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Epithelial-mesenchymal transition (EMT) plays an irreplaceable role in the development of silicosis. However, molecular mechanisms of EMT induced by silica exposure still remain to be addressed. Herein, metabolic profiles of human alveolar type II epithelial cells (A549 cells) exposed directly to silica were characterized using non-targeted metabolomic approaches. A total of 84 differential metabolites (DMs) were identified in silica-treated A549 cells undergoing EMT, which were mainly enriched in metabolisms of amino acids (e.g., glutamate, alanine, aspartate), purine metabolism, glycolysis, etc. The number of DMs identified in the A549 cells obviously increased with the elevated exposure concentration of silica. Remarkably, glutamine catabolism was significantly promoted in the silica-treated A549 cells, and the levels of related metabolites (e.g., succinate) and enzymes (e.g., α-ketoglutarate (α-KG) dehydrogenase) were substantially up-regulated, with a preference to α-KG pathway. Supplementation of glutamine into the cell culture could substantially enhance the expression levels of both EMT-related markers and Snail (zinc finger transcription factor). Our results suggest that the EMT of human alveolar epithelial cells directly induced by silica can be essential to the development of silicosis.

Assuntos

Células Epiteliais Alveolares , Transição Epitelial-Mesenquimal , Dióxido de Silício , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Dióxido de Silício/toxicidade , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Células A549 , Silicose/metabolismo , Metaboloma/efeitos dos fármacos

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BACKGROUND: Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume. However, in patients with huge HCC, high lung absorbed dose often prevents them from receiving SIRT. CASE SUMMARY: A 35-year-old man was admitted because of emaciation and pain in the hepatic region for about 1 month. The computed tomography scan showed a 20.2 cm × 19.8 cm tumor located in the right lobe-left medial lobes with right portal vein and right hepatic vein invasion. After the pathological type of HCC was confirmed by biopsy, two conversions were presented. The first one was drug-eluting bead transarterial chemoembolization plus hepatic arterial infusion chemotherapy and lenvatinib and sintilimab, converted to SIRT, and the second one was sequential SIRT with continued systemic treatment. The tumor size significantly decreased from 20.2 cm × 19.8 cm to 16.2 cm × 13.8 cm, then sequentially to 7.8 cm × 6.8 cm. In the meantime, the ratio of spared volume to total liver volume increased gradually from 34.4% to 55.7%, then to 62.9%. Furthermore, there was visualization of the portal vein, indicating regression of the tumor thrombus. Finally, owing to the new tumor in the left lateral lobe, the patient underwent LT instead of resection without major complications. CONCLUSION: Patients with inoperable huge HCC with PVTT could be converted to SIRT first and accept surgery sequentially.

Assuntos

Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Invasividade Neoplásica , Veia Porta , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/diagnóstico por imagem , Masculino , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Veia Porta/patologia , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Transplante de Fígado/métodos , Adulto , Resultado do Tratamento , Quimioembolização Terapêutica/métodos , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Tomografia Computadorizada por Raios X , Fígado/patologia , Fígado/diagnóstico por imagem , Fígado/cirurgia , Quinolinas

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OBJECTIVE: The aim of the study was to develop and evaluate an automated preoperative planning algorithm based on anatomical landmark point recognition for enhancing the efficiency and intelligence of preoperative planning for mandibular angle osteotomy. METHODS: A retrospective cohort of 34 patients underwent preoperative planning with this algorithm. The present algorithm was developed using a method based on anatomical marker point recognition. The efficiency, symmetry, and safety of the automated preoperative planning and esthetics were statistically analyzed by paired t test and χ2 test. RESULTS: The results showed that the automated planning algorithm was able to achieve a great improvement in preoperative planning efficiency as well as safety and symmetry. A prospective case report of 2 patients is then reported, illustrating the safety and esthetics of the algorithm with 1-year postoperative follow-up and postoperative esthetic scores. CONCLUSION: This algorithm can help to improve the efficiency of preoperative planning for surgeons while ensuring safety and esthetics and can be further applied to other craniomaxillofacial personalized design surgeries in the preoperative design in the future.

