A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Bone-Targeted Biomimetic Nanogels Re-Establish Osteoblast/Osteoclast Balance to Treat Postmenopausal Osteoporosis.

Insufficient bone formation and excessive bone resorption caused by estrogen deficiency are the major factors resulting in the incidence of postmenopausal osteoporosis (PMOP). The existing drugs usually fail to re-establish the osteoblast/osteoclast balance from both sides and generate side-effects owing to the lack of bone-targeting ability. Here, engineered cell-membrane-coated nanogels PNG@mR&C capable of scavenging receptor activator of nuclear factor-κB ligand (RANKL) and responsively releasing therapeutic PTH 1-34 in the bone microenvironment are prepared from RANK and CXCR4 overexpressed bone mesenchymal stem cell (BMSC) membrane-coated chitosan biopolymers. The CXCR4 on the coated-membranes confer bone-targeting ability, and abundant RANK effectively absorb RANKL to inhibit osteoclastogenesis. Meanwhile, the release of PTH 1-34 triggered by osteoclast-mediated acid microenvironment promote osteogenesis. In addition, the dose and frequency are greatly reduced due to the smart release property, prolonged circulation time, and bone-specific accumulation. Thus, PNG@mR&C exhibits satisfactory therapeutic effects in the ovariectomized (OVX) mouse model. This study provides a new paradigm re-establishing the bone metabolic homeostasis from multitargets and shows great promise for the treatment of PMOP.

Effectiveness of bevacizumab in the treatment of metastatic colorectal cancer: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of clinical plans. METHODS: As of October 1, 2022, the randomized controlled clinical trials of bevacizumab in combination with metastatic colorectal cancer published in PubMed, Cochrane Library and Medline databases were searched. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the short-term disease control effect and long-term survival of the treatment strategy. RESULTS: 21 RCTs (6665 patients; 3356 patients in the experimental group and 3309 patients in the control group; average age, 55-75 years) were treated with bevacizumab as the experimental group for metastatic colorectal cancer. BEV has stronger anti-tumor activity than the single treatment scheme (OR = 1.30, 95% CI: 1.11-1.52). And Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. The disease control of BEV combined therapy was better (OR = 1.36, 95% CI: 1.04-1.78). The same as compared with cediranib (OR = 1.94, 95% CI: 1.06-3.55). However, the long-term prognosis of BEV, including the overall survival (HRs = 0.98, 95% CI: 0.84-1.15) and progression-free survival (HRs = 1.05,95% CI: 0.97-1.13) were not prolonged. The survival benefits of cetuximab and panitumumab were not reflected. CONCLUSION: The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability. However, it did not effectively improve the survival of patients. A more reasonable and effective treatment plan needs more clinical experimental support.

Sepsis as a Potential Risk Factor for Upper Gastrointestinal Bleeding in Critically Ill Patients: A Systematic Review and Meta-analysis.

Purpose: Sepsis is a common and critical condition in intensive care units (ICUs) known to complicate patient outcomes. Previous studies have indicated an association between sepsis and various ICU morbidities, including upper gastrointestinal bleeding (UGIB). However, the extent of this relationship and its implications in ICU settings remain inadequately quantified. This study aims to elucidate the association between sepsis and the risk of UGIB in ICU patients. Methods: A comprehensive meta-analysis was conducted, encompassing nine studies with a total of nearly 9000 participants. These studies reported events for both sepsis and nonsepsis patients separately. Pooled odds ratios (ORs) were calculated to assess the risk of UGIB in septic versus nonseptic ICU patients. Subgroup analyses were conducted based on age and study design, and both unadjusted and adjusted ORs were examined. Results: The pooled OR indicated a significant association between sepsis and UGIB (OR = 3.276, 95% CI: 1.931 to 5.557). Moderate heterogeneity was observed (I² = 43.9%). The association was significant in adults (pooled OR = 4.083) but not in children. No difference in association was found based on the study design. Unadjusted and adjusted ORs differed slightly, indicating the influence of confounding factors. Conclusion: This meta-analysis reveals a significant association between sepsis and an increased risk of UGIB in ICU patients, particularly in adults. These findings highlight the need for vigilant monitoring and proactive management of septic ICU patients to mitigate the risk of UGIB. Future research should focus on understanding the underlying mechanisms and developing tailored preventive strategies.

