Fluorinated liquid-crystal monomers in infant formulas and implication for health risk.

Fluorinated liquid-crystal monomers (FLCMs), a new class of potential persistent, bioaccumulative and toxic (PBT) emerging pollutants, are extensively utilized in the display panel of various electronic devices. These compounds have been found in various environmental matrixes and dietary. Our previous studies have documented their ubiquitous occurrence in high fat foodstuffs. Infants, a vulnerable group, are more susceptible to the impacts of these pollutants compared to adults. Herein, we provided an assessment of the health risks posed by FLCMs to infants, focusing on their exposure through infant formula. The presence of FLCMs was detected in all infant formulas, with median concentration of 16.5 ng/g dry weight (dw) and the 95th percentile concentration of 65.7 ng/g dw. The most prevalent pollutant in these formulas was 2-fluoro-4-[4'-propyl-1,1'-bi(cyclohexyl)-4-yl] phenyl trifluoromethyl ether (FPrBP), with median and a 95th percentile concentration of 12.2 ng/g dw and 23.8 ng/g dw, accounting for 55.2% to the total FLCMs. Infants aged 0-6 months had the highest estimated daily intakes (EDIs) of FLCMs, with the EDImedian of 267 ng/kg bw/day. FPrBP and 4-[trans-4-(trans-4-Propylcyclohexyl) cyclohexyl]-1-trifluoromethoxybenzene (PCTB) together made up 83.3% of the total EDIs in median exposure scenario of 0-6 months infant. The highest EDI value was 1.30 × 103 ng/kg bw/day, 77.1% of which was attributed to a combination of FPrBP, 4″-ethyl-2'-fluoro-4-propyl-1,1':4',1″-terphenyl (EFPT), 2-[4'-[difluoro(3,4,5-trifluoro-2-methyl-phenoxy)methyl]-3',5'-difluoro-[1,1'-biphenyl]-4-yl]-5-ethyl-tetrahydro-pyran (DTMPMDP), 4-[Difluoro-(3,4,5-trifluoro-2-methyl-phenoxy)-methyl]-3,5-difluoro-4'-propyl-1,1-biphenyl (DTMPMDB), 2,3-difluoro-1-methyl-4-[(trans, trans)-4'-pentyl[1,1'-bicyclohexyl]-4-yl]benzene (DMPBB) and PCTB. It's worth noting that FLCMs have higher exposure risk. Based on the threshold of toxicological concern (TTC) method, the EDImedian of FPrBP (183 ng/kg bw/day) and FPCB (3.27 ng/kg bw/day) were beyond their TTC values (2.5 ng/kg bw/day) in 0-6 months infant, implying their prospective health risk.

Integrated approach of network pharmacology, molecular docking, and clinical observations in evaluating the efficacy and safety of Bufei Huoxue capsules for pulmonary hypertension associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a persistent and progressive disorder characterized by airway or alveolar abnormalities, commonly leading to pulmonary hypertension (PH). This clinical observational study investigates the therapeutic mechanisms of Bufei Huoxue capsules (BHC) in treating PH in patients with COPD-linked PH (COPD-PH) using network pharmacology and molecular docking methods, and assesses the therapeutic efficacy and safety of BHCs. The active compounds and their target proteins in BHCs were sourced from the Traditional Chinese Medicine Systems Pharmacology database, with additional target proteins derived from the GeneCards and OMIM databases. An active network was constructed using Cytoscape 3.7.1, and interaction networks were established. Intersecting targets underwent Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Metascape database. Network pharmacology and molecular docking studies demonstrated favorable binding affinities of BHC active ingredients, such as quercetin, bavachalcone, and isobavachin, for key targets including PTGS1, ESR1, and PTGS2. Gene Ontology enrichment analysis highlighted the involvement of these targets in processes such as the positive regulation of locomotion, the transmembrane receptor protein tyrosine kinase signaling pathway, and peptidyl-tyrosine phosphorylation. KEGG pathway analysis indicated their roles in pathways related to cancer, AGE-RAGE signaling in diabetic complications, and prostate cancer. BHCs exhibit therapeutic effects on COPD-PH through multi-component, multi-target, and multi-pathway interactions. This clinical observational study confirms the efficacy and safety of BHCs in improving cardiac and pulmonary functions, enhancing exercise tolerance, and elevating the quality of life in patients with COPD-PH.