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BACKGROUND: This study aimed to explore the genetic basis of a fetus with ultrasound indicating a thickening of the nuchal translucency (NT) and a choroid plexus cyst. METHODS: Fetal amniotic fluid and peripheral blood were collected for a G-banding karyotype analysis and single nucleotide polymorphism array (SNP-array) detection. RESULTS: The chromosome karyotypes of the fetus and its parents were normal. SNP-array showed the fetus had carried 277 kb microdeletion at 14q11.2, which was a new mutation. After the induced abortion, the fetus was diagnosed with macrocephaly. CONCLUSIONS: A prenatal diagnosis of a fetus with 14q11.2 microdeletion-induced intrauterine growth retardation was confirmed, which has provided guidance for the subsequent pregnancy.

Assuntos

Deleção Cromossômica , Polimorfismo de Nucleotídeo Único , Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Adulto , Cromossomos Humanos Par 14/genética , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/diagnóstico , Cariotipagem , Medição da Translucência Nucal , Feto/diagnóstico por imagem , Feto/anormalidades , Megalencefalia/genética , Megalencefalia/diagnóstico por imagem

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Introduction: Mandible distraction osteogenesis (MDO) is widely used to reconstruct the mandible in patients with mild Hemifacial microsomia (HFM). However, the masseter's response to mandible distraction remains unclear. Methods: In this study, we analyze the effect of the surgical intervention on masseter muscle by a retrospective analysis. The procedure consisted of a five-day latent period, a three-week distraction period, and a six-month consolidation period. CT data were manually segmented and measured with Mimics software before surgery, within 3 months, and more than 1 year postoperatively. Masseter volume, masseter length, masseter width, and mandible ramus height were measured and analyzed using paired t-test, Pearson, and Spearman correlation analysis. Results: We included 21 patients with HFM who underwent mandible distraction osteogenesis from 2015 to 2020. The masseter volume on the affected side increased immediately after surgery from (6,505.33 ± 3,671.95) mm3 to (10,194.60 ± 5638.79) mm3, but decreased to (8,148.38 ± 3,472.57) mm3 at the second follow-up correlated to mandible ramus height (r = 0.395, P = 0.038). A similar trend was observed in changes in masseter length. Symmetry and width of masseter muscle had no longitudinal statistical significance. Discussion: Masseter muscle involvement benefits from MDO in the short term. To achieve long-term efficacy, more attention should be paid to muscle reconstruction.

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Primary endometrial squamous cell carcinoma (PESCC) is a rare malignant tumor. To investigate the clinical and pathological features of PESCC, two cases of PESCC in Fujian Maternal and Child Health Hospital were retrospectively studied and the literatures were reviewed. Both of the two cases were menopausal women aged 57-62 years, clinically presenting with "vaginal discharge". Case 1 was a non-keratinising squamous cell carcinoma with high-risk HPV infection. Tumor infiltrated in deep myometrium with multifocal intravascular thrombus and macro metastases to one pelvic lymph node (1/15) and abdominal aortic lymph node (1/1). Lung metastasis occurred 36 months after the surgery. After surgical resection and without postoperative supplemental therapy, the patient remained tumor-free for 110 months to date. Case 2 had a history of breast cancer for 5 years and long-term intake of aromatase inhibitor drugs without HPV infection. It was a keratinized squamous cell carcinoma. Tumor also infiltrated in deep myometrium with multifocal intravascular thrombus and one pelvic lymph node metastasis (1/18), However, no metastasis was seen elsewhere. To date, the patient survived for 16 months without tumor after surgery. Both of the two cases expressed squamous epithelial markers P40, P63, and CK5/6, but neither expressed PAX8 or PR. Case 1 had diffuse expression of P16, wild-type P53, and ER-negative. Case 2 had negative P16, mutant P53, and focal positive ER. PESCC is often associated with HPV infection and low estrogen levels. However, studies in the literatures have found that P16 expression is not always consistent with HPV infection, indicating that PESCC cannot be easily classified as HPV-associated or non-dependent like cervical cancer. There are two main patterns of P16 and P53 expression, P16-positive/P53 wild-type and P16-negative/P53-mutant, but no positive expression of both has been seen so far. It is worth noting that we reported the second case of PESCC with a history of breast cancer, where the patient had been taking the oral aromatase inhibitor drug (exemestane) for a long period of time to reduce the estrogen level, indicating the low estrogen level may be also a key factor in the pathogenesis of PESCC.