Viola yedoensis Makino alleviates lipopolysaccharide-induced intestinal oxidative stress and inflammatory response by regulating the gut microbiota and NF-κB-NLRP3/ Nrf2-MAPK signaling pathway in broiler.

Viola yedoensis Makino (Vy) is a well-known traditional Chinese medicine widely used to treat inflammatory diseases. However, the regulatory effects of dietary Vy supplementation on lipopolysaccharide (LPS)-induced intestinal damage in broilers and the underlying molecular mechanisms remain unclear. In this study, broilers were intraperitoneally injected with 1 mg/kg LPS on days 17, 19 and 21 to induce intestinal damage. Vy supplementation at 0.5, 1.5 and 4.5 % in the diet was administered separately for 21 days to investigate the potential protective effects of Vy supplementation against LPS-induced intestinal impairment in broilers. Vy supplementation improved intestinal morphology and restored growth performance. Vy supplementation attenuated intestinal inflammation by regulating the nuclear factor kappa B (NF-κB) / NLR family pyrin domain-containing 3 (NLRP3) signaling pathway and inhibited its downstream pro-inflammatory factor levels. In addition, Vy supplementation relieved intestinal oxidative impairment by regulating the nuclear factor erythroid-2 related factor 2 (Nrf2) / mitogen-activated protein kinase (MAPK) signaling pathway and downstream antioxidant enzyme activity. Vy supplementation reduced LPS-induced mitochondrial damage and apoptosis. Furthermore, Vy supplementation alleviated LPS-induced intestinal inflammation and oxidative damage in chickens by increasing the abundance of protective bacteria (Lactobacillus and Romboutsia) and reducing the number of pathogenic bacteria (unclassified_f_Ruminococcaceae, unclassified_f_Oscillospiraceae and norank_f_norank_o_Clostridia_vadinBB60_group). Overall, Vy supplementation effectively ameliorated LPS-induced intestinal damage by regulating the NF-κB-NLRP3/Nrf2-MAPK signaling pathway and maintaining intestinal microbiota balance. Vy supplementation can be used as a dietary supplement to protect broilers against intestinal inflammation and oxidative damage.

Bioinformatic analysis of the role of immune checkpoint genes and immune infiltration in the pathogenesis and development of premature ovarian insufficiency.

PURPOSE: With advances in immunology, increasing evidence suggests that immunity is involved in premature ovarian insufficiency (POI) pathogenesis. This study investigated the roles of immune checkpoint genes and immune cell infiltration in POI pathogenesis and development. METHODS: The GSE39501 dataset and immune checkpoint genes were obtained from the Gene Expression Omnibus database and related literature. The two datasets were intersected to obtain immune checkpoint-related differentially expressed genes (ICRDEGs), which were analyzed using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes enrichment analysis, weighted correlation network analysis, protein-protein interaction and related microRNAs, transcription factors, and RNA binding proteins. The immune cell infiltration of ICRDEGs was explored, and receiver operating characteristic curves were used to validate the diagnostic value of ICRDEGs in POI. RESULTS: We performed ICRDEG functional enrichment analysis and found that these genes were closely related to immune processes, such as T cell activation. Specifically, they are enriched in various biological processes and pathways, such as cell adhesion molecule and T cell receptor signaling pathways. Weighted correlation network analysis identified seven hub genes: Cd200, Cd274, Cd28, neurociliary protein-1, Cd276, Cd40lg, and Cd47. Furthermore, we identified 112 microRNAs, 17 RNA-binding proteins, and 101 transcription factors. Finally, immune infiltration analysis showed a clear positive correlation between hub genes and multiple immune cell types. CONCLUSION: Bioinformatic analysis identified seven potential ICRDEGs associated with POI, among which the immune checkpoint molecules CD200 and neurociliary protein-1 may be involved in the pathogenesis of POI.

O-GlcNAc Modification Is a Promising Therapeutic Target for Diabetic Retinopathy.

