Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

The Application of Nanoparticles Targeting Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in the tumor microenvironment (TME), especially in solid tumors. It has been confirmed that it can not only interact with tumor cells to promote cancer progression and metastasis, but also affect the infiltration and function of immune cells to induce chemotherapy and immunotherapy resistance. So, targeting CAF has been considered an important method in cancer treatment. The rapid development of nanotechnology provides a good perspective to improve the efficiency of targeting CAF. At present, more and more researches have focused on the application of nanoparticles (NPs) in targeting CAF. These studies explored the effects of different types of NPs on CAF and the multifunctional nanomedicines that can eliminate CAF are able to enhance the EPR effect which facilitate the anti-tumor effect of themselves. There also exist amounts of studies focusing on using NPs to inhibit the activation and function of CAF to improve the therapeutic efficacy. The application of NPs targeting CAF needs to be based on an understanding of CAF biology. Therefore, in this review, we first summarized the latest progress of CAF biology, then discussed the types of CAF-targeting NPs and the main strategies in the current. The aim is to elucidate the application of NPs in targeting CAF and provide new insights for engineering nanomedicine to enhance immune response in cancer treatment.

Deep Brain Stimulation Modulates the Visual Pathway to Improve Freezing of Gait in Parkinson's Disease Patients.

OBJECTIVE: To investigate the involvement of the visual cortex in improving freezing of gait (FoG) after subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients using whole-brain seed-based functional connectivity. METHODS: A total of 66 PD patients with FoG who underwent bilateral STN-DBS were included in our study. Patients were divided into a FoG responder group and an FoG nonresponder group according to whether FoG improved 1 year after DBS. We compared the differences in clinical characteristics, brain structural imaging, and seed-based functional connectivity between the 2 groups. The locations of active contacts were further analyzed. RESULTS: All PD patients benefited from STN-DBS. No significant differences in the baseline characteristics or brain structures were found between the 2 groups. Seed-based functional connectivity analysis revealed that better connectivity in bilateral primary visual areas was associated with better clinical improvement in FoG (P < 0.05 familywise error corrected). Further analysis revealed that this disparity was associated with the location of the active contacts within the rostral region of the sensorimotor subregion in the FoG responder group, in contrast to the findings in the FoG nonresponder group. CONCLUSIONS: This study suggested that DBS in the rostral region of the STN sensorimotor subregion may alleviate FoG by strengthening functional connectivity in primary visual areas, which has significant implications for guiding surgical strategies for FoG in the future.

Association between exposure to per- and polyfluoroalkyl substances and levels of lipid profile based on human studies.

Epidemiological evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) is associated with lipid profile levels, but with inconsistent conclusions from different studies. The aim of this study was to conduct a meta-analysis of the relationship between PFAS exposure and lipid profile levels based on population-based epidemiological studies. Embase, PubMed, Ovid database, The Cochrane Library and Web of Science database were used to search appropriate studies (before September 6, 2022) on the correlation between PFAS exposure and lipid profile levels. ß value, odd ratio (OR) and 95 % confidence intervals (CIs) were extracted from studies. In this study, we found that higher low-density lipoprotein (LDL) levels were associated with exposure to perfluoroundecanoic acid (PFUnDA) (ß value=0.13, 95 % CIs: 0.02, 0.24) and perfluorooctane sulfonic acid (PFOS) (ß value=0.13, 95 % CIs: 0.04, 0.21). PFOA, PFOS and PFNA exposure were significantly related to the higher levels of total cholesterol (TC) with the pooled effect estimates of 0.08 (95 % CI: 0.02, 0.14), 0.13 (95 % CI: 0.05, 0.21) and 0.14 (95 % CI: 0.08, 0.20) respectively. In sum, our results identified that PFOA, PFOS, PFNA and PFUnDA were the most important risk factors for abnormal levels of lipid profile, indicating that we should prevent cerebrovascular disease by reducing and controlling PFAS exposure.

Association between per- and polyfluoroalkyl substances and sex hormone levels in males based on human studies.