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OBJECTIVE: Fetal venous system malformations frequently coincide with cardiac or extracardiac anomalies. This study explores our experience with an integrated fetal echocardiography approach and analyzes the characteristics and outcomes of fetal venous system disorders. MATERIALS AND METHODS: We conducted a retrospective study with 7048 pregnant women (7255 fetuses) who underwent complete two-dimensional (2D) fetal echocardiographic examinations. We primarily employed an integrated 2D approach. Three-/four-dimensional (3D/4D) spatiotemporal image correlation was supplemental. Fetal venous disorders were classified into 3 groups: cardinal (Group 1), umbilical and vitelline (Group 2), and pulmonary (Group 3) systems, based on embryological-anatomical considerations. Maternofetal data were recorded alongside imaging diagnoses. RESULTS: Congenital venous malformations were identified in 98 fetuses, yielding a prevalence of 1.35% (98/7255). Six participants had coexisting venous disorders from different groups. Group 1 included 48 fetuses with persistent left superior vena cava (LSVC) and 3 others (unidentified brachiocephalic vein, left inferior vena cava (IVC), and interrupted IVC with azygous continuation to SVC). Group 2 had 39 fetuses with persistent right umbilical vein and 7 with umbilical-portal-ductus venosus disorders. Group 3 had 7 fetuses with pulmonary venous return disorders. Group 2 showed the most favorable outcomes (alive and without neonatal death), while Group 3 exhibited the poorest. Associated cardiac defects were observed in 43.1% of Group 1, 8.7% of Group 2, and 57.1% of Group 3 (P < 0.001), displaying a broad spectrum of non-specific anomalies. Meanwhile, Group 2 had a greater occurrence of a single venous disorder (93.5%) compared to Group 1 (88.2%) and Group 3 (57.1%) (P = 0.020). CONCLUSION: Our approach offers an integrated strategy for assessing the fetal venous system during fetal echocardiography, providing multiple views to characterize venous anomalies. The presence of a fetal venous disorder may indicate the coexistence of more severe abnormalities, and the prognosis depends on associated anomalies or the venous disorders per se.

Assuntos

Ultrassonografia Pré-Natal , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal/métodos , Adulto , Ecocardiografia/métodos , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/embriologia , Veias Umbilicais/diagnóstico por imagem , Veias Umbilicais/anormalidades , Veias Umbilicais/embriologia , Doenças Fetais/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/embriologia , Relevância Clínica

RESUMO

PURPOSE: This study was designed to investigate the function of RAD51AP1 in the self-renewal and chemosensitivity of CD133 positive (CD133+) ovarian cancer (OC) stem-like cells. METHODS: CD133+ (CD133 positive) OVCAR4 and CD133 negative (CD133-) OVCAR4 cells were separated from OVCAR4 by flow cytometry. Then, the separated CD133+OVCAR4 cells were divided into the following groups: Vector group; RAD51AP1 group; siNC group; si-RAD51AP1 group. Next, sphere-formation assay and colony forming assay were used to evaluate the self-renewal and proliferation ability of cells; western blot to detect the expression of RAD51AP1, transforming growth factor beta 1 (TGF-ß1) and SMAD4 proteins in tissues and cells; qRT-PCR to assess the mRNA levels of sex-determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG and Kruppel-like factor 4 (KLF4). RESULTS: The performance of CD133+OVCAR4 cells was much better than that of CD133-OVCAR4 cells in sphere-formation assay and colony forming assay. Besides, compared with adjacent group and CD133-OVCAR4 cells, the expression level of RAD51AP1 increased significantly in OC group and CD133+OVCAR4 cells. Moreover, the over-expression of RAD51AP1 promoted the self-renewal and proliferation of CD133+OVCAR4 cells. On the contrary, knocking down the expression level of RAD51AP1 could inhibit the self-renewal and proliferation of CD133+OVCAR4 cells and improve the sensitivity of cells to chemotherapy drugs. CONCLUSION: The findings of this study showed that RAD51AP1 was highly expressed in OC tissue and CD133+OVCAR4 cells, and regulated the self-renewal and chemosensitivity of tumor cells through the TGF-ß1/SMAD4 signaling pathway.