Diabetic retinopathy (DR) is a very serious diabetes complication. Changes in the O-linked N-acetylglucosamine (O-GlcNAc) modification are associated with many diseases. However, its role in DR is not fully understood. In this research, we explored the effect of O-GlcNAc modification regulation by activating AMP-activated protein kinase (AMPK) in DR, providing some evidence for clinical DR treatment in the future. Bioinformatics was used to make predictions from the database, which were validated using the serum samples of diabetic patients. As an in vivo model, diabetic mice were induced using streptozotocin (STZ) injection with/without an AMPK agonist (metformin) or an AMPK inhibitor (compound C) treatment. Electroretinogram (ERG) and H&E staining were used to evaluate the retinal functional and morphological changes. In vitro, 661 w cells were exposed to high-glucose conditions, with or without metformin treatment. Apoptosis was evaluated using TUNEL staining. The protein expression was detected using Western blot and immunofluorescence staining. The angiogenesis ability was detected using a tube formation assay. The levels of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in the serum changed in the DR patients in the clinic. In the diabetic mice, the ERG wave amplitude and retinal thickness decreased. In vitro, the apoptotic cell percentage and Bax expression were increased, and Bcl2 expression was decreased in the 661 w cells under high-glucose conditions. The O-GlcNAc modification was increased in DR. In addition, the expression of GFAT/TXNIP O-GlcNAc was also increased in the 661 w cells after the high-glucose treatment. Additionally, the Co-immunoprecipitation(CO-IP) results show that TXNIP interacted with the O-GlcNAc modification. However, AMPK activation ameliorated this effect. We also found that silencing the AMPKα1 subunit reversed this process. In addition, the conditioned medium of the 661 w cells may have affected the tube formation in vitro. Taken together, O-GlcNAc modification was increased in DR with photoreceptor cell degeneration and neovascularization; however, it was reversed after activating AMPK. The underlying mechanism is linked to the GFAT/TXNIP-O-GlcNAc modification signaling axis. Therefore, the AMPKα1 subunit plays a vital role in the process.

Thioredoxin 1 overexpression attenuated diabetes-induced endoplasmic reticulum stress in Müller cells via apoptosis signal-regulating kinase 1.

As one of the common and serious chronic complications of diabetes mellitus (DM), the related mechanism of diabetic retinopathy (DR) has not been fully understood. Müller cell reactive gliosis is one of the early pathophysiological features of DR. Therefore, exploring the manner to reduce diabetes-induced Müller cell damage is essential to delay DR. Thioredoxin 1 (Trx1), one of the ubiquitous redox enzymes, plays a vital role in redox homeostasis via protein-protein interactions, including apoptosis signal-regulating kinase 1 (ASK1). Previous studies have shown that upregulation of Trx by some drugs can attenuate endoplasmic reticulum stress (ERS) in DR, but the related mechanism was unclear. In this study, we used DM mouse and high glucose (HG)-cultured human Müller cells as models to clarify the effect of Trx1 on ERS and the underlying mechanism. The data showed that the diabetes-induced Müller cell damage was increased significantly. Moreover, the expression of ERS and reactive gliosis was also upregulated in diabetes in vivo and in vitro. However, it was reversed after Trx1 overexpression. Besides, ERS-related protein expression, reactive gliosis, and apoptosis were decreased after transfection with ASK1 small-interfering RNA in stable Trx1 overexpression Müller cells after HG treatment. Taken together, Trx1 could protect Müller cells from diabetes-induced damage, and the underlying mechanism was related to inhibited ERS via ASK1.