BACKGROUND: Per- and poly-fluoroalkyl substances (PFAS) are ubiquitous chemicals in the environment and our daily lives. Several epidemiological studies have revealed that PFAS exposure is linked to male sex hormone levels; however, the conclusions are inconsistent across studies. Consequently, we performed a meta-analysis to systematically evaluate the association between PFAS exposure and male sex hormones. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards were followed during the meta-analysis. PubMed, Wed of Science, Embase, Cochrane Library, and Ovid databases were used to identify suitable articles before June 2023. The 95% CI and ß values were calculated to assess the association between male sex hormone levels and PFAS exposure. Heterogeneity among the included studies was tested using inconsistency statistics (I2). RESULTS: The literature search identified 12 published articles that met our search criteria, involving 7506 participants. Our results revealed that perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA) exposures were negatively correlated with testosterone (ß = -0.05; 95% CI: -0.09, -0.02, P = 0.003) and (ß = -0.04; 95% CI: -0.08, 0.00, P = 0.049), respectively. CONCLUSION: Exposure to PFNA and PFOA is negatively correlated with changes in male testosterone levels. This correlation suggests that we need to pay attention in the future to whether they are potential risk factors for male reproductive health.

Clinical value of oral contrast-enhanced ultrasonography in diagnosis of gastric tumors.

BACKGROUND: The incidence of gastric cancer remains high, and it is the sixth most common cancer and the fourth leading cause of cancer deaths worldwide. Oral contrast-enhanced ultrasonography is a simple, non-invasive, and painless method for the diagnosis of gastric tumors. AIM: To explore the diagnostic value of oral contrast-enhanced ultrasonography for the detection of gastric tumors. METHODS: The screening results based on oral contrast-enhanced ultrasonography and electronic gastroscopy were compared with those of the postoperative pathological examination. RESULTS: Among 42 patients with gastric tumors enrolled in the study, the diagnostic accordance rate was 95.2% for oral contrast-enhanced ultrasonography (n = 40) and 90.5% for electronic gastroscopy (n = 38) compared with postoperative pathological examination. The Kappa value of consistency test with pathological findings was 0.812 for oral contrast-enhanced ultrasonography and 0.718 for electronic gastroscopy, and there was no significant difference between them (P = 0.397). For the TNM staging of gastric tumors, the accuracy rate of oral contrast-enhanced ultrasonography was 81.9% for the overall T staging and 50%, 77.8%, 100%, and 100% for T1, T2, T3, and T4 staging, respectively. The sensitivity and specificity were both 100% for stages T3 and T4. The diagnostic accuracy rate of oral contrast-enhanced ultrasonography was 93.8%, 80%, 100%, and 100% for stages N0, N1-N3, M0, and M1, respectively. CONCLUSION: The accordance rate of qualitative diagnosis by oral contrast-enhanced ultrasonography is comparable to that of gastroscopy, and it could be used as the preferred method for the early screening of gastric tumors.

Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation.

ABBREVIATIONS: AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.

Oncogene goosecoid is transcriptionally regulated by E2F1 and correlates with disease progression in prostate cancer.

BACKGROUND: Although some well-established oncogenes are involved in cancer initiation and progression such as prostate cancer (PCa), the long tail of cancer genes remains to be defined. Goosecoid (GSC) has been implicated in cancer development. However, the comprehensive biological role of GSC in pan-cancer, specifically in PCa, remains unexplored. The aim of this study was to investigate the role of GSC in PCa development. METHODS: We performed a systematic bioinformatics exploration of GSC using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, German Cancer Research Center, and our in-house cohorts. First, we evaluated the expression of GSC and its association with patient prognosis, and identified GSC-relevant genetic alterations in cancers. Further, we focused on the clinical characterization and prognostic analysis of GSC in PCa. To understand the transcriptional regulation of GSC by E2F transcription factor 1 (E2F1), we performed chromatin immunoprecipitation quantitative polymerase chain reaction (qPCR). Functional experiments were conducted to validate the effect of GSC on the tumor cellular phenotype and sensitivity to trametinib. RESULTS: GSC expression was elevated in various tumors and significantly correlated with patient prognosis. The alterations of GSC contribute to the progression of various tumors especially in PCa. Patients with PCa and high GSC expression exhibited worse progression-free survival and biochemical recurrence outcomes. Further, GSC upregulation in patients with PCa was mostly accompanied with higher Gleason score, advanced tumor stage, lymph node metastasis, and elevated prostate-specific antigen (PSA) levels. Mechanistically, the transcription factor, E2F1, stimulates GSC by binding to its promoter region. Detailed experiments further demonstrated that GSC acted as an oncogene and influenced the response of PCa cells to trametinib treatment. CONCLUSIONS: GSC was highly overexpressed and strongly correlated with patient prognosis in PCa. We found that GSC, regulated by E2F1, acted as an oncogene and impeded the therapeutic efficacy of trametinib in PCa.