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Background: Hepatitis B, often leading to Hepatocellular carcinoma (HCC), poses a major global health challenge. While Tenofovir (TDF) and Entecavir (ETV) are potent treatments, their comparative effectiveness in improving recurrence-free survival (RFS) and overall survival (OS) rates in HBV-related HCC is not well-established. Methods: We conducted an individual patient data meta-analysis using survival data from randomized trials and high-quality propensity score-matched studies to compare the impact of Tenofovir (TDF) and Entecavir (ETV) on RFS and OS in HBV-related HCC patients. Data from six databases and gray literature up to 30 August 2023, were analyzed, utilizing Kaplan-Meier curves, stratified Cox models, and shared frailty models for survival rate assessment and to address between-study heterogeneity. The study employed restricted mean survival time analysis to evaluate differences in RFS and OS between TDF-treated and ETV-treated patients. Additionally, landmark analyses compared early (<2 years) and late (≥2 years) tumor recurrence in these cohorts. Results: This study incorporated seven research articles, covering 4,602 patients with HBV-related HCC (2,082 on TDF and 2,520 on ETV). Within the overall cohort, TDF recipients demonstrated significantly higher RFS (p = 0.042) and OS (p < 0.001) than those on ETV. The stratified Cox model revealed significantly improved OS for the TDF group compared to the ETV group (hazard ratio, 0.756; 95% confidence interval, 0.639-0.896; p = 0.001), a result corroborated by the shared frailty model. Over a follow-up period of 1-8 years, no significant difference was noted in the mean time to death between the TDF and ETV groups. The rates of early recurrence did not significantly differ between the groups (p = 0.735). However, TDF treatment was significantly associated with a reduced risk of late recurrence compared to ETV (p < 0.001). In the HCC resection subgroup, the disparities in OS, early, and late recurrence rates between the two treatments paralleled those seen in the overall cohort. Conclusion: Compared to ETV, TDF may enhance OS and reduce late tumor recurrence risk in HBV-related HCC patients receiving curative treatment. However, there was no statistically significant distinction in the timing of tumor recurrence and mortality between patients administered TDF and those prescribed ETV. Systematic Review Registration: http://www.crd.york.ac.uk/prospero/.

RESUMO

BACKGROUND: Colorectal cancer remains a major global public health challenge. Its incidence is shaped by a complex interplay of screening programmes and age, period and cohort factors. METHODS: We introduce a novel Age-Period-Cohort-Screening (APCS) model to analyse trends in colorectal cancer incidence in Taiwan from 2000 to 2019. RESULTS: In 2010, the incidence of colorectal cancer in Taiwan increased by 19.2% (95% CI: 13.5%, 25.3%) for men and 15.6% (95% CI: 9.2%, 22.4%) for women. This was followed by annual declines of 3.4% (95% CI: 2.8%, 4.1%) and 3.1% (95% CI: 2.4%, 3.9%), respectively. By 2015 for men and 2014 for women, the age-standardized incidence had fallen below the levels projected in a no-screening scenario. By 2019, the incidence had further declined by 12.4% (95% CI: 11.8%, 13.1%) for men and 11.6% (95% CI: 10.7%, 12.6%) for women, compared with the no-screening scenario. Cohort effects have shown a persistent rise from 1920 to 1980: incidence increased 5.8-fold for men and 3.1-fold for women. The trend began to plateau after 1980, with a noticeable decline in women. CONCLUSION: Through its screening programme, Taiwan has successfully reduced colorectal cancer incidence by 10% as of 2019. Furthermore, the incidence due to cohort effects has plateaued and even begun to decline. However, continued monitoring remains crucial. The advanced APCS model could serve as a robust analytical tool for other researchers and policy makers evaluating the impacts of cancer screening programmes on incidence trends.