Gut microbiome characteristics in subjective cognitive decline, mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The gut microbiome has been reported to be closely related to Alzheimer's disease (AD) progression. Here, a comprehensive meta-analysis of gut microbial characteristics in AD, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) was performed to compare gut microbial alterations at each stage. METHODS: A total of 10 databases (CNKI, WanFang, VIP, SinoMed, WOS, PubMed, Embase, Cochrane Library, PsycINFO and Void) were searched and 34 case-control studies were included. α and ß diversity and the relative abundance of gut microbiota were analysed as outcome indices. Data analysis was performed using Review Manager (5.4.1) and R. RESULTS: Chao1 and Shannon index levels in AD were significantly lower compared with healthy controls (HCs), and the Chao1 index was significantly lower in MCI compared with HCs. There was a significant difference in ß diversity of gut microbiomes in patients (SCD, MCI, AD) compared with HCs. The relative abundance of Firmicutes at the phylum level was significantly lower in patients with AD and MCI than HCs. However, the relative abundance of Bacteroidetes at the phylum level was significantly higher in patients with MCI than HCs. There was an increasing trend for Enterobacteriaceae and a decreasing trend for Ruminococcaceae, Lachnospiraceae and Lactobacillus during AD; Lactobacillus showed a decreasing trend early in SCD. CONCLUSION: Our results indicated that there were gut microbiological abnormalities in AD, even as early as the SCD stage. The dynamic, consistent changes in gut microbes with the disease process showed that they might serve as potential biomarkers for early identification and diagnosis of AD.

High-precision non-invasive RBC and HGB detection system based on spectral analysis.

Non-invasive blood composition analysis based on dynamic spectrum (DS) theory has gained significant attention due to its non-invasive, simple, and fast performance. However, most of the multi-wavelength photoplethysmography (PPG) detection devices used to obtain DS are composed of halogen light sources and spectrometers and cannot detect effective PPG signals in the visible light short band (400-620 nm), which limits the detection accuracy of blood components with significant absorption spectral differences in that band. Therefore, this paper designs a multi-wavelength spectral acquisition system that can measure high signal-to-noise ratio (SNR > 65 dB) PGG signals at wavelengths of 405, 430, 450, 505, 520, and 570 nm and combines this system with a halogen lamp spectrometer acquisition system for non-invasive blood component detection. Furthermore, this paper collects the DS of 272 subjects with the combined system and establishes a predictive model for DS with the content of red blood cell (RBC) and hemoglobin (HGB) components. The results show that, compared with the halogen lamp spectrometer acquisition system, the correlation coefficient (Rp) of RBC and HGB prediction model established by the combined system has increased by 0.0619 and 0.0489, respectively, and the root mean square error (RMSE) has decreased by 0.08 1e12/L and 0.85 g/L, which confirm the feasibility of the designed multi-wavelength spectrum acquisition system to enhance the accuracy of blood component detection.

TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis.

Immune homeostasis is essential for the normal functioning of the immune system, and its breakdown leads to fatal inflammatory diseases. We report here the identification of a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan inflammation, splenomegaly, and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappaB activation while promoting Fas-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.

Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities.

In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK enzyme and three cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated. Among them, compound 12s displayed potent inhibitory potency on FAK (IC50 = 47 nM), and demonstrated more significant antiproliferative activities in MGC-803, HCT-116 and KYSE30 cells (IC50 values were 0.24, 0.45 and 0.44 µM, respectively) compared to TAE-226. Furthermore, compound 12s significantly inhibited FAK activation leading to the negative regulation of FAK-related signaling pathways such as AKT/mTOR and MAPK signaling pathways. Molecular docking study suggested that compound 12s could well occupy the ATP-binding pocket site of FAK similar to TAE-226. In addition, compound 12s also efficiently inhibited the proliferation, induced apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK inhibitor that could exert potent inhibitory activity against gastric cancer cells.

Neurological soft signs and structural network changes: a longitudinal analysis in first-episode schizophrenia.