Integrating bioinformatic analysis and detailed experiments reveal an EMT-related biomarker for clear cell renal cell carcinoma.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is associated with early recurrence and a poor prognosis in clear cell renal cell carcinoma (ccRCC). Studies have shown that EMT-related genes play an important regulatory role in tumor invasion, metastasis, and drug resistance, but the biological functions of EMT-related genes in ccRCC have not been specifically described. METHODS: The mRNA and clinicopathological data of 532 ccRCC and 72 normal samples were downloaded from The Cancer Genome Atlas as a training set. The gene expression matrix and survival data of 91 and 101 ccRCC samples were obtained from the International Cancer Genome Consortium and the ArrayExpress databases as validation sets, respectively. Univariate Cox analysis was used to identify and cluster prognostic genes, and multivariate Cox was performed to construct a prognostic signature. Moreover, CIBERSORT and CellMiner were used to assess immune cell infiltration and prognostic gene-drug sensitivity of the signature, respectively. Most importantly, we performed detailed experiments to verify the oncogenic function of a significant gene, OLFML2B, in vitro and in vivo. RESULTS: We constructed a prognostic signature including seven genes and divided patients into high-risk and low-risk groups. The prognosis of the high-risk group was significantly worse than that of the low-risk group through Kaplan-Meier survival analysis. Interestingly, significant differences were observed in clinical characteristics and immune cell infiltration between the two groups. In addition, a significant correlation was found between the expression of prognostic genes and the sensitivity of tumor cells to chemotherapeutics. Most importantly, OLFML2B was proved to contribute to the proliferation and metastasis of ccRCC through detailed functional experiments in vitro and in vivo, and its prognostic efficacy for ccRCC patients was affirmed. CONCLUSION: We identified the prognostic signature of seven genes based on EMT-related genes as prognostic biomarkers for ccRCC. Besides, OLFML2B was validated as a potential diagnostic and therapeutic target for ccRCC by our detailed experiments.

Identifying the active ingredients of carbonized Typhae Pollen by spectrum-effect relationship combined with MBPLS, PLS, and SVM algorithms.

Typhae Pollen (TP) and its carbonized product (carbonized Typhae Pollen, CTP), as cut-and-dried herbal drugs, have been widely used in the form of slices in clinical settings. However, the two drugs exhibit a great difference in terms of their clinical efficacy, for TP boasts an effect of removing blood stasis and promoting blood circulation, while CTP typically presents a hemostatic function. Since the active ingredients of CTP, so far, still remain unclear, this study aimed at identifying the active ingredients of CTP by spectrum-effect relationship approach coupled with multi-block partial least squares (MBPLS), partial least squares (PLS), and support vector machine (SVM) algorithms. In this study, the chemical profiles of a series of CTP samples which were stir-fried for different duration (denoted as CTP0∼CTP9) were firstly characterized by UHPLC-QE-Orbitrap MS. Then the hemostatic effect of the CTP samples was evaluated from the perspective of multiple parameters-APTT, PT, TT, FIB, TXB2, 6-keto-PGF1α, PAI-1 and t-PA-using established rat models with functional uterine bleeding. Subsequently, MBPLS, PLS and SVM were combined to perform spectrum-effect relationship analysis to identify the active ingredients of CTP, followed by an in vitro hemostatic bioactivity test for verification. As a result, a total of 77 chemical ingredients were preliminarily identified from the CTP samples, and the variations occurred in these ingredients were also analyzed during the carbonizing process. The study revealed that all the CTP samples, to a varying degree, showed a hemostatic effect, among which CTP6 and CTP7 were superior to the others in terms of the hemostatic effect. The block importance in the projection (BIP) indexes of MBPLS model indicated that flavonoids and organic acids made more contributions to the hemostatic effect of CTP in comparison to other ingredients. Consequently, 9 bioactive ingredients, including quercetin-3-O-glucoside, kaempferol-3-O-rutinoside, quercetin, kaempferol, isorhamnetin, 2-methylenebutanedioic acid, pentanedioic acid, benzoic acid and 3-hydroxybenzoic acid, were further identified as the potential active ingredients based on PLS and SVM models as well as the in vitro verification. This study successfully revealed the bioactive ingredients of CTP associated with its hemostatic effect, and also provided a scientific basis for further understanding the mechanism of TP processing. In addition, it proposed a novel path to identify the active ingredients for Chinese herbal medicines.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