Phenanthroimidazole-based fluorescence probe for discriminative detecting of hydrazine and bisulfite and its applications in environmental samples.

Hydrazine (N2H4) and bisulfite (HSO3-) detection methods are urgently needed due to its harmful to the human health and environment safety. Herein, we reported a dual-response fluorescence probe EPC, which is capable of sequential detection of N2H4 and HSO3- by two different fluorescence signals. The probe EPC itself showed yellow florescence. In presence of N2H4, probe EPC exhibited an obviously fluorescence change (from yellow to green). However, a new addition product came into being after probe EPC mixed with HSO3-, followed with weak yellow emission. More important, probe EPC exhibited excellent fluorescence response properties for N2H4 and HSO3-, such as high sensitivity (0.182 µM for N2H4, 0.093 µM for HSO3-), rapid response (55 s for N2H4, 45 s for HSO3-), excellent selectivity and anti-interference performance. The sensing mechanisms for N2H4 and HSO3- were proved by 1H NMR and MS spectra. Practical applications were studied. EPC based test paper can be utilized for quantitative detecting N2H4 in actual water samples. And, probe EPC has been successfully applied to recognize N2H4 contaminant in soil samples. Moreover, EPC has great potential to be used to detect HSO3- in real food samples.

Reflectance confocal microscopy for plaque psoriasis therapeutic follow-up during an anti-interleukin-17A monoclonal antibody: an observational study.

Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1-4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient's response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP's response to biological therapy.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease.

BACKGROUND: As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats. METHODS: PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg- 1·wk- 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined. RESULTS: Inhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9. CONCLUSION: Inhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.

Risk prediction models for diabetic nephropathy among type 2 diabetes patients in China: a systematic review and meta-analysis.

Objective: This study systematically reviews and meta-analyzes existing risk prediction models for diabetic kidney disease (DKD) among patients with type 2 diabetes, aiming to provide references for scholars in China to develop higher-quality risk prediction models. Methods: We searched databases including China National Knowledge Infrastructure (CNKI), Wanfang Data, VIP Chinese Science and Technology Journal Database, Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, Embase, and the Cochrane Library for studies on the construction of DKD risk prediction models among type 2 diabetes patients, up until 28 December 2023. Two researchers independently screened the literature and extracted and evaluated information according to a data extraction form and bias risk assessment tool for prediction model studies. The area under the curve (AUC) values of the models were meta-analyzed using STATA 14.0 software. Results: A total of 32 studies were included, with 31 performing internal validation and 22 reporting calibration. The incidence rate of DKD among patients with type 2 diabetes ranged from 6.0% to 62.3%. The AUC ranged from 0.713 to 0.949, indicating the prediction models have fair to excellent prediction accuracy. The overall applicability of the included studies was good; however, there was a high overall risk of bias, mainly due to the retrospective nature of most studies, unreasonable sample sizes, and studies conducted in a single center. Meta-analysis of the models yielded a combined AUC of 0.810 (95% CI: 0.780-0.840), indicating good predictive performance. Conclusion: Research on DKD risk prediction models for patients with type 2 diabetes in China is still in its initial stages, with a high overall risk of bias and a lack of clinical application. Future efforts could focus on constructing high-performance, easy-to-use prediction models based on interpretable machine learning methods and applying them in clinical settings. Registration: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a recognized guideline for such research. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024498015.

AIM2 enhances Candida albicans infection through promoting macrophage apoptosis via AKT signaling.

Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2-/- mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2-/- mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2-/- mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2-/- mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2-/- mice. Furthermore, the reduction in apoptosis is observed in Aim2-/- mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2-/- mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections.

Prediction of clinical risk assessment and survival in chronic obstructive pulmonary disease with pulmonary hypertension.