BACKGROUND: Neurological soft signs (NSS) are often reported in patients with schizophrenia and may vary with psychopathological symptoms during the course of disease. Many cross-sectional neuroimaging studies have shown that NSS are associated with disturbed network connectivity in schizophrenia. However, it remains unclear how these associations change over time during the course of disorder. METHODS: In present study, 20 patients with first-episode schizophrenia and 20 controls underwent baseline structural magnetic resonance imaging (MRI) scan and at one-year follow-up. Structural network characteristics of patients and controls were analyzed using graph theoretical approach based on MRI data. NSS were assessed using the Heidelberg scale. RESULTS: At baseline, patients demonstrated significant changes of the local network properties mainly involving regions of the cortical-subcortical-cerebellar circuits compared to healthy controls. For further analysis, the whole patient group was dichotomized into a NSS-persisting and NSS-decreasing subgroup. After one-year follow-up, the NSS-persisting subgroup showed decreased betweenness in right inferior opercular frontal cortex, left superior medial frontal cortex, left superior temporal cortex, right putamen and cerebellum vermis and increased betweenness in right lingual cortex. However, the NSS-decreasing subgroup exhibited only localized changes in right middle temporal cortex, right insula and right fusiform with decreased betweenness, and in left lingual cortex with increased betweenness. CONCLUSIONS: These findings provide evidence for brain network reorganization subsequent to clinical disease manifestation in patients with first-episode schizophrenia, and support the hypothesis that persisting NSS refer to progressive brain network abnormalities in patients with schizophrenia. Therefore, NSS could help to establish a better prognosis in first-episode schizophrenia patients.

Simultaneous determination of serum tryptophan metabolites in an older Chinese population.

Tryptophan (TRP) and its metabolites exhibit significant biological effects and are strongly associated with age-related disease and mortality. However, reports on quantitatively analyzing these metabolites in older individuals are not available. We used ultra-high-performance liquid chromatography-tandem mass spectrometry to optimize and validate a method for isotope dilution analysis of TRP metabolites in older individuals. The targeted analytes are TRP, serotonin or 5-hydroxytryptamine, kynurenine, kynurenic acid, xanthurenic acid, indole-3-acetic acid, indole-3-propionic acid, and tryptamine. The serum sample was purified using solid-phase extraction and was separated on a Waters HSS T3 column (100 mm × 2.1 mm, 1.8 µm). The analytes were detected in the multiple reaction monitoring mode under positive ionization. TRP was confirmed and measured after being diluted 100 times. This method exhibited satisfactory linearity (r > 0.99). The intrabatch and interbatch accuracies (85.7-114%) and precisions (<15%) were acceptable. The standard-normalized matrix effects ranged from 51.6 to 145%. This method was successfully applied to a cohort of 1021 older Chinese individuals, and this study may enable further understanding of the metabolic phenotypes associated with TRP in other populations.

An IFNT/FOXO1/PTGS2 axis regulates prostaglandin F2α synthesis in goat uterus during early pregnancy.

In ruminants, IFN-tau (IFNT) regulates the production of prostaglandins (PG) in the endometrium, which is crucial for conceptus adhesion. However, the related molecular regulatory mechanisms remain unclear. Forkhead box O1 (FOXO1), a member of the FOXO subfamily of transcription factors, is known to be important for mouse implantation and decidualization. In this study, we determined the spatiotemporal expression profile of FOXO1 in goat endometrium during early pregnancy. FOXO1 was highly expressed in the glandular epithelium since the onset of conceptus adhesion (d 16 of pregnancy). Then, we validated that FOXO1 could bind to the promoter of prostaglandin-endoperoxide synthase 2 (PTGS2) and increase its transcription. And the expression profile of PTGS2 was similar to that of FOXO1 in the peri-implantation uterus. Moreover, IFNT could upregulate the levels of FOXO1 and PTGS2 in goat uterus and primary endometrial epithelium cells (EEC). In EEC, the intracellular content of PGF2α was positively correlated with the levels of IFNT and FOXO1. Altogether, we found an IFNT/FOXO1/PTGS2 axis that controls the synthesis of PGF2α but not prostaglandin E2 in goat uterine glands. These findings contribute to better understanding the function of FOXO1 in the reproductive physiology of goats and provide more insights into the implantation of small ruminants.

Luminescent Properties and Charge Compensator Effects of SrMo0.5W0.5O4:Eu3+ for White Light LEDs.