The roles of natural triterpenoid saponins against Alzheimer's disease.

The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.

Quality assessment of Rheum species cultivated in Japan by focusing on M2 polarization of microglia.

In traditional Japanese medicine, Rhei Rhizoma is used as a purgative, blood stasis-resolving and antipsychotic drug. The latter two properties are possibly related to anti-inflammatory effects. Microglia regulate inflammation in the central nervous system. M1 microglia induce inflammation, while M2 microglia inhibit inflammation and show neurotrophic effects. This study investigated the effects from water extracts of roots of cultivated Rheum species in Nagano Prefecture, Japan (strain C, a related strain to a Japanese cultivar, 'Shinshu-Daio'; and strain 29, a Chinese strain) and 3 kinds of Rhei Rhizoma available in the Japanese market, and also examined their constituents on the polarization of cultured microglia. All extracts significantly decreased M1 microglia, and strains C and 29 significantly increased M2 microglia. Furthermore, the extracts of both strains significantly increased the M2/M1 ratio. Among the constituents of Rhei Rhizoma, ( +)-catechin (2), resveratrol 4'-O-ß-D-(6″-O-galloyl) glucopyranoside (5), isolindleyin (8), and physcion (15) significantly increased the M2/M1 ratio. The contents of the constituents in water extract of each strain were quantified using HPLC. The extracts of strains C and 29 contained relatively large amounts of 2 and 5; and 2, 8, and 15, respectively. This study showed the water extracts of roots of cultivated Rheum strains in Japan had the effects of M2 polarization of microglia, suggesting that these strains become the candidate to develop anti-inflammatory Rhei Rhizoma. Moreover, the suitable chemical composition to possess anti-inflammatory activity in the brain was clarified for the future development of new type of Rhei Rhizoma.

Pathogen Diagnosis Value of Nanopore Sequencing in Severe Hospital-Acquired Pneumonia Patients.

Background: Next-generation sequencing of the metagenome (mNGS) is increasingly used in pathogen diagnosis for infectious diseases due to its short detection time. The time for Oxford Nanopore Technologies (ONT) sequencing-based etiology detection is further shortened compared with that of mNGS, but only a few studies have verified the time advantage and accuracy of ONT sequencing for etiology diagnosis. In 2022, a study confirmed that there was no significant difference in sensitivity and specificity between ONT and mNGS in suspected community-acquired pneumonia patients, which there was no clinical study verified in patients with SHAP. Methods: From October 24 to November 20, 2022, 10 patients with severe hospital-acquired pneumonia (SHAP) in the Nanfang Hospital intensive care unit (ICU) were prospectively enrolled. Bronchoalveolar lavage fluid (BALF) was collected for ONT sequencing, mNGS, and traditional culture. The differences in pathogen detection time and diagnostic agreement among ONT sequencing, mNGS, traditional culture method, and clinical composite diagnosis were compared. Results: Compared with mNGS and the traditional culture method, ONT sequencing had a significant advantage in pathogen detection time (9.6±0.7 h versus 24.7±2.7 h versus 132±58 h, P <0.05). The agreement rate between ONT sequencing and the clinical composite diagnosis was 73.3% (kappa value=0.737, P <0.05). Conclusion: ONT sequencing has a potential advantage for rapidly identifying pathogens.

The role of circular RNA in tumor microenvironment and immunotherapy.

