures that avoid premature degradation of active electronic components. Here, this work presents a materials design that addresses this need, with properties in water impermeability, mechanical flexibility, and processability that are superior to alternatives. The approach uses multilayer assemblies of alternating films of polyanhydride and silicon oxynitride formed by spin-coating and plasma-enhanced chemical vapor deposition , respectively. Experimental and theoretical studies investigate the effects of material composition and multilayer structure on water barrier performance, water distribution, and degradation behavior. Demonstrations with inductor-capacitor circuits, wireless power transfer systems, and wireless optoelectronic devices illustrate the performance of this materials system as a bioresorbable encapsulating structure.

Associations between parental adherence to healthy lifestyles and risk of obesity in offspring: a prospective cohort study in China.

BACKGROUND: Maternal adherence to a healthy lifestyle has been associated with a lower risk of obesity in offspring. However, little is known about the potential effect of an overall healthy parental lifestyle on the development of obesity in children. We aimed to investigate the prospective association of parental adherence to a combination of healthy lifestyle factors with the risk of obesity in offspring. METHODS: Participants in the China Family Panel Studies, without obesity at baseline, were enrolled between April and September, 2010; between July, 2012, and March, 2013; and between July, 2014, and June, 2015; and followed up until the end of 2020. Parental healthy lifestyle score (ranged 0-5) was characterised by five modifiable lifestyle factors: smoking, alcohol consumption, exercise, diet, and BMI. The first occurrence of offspring obesity during the study follow-up period was defined by age-specific and sex-specific cutoff values of BMI. We used multivariable-adjusted Cox proportional hazard models to examine the associations between parental healthy lifestyle scores and risk of obesity in children. FINDINGS: We included 5881 participants aged 6-15 years; median follow-up was 6 years (IQR 4-8). A total of 597 (10·2%) participants developed obesity during follow-up. Compared with those in the lowest tertile of parental healthy lifestyle scores, participants in the top tertile had a 42% lower risk of obesity (multivariable-adjusted hazard ratio [HR] 0·58 [95% CI 0·45-0·74]). The association persisted in sensitivity analyses and was similar across major subgroups. Both maternal (HR 0·75 [95% CI 0·61-0·92]) and paternal (0·73 [0·60-0·89]) healthy lifestyle scores were independently associated with lower risks of obesity in offspring, with significant contributions observed for paternal diverse diet and healthy BMI. INTERPRETATION: Adherence to an overall parental healthier lifestyle was associated with a substantially lower risk of obesity in childhood and adolescence. This finding highlights the potential benefits of promoting a healthy lifestyle among parents for the primary prevention of obesity in offspring. FUNDING: Special Foundation for National Science and Technology Basic Research Program of China (grant reference 2019FY101002) and National Natural Science Foundation of China (grant reference 42271433).

Patterns of pediatric and adolescent female genital inflammation in China: an eight-year retrospective study of 49,175 patients in China.

Background: Genital inflammation is one of the most frequent clinical complaints among girls, which was easily overlooked by the general public. This study aimed to investigate the patterns and epidemiological characteristics of pediatric and adolescent female genital inflammation in China. Methods: A retrospective observational study (2011 to 2018) was conducted among all female patients under the age of 0-18 years at the Department of Pediatric and Adolescent Gynecology of The Children's Hospital, Zhejiang University School of Medicine. Data were collected from the electronic medical records. The abnormal vaginal discharge of patient was collected for microbiological investigation by bacterial and fungal culture. Descriptive analysis was conducted to evaluate the genital inflammation pattern and epidemiological characteristics, including age, season, and type of infected pathogens. Results: A total of 49,175 patients met the eligibility criteria of genital inflammation and 16,320 patients later came to the hospital for follow-up over the study period. The number of first-visit increased gradually from 3,769 in 2011 to 10,155 in 2018. The peak age of the first visit was 0-6 years old. Non-specific vulvovaginitis, lichen sclerosis, and labial adhesion were the top three genital inflammation. Among the top five potential common pathogens of vaginal infection, the prevalence of Haemophilus influenzae cases was the highest (31.42%, 203/646), followed by Streptococcus pyogenes (27.74%, 176/646), Candida albicans (14.09%, 91/646), Escherichia coli (8.51%, 55/646), and Staphylococcus aureus (6.35%, 41/636). The specific disease categories and pathogens of genital inflammation vary by age groups and season. Conclusion: Our study summarizes the pattern of pediatric and adolescent female genital inflammation over an 8-year period in China, emphasizing the need for more public awareness, healthcare services and research in this field.