The high-temperature solid-phase approach was used to synthesize Eu3+-doped SrMo0.5W0.5O4 phosphors, whose morphological structure and luminescence properties were then characterized by XRD, SEM, FT-IR, excitation spectra, emission spectra, and fluorescence decay curves. The results reveal that the best phosphor synthesis temperature was 900 °C and that the doping of Eu3+ and charge compensators (K+, Li+, Na+, NH4+) had no effect on the crystal phase change. SrMo0.5W0.5O4:Eu3+ has major excitation peaks at 273 nm, 397 nm, and 464 nm, and a main emission peak at 615 nm, making it a potential red fluorescent material to be used as a down converter in UV LEDs (273 nm and 397 nm) and blue light LEDs (464 nm) to achieve Red emission. The emission spectra of Sr1-yMo0.5W0.5O4:yEu3+(y = 0.005, 0.01, 0.02, 0.05, 0.07) excited at 273 were depicted, with the Eu3+ concentration increasing the luminescence intensity first increases and then decreases, the emission peak intensity of SrMo0.5W0.5O4:Eu3+ achieves its maximum when the doping concentration of Eu3+ is 1%, and the critical transfer distance is calculated as 25.57 Å. When various charge compensators such as K+, Li+, Na+, and NH4+ are added to SrMo0.5W0.5O4:Eu3+, the NH4+ shows the best effect with the optimal doping concentration of 3wt%. The SrMo0.5W0.5O4:Eu3+,NH4+ color coordinate is (0.656,0.343), which is close to that of the ideal red light (0.670,0.333).

Urinary antibiotic exposure and low grip strength risk in community-dwelling elderly Chinese by gender and age.

Emerging studies have shown that environmental contaminants were related to decreased handgrip strength. Nevertheless, no prior research has investigated the relationship of exposure to environmental antibiotics with grip strength. Thus, we explored the relationship between urinary antibiotic burden and grip strength among the elderly in China. This study consisted of 451 men and 539 women from the baseline survey of a cohort study. Commonly used antibiotics for humans and animals were detected in 990 urine samples through a biomonitoring method. Grip strength was measured by an electronic dynamometer. We examined the associations of antibiotic exposure with low grip strength (LGS), grip strength, and grip strength index, respectively. Results suggested that 34.9% of participants developed LGS, and 93.0% of individuals were exposed to 1-10 antibiotics. Among women, oxytetracycline (Quartile 2: odds ratio: 2.97, 95% confidence interval: 1.36-6.50), florfenicol (Quartile 3: 2.60 [1.28-5.27]), fluoroquinolones (Quartile 4: 1.88 [1.07-3.30]), and chloramphenicols (Quartile 3: 2.73 [1.35-5.51]) could enhance LGS risk. Among men, ofloxacin (Quartile 2: 3.32 [1.45-7.59]) increased LGS risk, whereas tetracycline (Quartile 2: 0.31 [0.11-0.88]) was implicated in reduced LGS risk. In participants < 70 years, ofloxacin (Quartile 2: 3.00 [1.40-6.42]) could increase LGS risk. For participants who were 70 years of age or older, veterinary antibiotics (Quartile 3: 1.73 [1.02-2.94]) were linked to a 73% increased risk of LGS. Our findings suggested that antibiotics mainly pertained to LGS, and there were gender and age disparities in associations between antibiotic exposure and muscle strength indicators in the elderly Chinese population.

Smilax china L. Polyphenols Improves Insulin Resistance and Obesity in High-fat Diet-induced Mice Through IRS/AKT-AMPK and NF-κB Signaling Pathways.

Smilax china L. is an important herb used in traditional Chinese medicine. In this study, the mechanism of Smilax china L. polyphenols (SCP) on insulin resistance and anti-obesity in mice induced by a high-fat diet (HFD) was investigated. Fifty female mice were randomly divided into five groups: control, HFD and low, medium, and high doses of SCP for 70 d. SCP significantly decreased intraperitoneal adipose tissue index, body weight gain, liver lipids, and serum inflammatory factor levels. Blood glucose and insulin concentrations, as well as insulin resistance index in SCP, were significantly lower than those in HFD. In addition, SCP markedly up-regulated the gene expression of glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), serine-threonine kinase (AKT), Acyl-CoA oxidase (ACO), and protein kinase A (PKA), and down-regulated the expression of mammalian target of rapamycin complex 1 (mTORC1), sterol-responsive element-binding protein-1c (SREBP1c), fatty acid synthase (FAS), 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), and forkhead box protein O1 (FOXO1). SCP significantly increased the protein expression of AKT, GLUT4, AMP-activated protein kinase (AMPK), phosphorylated-AMPK (p-AMPK), phosphorylated-AKT (p-AKT), and uncoupling protein 1 (UCP-1), and decreased the expression of SREBP1c, FAS, HMGCR, phosphorylation of IKBα (p-IKBα), and nuclear factor kappa B subunit p65 (P65) in the liver. Overall, SCP effectively reduced HFD-induced insulin resistance and obesity in mice, partly through NF-κB and IRS/AKT-AMPK signaling pathways to regulate inflammatory factors. Therefore, SCP may improve lifestyle diseases.