Cancer immunotherapy has favorable efficacy in various types of tumors, and has become an important weapon in the treatment of tumors in recent years. Long noncoding RNAs and microRNAs have been identified to play important roles in regulating cancer immunotherapy. Circular RNAs (circRNAs) are involved in the pathological process of many diseases, especially cancer. Many functions of circRNAs have been extensively studied. However, the functions of circRNAs in the tumor microenvironment and cancer immunotherapy do not appear to be fully elucidated. Therefore, we review the roles of circRNAs in tumor microenvironment and cancer immunotherapy.

Combined Metabolite Analysis and Network Pharmacology to Elucidate the Mechanisms of Therapeutic Effect of Melastoma dodecandrum Ellagitannins on Abnormal Uterine Bleeding.

The abnormal uterine bleeding (AUB) is complex and usually leads to severe anemia. Melastomadodecandrum (MD) is clinically used for the treatment of metrorrhagia bleeding. The MD ellagitannins (MD-ETs) had been evidenced being effective at hemorrhage, and exerts biological activities upon their metabolites including ellagic acid and urolithins. In this study, the blood-permeated metabolites from theMD-ETs were analyzed using LC-MS approach, and 19 metabolites including ellagic acid and urolithin A derivatives were identified. Furthermore, a network pharmacology analysis including the target prediction analysis, AUB target analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to reveal the relationships between "metabolites-targets-pathways", which was further verified by molecular docking analysis. The results showed that methyl ellagic acid, urolithin A and isourolithin A produced from MD-ETs can be absorbed into the blood, and might act on the core targets of VEGFA, SRC, MTOR, EGFR and CCND1. And the hemostatic effects were exerted through PI3K-Akt, endocrine resistance and Rap 1 signaling pathways. These results implied the potential effective constituents and action mechanism of MD-ETs in the therapy of AUB, which will promote the application of MD-ETs as natural agent for the treatment of gynecological bleeding diseases.

Global epidemiology of animal influenza infections with explicit virus subtypes until 2016: A spatio-temporal descriptive analysis.

Influenza virus, with a global distribution, diverse animal host range and multiple virus subtypes, has caused several pandemics. To better prepare for the emergence of new subtypes and the possible threat of the next pandemic, the global status of animal influenza must be defined and documented. We created a global database of animal influenza events by searching scientific databases and the primary literature on animal influenza-related events up to and including 2016. The temporal, spatial and host distribution of animal influenza and the diversity of influenza subtypes in different regions were analyzed. A total of 70,472 records and 4712 events of animal influenza throughout the world were identified. Events involving subtypes H5N2, H7N7 and H7N9 were relatively constant, with a slow upward trend during the past decade. Asia was the region with the most clusters of events. Poultry was the main host reported in Asia and Africa, and wild birds in Europe and North America. We found that wild birds carried a very rich array of virus subtypes, a warning for the possible generation of reassortment viruses with pandemic potential. Influenza virus subtype diversity - a risk for virus reassortment - was greatest in Asia, North America and Europe. Our database provides a comprehensive overview of the historical and current status of animal influenza events throughout the world. Influenza surveillance needs to be strengthened in some countries and regions to prevent the emergence of new subtypes. Importantly, improvement of the global influenza surveillance system and structures to enable sharing of surveillance data is very much needed to prepare for the next pandemic.

Molecular networking-assisted systematical profiling and the in vivo neuroprotective effect of ellagitannins from the Melastoma dodecandrum Lour.

BACKGROUND: Ellagitannins (ETs) are a major classification of natural tannins, with relatively large and complex structures. ETs from medicinal plants are focused increasingly due to urolithins, a kind of intestinal metabolite of ETs, which showed promising anti-Alzheimer's disease (AD) effects. Melastoma dodecandrum (MD), a widely used traditional Chinese medicine is rich in ETs, but their chemistry and potential neuroprotective effects have not been investigated. PURPOSE: This study aimed to identify the chemical composition of ETs in the crude extract of MD and to investigate their neuroprotective effects in vivo. METHODS: UPLC-QTOF-MS-based molecular networking (MN) and structural characterization were applied to targeted profiling of the MD-ETs. Animal behavior experiments, including the novel object recognition test (NOR), open field test (OFT), and Morris water maze test (MWM), were conducted to assess the memory improvement effects of MD-ETs in AD model mice. RESULTS: A total of 70 ETs, ranging from monomers to tetramers, were tracked and characterized in the MD extract using MN-guided targeted profiling, with 59 of them reported for the first time in this species. MD-ETs significantly improved memory impairment in AD mice, as indicated by decreased escape latency, increased number of crossings and target quadrant distance in MWM, increased rearing number in OFT, and increased preference index in NOR. CONCLUSION: This study systematically characterized the composition and structural features of ETs in MD using targeted LC-MS profiling, expanding the chemical information of ETs in MD. Furthermore, the results demonstrate that MD-ETs have significant effects on improving impaired memory in AD mice, suggesting their potential as alternative natural medicines for the treatment of neurodegenerative diseases.