BACKGROUND: Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non-invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD-PH). METHODS: This study included 535 patients with COPD-PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD-PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan-Meier curves were used for a survival analysis. The nomograms were developed as online network software. RESULTS: Tricuspid regurgitation velocity, right ventricular diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), the red blood cell count, New York Heart Association functional class and sex were non-invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT-proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD-PH and were used to create a predictive nomogram of overall survival rates. CONCLUSIONS: The proposed nomograms based on a large sample size of patients with COPD-PH could be used as non-invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD-PH. Additionally, the online network has the potential to provide artificial intelligence-assisted diagnosis and treatment. HIGHLIGHTS: A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non-invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD-PH.

Comparison of clinical outcomes between family caregivers and professional caregivers in in-hospital patients with acute ischaemic stroke: A prospective cohort study.

AIM: This study explored the impact of different care modes on the outcome of hospitalized patients with acute ischaemic stroke (AIS) during hospitalization and 3 months after discharge. METHODS: This was a prospective cohort study comparing the outcomes at hospitalization, at discharge, and at 3 months post discharge among AIS patients with different caregiving arrangements from 9, December 2022 to 20, August 2023. The general information questionnaire, Modified Barthel Index, Shortened General Comfort Questionnaire, Perceived Social Support scale, Herth Hope Index, modified Rankin scale and EQ-5D-5L were utilized for the investigation. RESULTS: The psychological evaluation scores during hospitalization, including comfort, perceived social support, and hope, did not significantly differ between the two groups of AIS patients (p > .05). Moreover, there were no significant impacts observed in terms of length of stay (LOS) at the hospital or hospitalization expense (p > .05). The proportion of patients with intact functionality was greater in the family caregiver group 3 months after discharge (16.5%). However, when stratified based on prognosis, the difference in outcomes between the two groups of patients did not reach statistical significance (p > .05). The analysis of ADL, quality of life and stroke recurrence in 276 surviving ischaemic stroke patients 3 months post discharge indicated no differences between the two groups across all three aspects (p > .05). CONCLUSION: Older and divorced or widowed AIS patients tend to prefer professional caregivers. The psychological state during hospitalization, length of hospital stay and hospitalization expenses are not influenced by the caregiving model. Three months post discharge, a greater proportion of patients in the family caregiving group had intact mRS functionality, but this choice did not impact patient prognosis, stroke recurrence, quality of life or independence in ADL.

Category-Based Effect on False Memory of People with Down Syndrome.

Background: People with Down syndrome (DS) are deficient in verbal memory but relatively preserved in visuospatial perception. Verbal memories are related to semantic knowledge. Receptive ability is better than expressive ability in people with DS but still seriously lags behind their age-matched controls. This lag may result in the weak semantic integration of people with DS. Aims: This study aimed to examine the ability of semantic integration of people with DS by using false-memory tasks. Possible differences in the number of false memories induced by nouns and verbs were of focus. Methods and Procedures: Two phases were involved in the false-memory task. In the study phase, ten-word lists with semantically related associates were presented. In the recognition phase, judgments were to be made about whether the words presented had been heard before. Three types of words were tested: previously presented associates, semantically related lures, and semantically unrelated new words. Outcomes and Results: People with DS overall showed the lowest accuracy among groups in response to tested word types. In the processing of lures, people with DS were worse in recognition than MA controls. In processing unrelated words, people with DS responded least accurately to all types of words compared to control groups. In the processing of associates, people with DS showed similar recognition rates as the MA controls but were less accurate than the CA controls. No difference was observed between nouns and verbs in recognizing word types among groups, though faster responses to nouns than to verbs emerged in college students. Further analyses on topic-wised comparisons of errors across syntactic categories revealed differences in specific concepts among groups, suggesting people with DS were atypical in semantic organization. Conclusions and Implications: People with DS showed mixed patterns in semantic integration by false-memory tasks with delay to associates and deviance to lures together with unrelated words. People with DS showed distinct patterns in processing nouns and verbs while conducting topic-wise comparisons, suggesting that they formed false memories differently based on distinct syntactic categories. We concluded that people with DS develop a deviant semantic structure, hence showing problems in language and social cognition. Category-based rehabilitation is suggested to be implemented for people with DS to improve their semantic knowledge through lexical connections.

Advancing perspectives on the off-label use of anticancer drugs: an updated classification and exploration of categories.