Neurological soft signs and brain morphology in people living with HIV.

Neurological soft signs (NSS) are a common feature of severe psychiatric disorders such as schizophrenia but are also prevalent in organic brain diseases like HIV-associated neurocognitive disorder (HAND) or Alzheimer's disease. While distinct associations between NSS, neurocognition, and cerebral regions were demonstrated in schizophrenia, these associations still have to be elucidated in HIV. Therefore, we investigated 36 persons with HIV of whom 16 were neurocognitively healthy and 20 were diagnosed with HAND. NSS were assessed using the Heidelberg scale. NSS scores were correlated with gray matter (GM) using whole brain voxel-based morphometry. Results showed significantly elevated NSS in the HAND group when compared to the neurocognitively healthy with respect to NSS total score and the subscores "orientation" and "complex motor tasks". While the two groups showed only minor, non-significant GM differences, higher NSS scores (subscales "motor coordination", "orientation") were significantly correlated with GM reduction in the right insula and cerebellum (FWE-corrected). Our results corroborate elevated NSS in HIV+ patients with HAND in contrast to cognitively unimpaired patients. In addition, cerebral correlates of NSS with GM reductions in insula and cerebellum were revealed. Taken together, NSS in this patient group could be considered a marker of cerebral damage and neurocognitive deficits.

All-in-one approaches for triple-negative breast cancer therapy: metal-phenolic nanoplatform for MR imaging-guided combinational therapy.

BACKGROUND: Conventional chemotherapy has poor efficacy in triple-negative breast cancer (TNBC) which is highly heterogeneous and aggressive. Imaging-guided therapy is usually combined with diverse treatment modalities, could realize the integration of diagnosis and treatments. Therefore, the primary challenge for combinational therapy is designing proper delivery systems to accomplish multiple synergistic effects. RESULTS: Herein, a facile nanoplatform was manufactured to fulfill the all-in-one approaches for TNBC combinational therapy. Fe3+-based metal-phenolic networks (MPNs) with bovine serum albumin (BSA) modification served as drug delivery carriers to encapsulate bleomycin (BLM), forming BFE@BSA NPs. The self-assembly mechanism, pH-responsive drug release behavior, and other physicochemical properties of this system were characterized. The potential of BFE@BSA NPs as photothermal transduction agents and magnetic resonance imaging (MRI) contrast agents was explored. The synergistic anti-tumor effects consisting of BLM-induced chemotherapy, Fenton reactions-mediated chemodynamic therapy, and photothermal therapy-induced apoptosis were studied both in vitro and in vivo. Once internalized into tumor cells, released BLM could cause DNA damage, while Fenton reactions were initiated to produce highly toxic •OH. Upon laser irradiation, BFE@BSA NPs could convert light into heat to achieve synergistic effects. After intravenous administration, BFE@BSA NPs exhibited great therapeutic effects in 4T1 tumor xenograft model. Moreover, as T1-weighted MRI contrast agents, BFE@BSA NPs could provide diagnosis and treatment monitoring for individualized precise therapy. CONCLUSIONS: A nano-system that integrated imaging and combinational therapy (chemotherapy, chemodynamic therapy and photothermal therapy) were developed to kill the tumor and monitor therapeutic efficacy. This strategy provided an all-in-one theranostic nanoplatform for MRI-guided combinational therapy against TNBC.