Parental adherence to healthy lifestyles in relation to the risk of obesity in offspring: A prospective cohort study in China.

Background: While maternal adherence to a healthy lifestyle was shown to be associated with a lower risk of obesity in offspring, the potential role of overall parental lifestyles has not yet been explored. We aimed to address this gap by exploring whether parental adherence to an overall healthy lifestyle was associated with a lower risk of obesity in offspring. Methods: We included 5881 children and adolescents aged 6-15 years at enrolment in the 2010, 2012, and 2014 waves of the China Family Panel Studies (CFPS) who were free of obesity and followed them until 2020. Parental healthy lifestyle score at study baseline was composed of five modifiable lifestyle factors (0-5; 1 for each): never smoking, non-habitual drinking, weekly exercise, modified dietary diversity score ≥5 points, and body mass index (BMI) of 18.5-23.9 kg/m2. We defined obesity according to the age- and gender-specific cutoffs by the BMI percentile curves for Chinese children aged 6-18 years. We used multivariable Cox proportional hazard models to examine the association between parental healthy lifestyle score (both as continuous and categorical variables) and risk of offspring obesity. Results: Overall, 597 (10.2%) offspring developed obesity during a median follow-up of 6 years. Compared to the lowest tertile of parental healthy lifestyle score, participants in the highest tertile had a 42% (hazard ratio (HR) = 0.58; 95% confidence interval (CI) = 0.45-0.74) lower risk of obesity. Both maternal (HR = 0.75; 95% CI = 0.61-0.92) and paternal (HR = 0.73; 95% CI = 0.60-0.89) healthy lifestyle scores were associated with lower risks of obesity in offspring. For specific lifestyle factors, we observed beneficial associations for paternal diverse diet (HR = 0.73; 95% CI = 0.60-0.88) and healthy BMI (HR = 0.65; 95% CI = 0.55-0.78). Conclusions: Adherence to an overall parental healthier lifestyle was associated with a lower risk of obesity in childhood and adolescence. This finding highlights the potential benefits of promoting a healthy lifestyle among parents for the primary prevention of offspring obesity.

Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate.

Many types of cancer feature TP53 mutations with oncogenic properties. However, whether the oncogenic activity of mutant p53 is affected by the cellular metabolic state is unknown. Here we show that cancer-associated mutant p53 protein is stabilized by 2-hydroxyglutarate generated by malic enzyme 2. Mechanistically, malic enzyme 2 promotes the production of 2-hydroxyglutarate by adjusting glutaminolysis, as well as through a reaction that requires pyruvate and NADPH. Malic enzyme 2 depletion decreases cellular 2-hydroxyglutarate levels in vitro and in vivo, whereas elevated malic enzyme 2 expression increases 2-hydroxyglutarate production. We further show that 2-hydroxyglutarate binds directly to mutant p53, which reduces Mdm2-mediated mutant p53 ubiquitination and degradation. 2-Hydroxyglutarate supplementation is sufficient for maintaining mutant p53 protein stability in malic enzyme 2-depleted cells, and restores tumour growth of malic enzyme 2-ablated cells, but not of cells that lack mutant p53. Our findings reveal the previously unrecognized versatility of malic enzyme 2 catalytic functions, and uncover a role for mutant p53 in sensing cellular 2-hydroxyglutarate levels, which contribute to the stabilization of mutant p53 and tumour growth.

Enhanced oral absorption of sorafenib via the layer-by-layer deposition of a pH-sensitive polymer and glycol chitosan on the liposome.