How socioeconomic status affected the access to health facilities and malaria diagnosis in children under five years: findings from 19 sub-Saharan African countries.

BACKGROUND: Prompt and appropriate clinical management of malaria is critical for reducing the continued high burden of malaria among children under five years in sub-Saharan countries. However, more remains to be known about how a patient's socioeconomic status (SES) would affect the access to diagnosis of malaria. METHODS: In this cross-sectional study using the Demographic and Health Survey and Malaria Indicators Survey, we pooled the data of 38,567 febrile under-five children in 2016-2018 from 19 sub-Saharan countries. Multivariable logistic regression was used to assess the associations between SES and two binary outcomes: the visit to a health facility and a blood test for fever. Stratified analyses were further conducted by the type of health facilities (public hospitals/public primary healthcare facilities/private hospitals/private primary healthcare facilities) for the latter outcome. RESULTS: Fifty-eight percent of the febrile children were taken to health facilities, among whom only 55% took blood tests. Compared to children from households in the highest wealth quintile, children in the lowest quintile were less likely to be taken to medical facilities [adjusted odds ratio (aOR) = 0.775, 95% confidence interval (CI): 0.675-0.889]. Parents with more than secondary education were more likely to seek care (aOR = 1.830, 95% CI: 1.561-2.145) and to have blood tests (aOR = 1.729, 95% CI: 1.436-2.082) for their febrile children than parents without formal education. The probabilities of receiving blood tests at public hospitals and public primary healthcare facilities stayed relatively high across parental education levels and wealth quintiles, while these probabilities remained the lowest at private primary healthcare facilities, ranging from 0.100 (95% CI: 0.074-0.127) to 0.139 (95% CI: 0.083-0.194) across parental education levels and from 0.104 (95% CI: 0.078-0.130) to 0.125 (95% CI: 0.090-0.160) across wealth quintiles. CONCLUSIONS: Significant socioeconomic disparities existed both in the access to health facilities and laboratory diagnosis of malaria in children in sub-Saharan African countries. These disparities were particularly evident in the private sector. Universal health coverage needs to be further strengthened to make formal healthcare in general and the laboratory diagnosis of malaria more accessible and affordable.

Vinyl chloride enhances high-fat diet-induced proteome alterations in the mouse pancreas related to metabolic dysfunction.

Alterations in physiological processes in pancreas have been associated with various metabolic dysfunctions and can result from environmental exposures, such as chemicals and diet. It was reported that environmental vinyl chloride (VC) exposure, a common industrial organochlorine and environmental pollutant, significantly exacerbated metabolic-related phenotypes in mice fed concurrently with high-fat diet (HFD) but not low-fat diet (LFD). However, little is known about the role of the pancreas in this interplay, especially at a proteomic level. The present study was undertaken to examine the protein responses to VC exposure in pancreas tissues of C57BL/6J mice fed LFD or HFD, with focus on the investigation of protein expression and/or phosphorylation levels of key protein biomarkers of carbohydrate, lipid, and energy metabolism, oxidative stress and detoxification, insulin secretion and regulation, cell growth, development, and communication, immunological responses and inflammation, and biomarkers of pancreatic diseases and cancers. We found that the protein alterations may indicate diet-mediated susceptibility in mouse pancreas induced by HFD to concurrent exposure of low levels of inhaled VC. These proteome biomarkers may lead to a better understanding of pancreas-mediated adaptive or adverse response and susceptibility to metabolic disease.