To date, the definition that the off-label usage of drugs refers to the unapproved use of approved drugs, which covers unapproved indications, patient populations, doses, and/or routes of administration, has been in existence for many years. Currently, there is a limited frequency and prevalence of research on the off-label use of antineoplastic drugs, mainly due to incomplete definition and classification issues. It is time to embrace new categories for the off-label usage of anticancer drugs. This review provided an insight into an updated overview of the concept and categories of the off-label use of anticancer drugs, along with illustrating specific examples to establish the next studies about the extent of the off-label usage of anticancer drugs in the oncology setting. The scope of the off-label use of current anticancer drugs beyond the previous definitions not only includes off-label uses in terms of indications, patient populations, doses, and/or routes of administration but also off-label use in terms of medication course, combination, sequence of medication, clinical purpose, contraindications scenarios, etc. In addition, the definition of the off-label usage of anticancer drugs should be added to the condition at a given time, and it varies from approval authorities. We presented a new and relatively comprehensive classification, providing extensive analysis and illustrative examples of the off-label usage of antineoplastic drugs for the first time. Such a classification has the potential to promote practical adoption and enhance management strategies for the off-label use of antitumor drugs.

Niaodukang mixture inhibits micro-inflammation in CKD rats by enhancing MiR-146a levels in enterogenous exosomes.

ETHNOPHARMACOLOGICAL RELEVANCE: The Niaodukang mixture (NDK) is a preparation known for its ability to lower serum creatine levels in individuals with chronic kidney disease (CKD) and is commonly administered at medical facilities like the Zhongshan Hospital of Traditional Chinese Medicine. The initial use of NDK was mainly to treat CKD. Our hospital frequently utilizes NDK, which consists of Rheum officinaleBaill., Salvia miltiorrhiza Bunge., Astragalus aaronii (Eig) Zohary., Carthamus tinctorius L., and Sanguisorba officinalis L., for treating patients with CKD-MBD. It has the effects of eliminating dampness and turbidity and dredging kidney collaterals. However, The impact and process of NDK in chronic kidney disease remain unknown. AIM OF THE STUDY: To determine whether microRNA-146a (miR-146a) is associated with CKD micro-inflammationand whether NDK protects against CKD micro-inflammation by modulating the miR-146a/nuclear factor kappa-B (NF-κB) signaling pathway. MATERIALS AND METHODS: (1) An adenine-induced rat model of chronic kidney disease was created through the use of materials and methods. The levels of miR-146a in exosomes from plasma and ileum were determined by RT-PCR. (2) Human cloned colon adenocarcinoma (Caco-2)cellswere stimulated with lipopolysaccharide (LPS)and transfected with miR-146a mimic and inhibitor. Following that, the Western blot and RT-PCR techniques were used to measure the protein and mRNA quantities of Toll-like receptor 4 (TLR4), NF-κB, and TNF receptor-associated factor 6 (TRAF6). (3) Enzyme-linked immunosorbent assay (ELISA) was used to identify serum levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). (4) Plasma exosomes were extracted, and the exosomes in intestinal tissues were extracted via ultrahigh-speed centrifugation.Negative staining electron microscopy was used to analyze the morphology of exosomes and the ultrastructure of intestinal tissue and exosomes. The particle size of the exosomes was measured using nanoparticle tracking analysis. RESULTS: The pathological characteristics of CKD rats included those associated with systemic micro-inflammation, which may be associated with the release of exosomes in intestinal tissue. NDK suppressed the inflammatory response in Caco-2 cells and decreased the levels of IL-1ß, IL-6, and TNF-α in rats with CKD. The expression of miR-146a, which regulates inflammation, differed between plasma-derived and enterogenous exosomes in CKD rats, which may be due to stimulation of ileal exosome release into the blood. NDK effectively reduced the levels of TRAF6, NF-κB, and TLR4 in the ileum tissue of CKD rats. CONCLUSION: NDK can effectively improve micro-inflammation in CKD ratsby enhancing the release of enterogenous exosomes, thereby enhancing the release of exosome-associated miR-146a and inhibiting micro-inflammation.

Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke.

BACKGROUND: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection. METHODS: A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined. RESULTS: C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α. CONCLUSION: Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.

Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury.

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.