This study aimed to design the effective formulation of sorafenib (SF) to enhance the oral drug absorption. Three liposomal formulations of SF were prepared including uncoated liposome (SF-Lip), glycol chitosan-coated liposome (GC-SF-Lip), and Eudragit S100-glycol-chitosan coated liposome (SGC-SF-Lip). All formulations showed a narrow size distribution with a high encapsulation efficiency. Both GC-SF-Lip and SGC-SF-Lip exhibited good stability at acidic and neutral pHs without any significant drug leakage, while SF-Lip appeared to be unstable at pH 1.2. In the case of double coated SGC-SF-Lip, its size changed significantly at pH 7.4, due to the dissolution of Eudragit S100 coating layer into the surrounding medium. Compared to SF solution, all liposomal formulations demonstrated a higher cellular uptake in Caco-2 cells. In particular, SGC-SF-Lip displayed a lower cellular uptake than GC-SF-Lip at pH 6.5, but it achieved a similar cellular uptake to GC-SF-Lip at pH 7.4. Consistently, SGC-SF-Lip was less cytotoxic than GC-SF-Lip at pH 6.5, whereas it showed a comparable cytotoxicity to GC-SF-Lip at pH 7.4, implying the removal of the Eudragit S100 coating layer at pH 7.4. After an oral administration to rats, SGC-SF-Lip significantly improved the systemic exposure of SF, where its Cmax and AUC were approximately fourfold higher than the untreated drug. Collectively, SGC-SF-Lip appeared to be promising to enhance the oral absorption of SF.

Enhanced Photocarrier Separation in Hierarchical Graphitic-C3N4-Supported CuInS2 for Noble-Metal-Free Z-Scheme Photocatalytic Water Splitting.

The effective separation of photogenerated electrons and holes in photocatalysts is a prerequisite for efficient photocatalytic water splitting. CuInS2 (CIS) is a widely used light absorber that works properly in photovoltaics but only shows limited performance in solar-driven hydrogen evolution due to its intrinsically severe charge recombination. Here, we prepare hierarchical graphitic C3N4-supported CuInS2 (denoted as GsC) by an in situ growth of CIS directly on exfoliated thin graphitic C3N4 nanosheets (g-C3N4 NS) and demonstrate efficient separation of photoinduced charge carriers in the GsC by forming the Z-scheme system for the first time in CIS-catalyzed water splitting. Under visible light illumination, the GsC features an enhanced hydrogen evolution rate up to 1290 µmol g-1 h-1, which is 3.3 and 6.1 times higher than that of g-C3N4 NS and bare-CIS, respectively, thus setting a new performance benchmark for CIS-based water-splitting photocatalysts.

Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein.

PURPOSE: The present study aimed to discover a new potent BCRP inhibitor overcoming multidrug resistance. METHODS: Effects of LW6 on the functional activity and gene expression of two major efflux transporters, BCRP and P-gp, were evaluated by using MDCKII cells overexpressing each transporter (MDCKII-BCRP and MDCKII-MDR1). Its effects on the cytotoxicity and pharmacokinetics of co-administered anticancer drugs were also evaluated in transfected cells and rats, respectively. RESULTS: In MDCKII-BCRP cells overexpressing BCRP, LW6 enhanced significantly (p < 0.05) the cellular accumulation of mitoxantrone, a BCRP substrate, and was more potent than Ko143, a well-known BCRP inhibitor. LW6 also down-regulated BCRP expression at concentrations of 0.1-10 µM. Furthermore, cells became more susceptible to the cytotoxicity of anticancer drugs in the presence of LW6. The CC50 values of mitoxantrone and doxorubicin were reduced by three- and tenfold, respectively, in MDCKII-BCRP cells, while LW6 did not affect the cytotoxicity of anticancer drugs in MDCKII-mock cells lacking BCRP transporter. Furthermore, LW6 improved the oral exposure of methotrexate by twofold in rats. In contrast to BCRP, LW6 had no inhibition effect on the functional activity and gene expression of P-gp. CONCLUSION: LW6 was newly identified as a potent BCRP inhibitor and could be useful to reduce the multidrug resistance of cancer cells via the inhibition of BCRP-mediated drug efflux as well as the down-regulation of BCRP expression.