Assuntos

Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/diagnóstico , Feminino , Masculino , Incidência , Taiwan/epidemiologia , Detecção Precoce de Câncer/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso , Coorte de Nascimento , Adulto , Programas de Rastreamento , Idoso de 80 Anos ou mais , Distribuição por Sexo

RESUMO

Griseofulvin (GF), which is mainly extracted from Penicillium griseofulvum, is a heat-resistant, chlorine-containing non-polyene antifungal antibiotic. Previous research shows that GF has a variety of pharmacological effects, such as anti-inflammatory, antifungal, antiviral, and antitumor effects. In recent years, GF has received extensive attention for its antitumor effects as a natural compound, offering a low price, a wide range of uses, and other beneficial characteristics. However, no comprehensive review of GF pharmacological activity in tumors has been published so far. In order to fully elucidate the antitumor activities of GF, this review focuses on the antitumor potential and toxicity of GF and its derivatives, based on a literature search using PubMed, Web of Science, and other databases, to lay a good foundation for further research of GF and the development of new drugs for antitumor activities.

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The gut microbiota refers to the diverse bacterial community residing in the gastrointestinal tract. Recent data indicate a strong correlation between alterations in the gut microbiota composition and the onset of various diseases, notably cardiovascular disorders. Evidence suggests the gut-cardiovascular axis signaling molecules released by the gut microbiota play a pivotal role in regulation. This review systematically delineates the association between dysbiosis of the gut microbiota and prevalent cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction and heart failure. Furthermore, it provides an overview of the putative pathogenic mechanisms by which dysbiosis in the gut microbiota contributes to the progression of cardiovascular ailments. The potential modulation of gut microbiota as a preventive strategy against cardiovascular diseases through dietary interventions, antibiotic therapies and probiotic supplementation is also explored and discussed within the present study.

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Developing effective vaccines is necessary in combating new virus pandemics. For HIV and SARS-CoV-2, the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore, broaden the protective Ab response induced by vaccination. However, the steps leading to Ab Fc-mediated inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is the most physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.

RESUMO

To detect the association between periodontitis and all-cause as well as cause-specific mortality rates among adults diagnosed with depression. Participants diagnosed with depression were selected from NHANES across three periods (1988-1994; 1999-2004; 2009-2014). Cox proportional hazards and Weibull accelerated failure time (AFT) models were utilized to calculate hazard ratios (HRs), time ratios (TRs), and their 95% confidence intervals (CIs) to evaluate the association between moderate-to-severe periodontitis and all-cause as well as cause-specific mortality among participants with depression. white blood counts and C-reactive protein were used to assess the mediating role of systemic inflammation. Among the 1,189 participants with a median follow-up of 9.25 years, 133 deaths were recorded. After adjusting for multiple variables, moderate-to-severe periodontitis was obvious associated with an increased risk of cancer-related mortality in individuals with depression (Cox: HR 3.22, 95% CI 1.51-6.83, P = 0.002; AFT: TR 0.70, 95% CI 0.52-0.94, P = 0.017). Neither WBC nor CRP significantly mediate the association between periodontitis and cancer-related mortality. The risk of cancer-related mortality rose with the severity of periodontitis (P for trend = 0.021). However, no association was observed between moderate-to-severe periodontitis and other kinds of mortality. Moderate-to-severe periodontitis is linked to an elevated risk of cancer-related mortality among adults diagnosed with depression, with the mortality risk increasing alongside the severity of periodontitis. No significant mediating effect of systemic inflammation was found in this association. These findings highlight the importance of addressing periodontal health in individuals with depression. By uncovering the association between periodontitis and mortality in this population, our study underscores the potential benefits of preventive dental care and periodontal treatment in reducing the risk of cancer-related mortality in individuals with depression.

Assuntos

Depressão , Periodontite , Humanos , Masculino , Feminino , Periodontite/mortalidade , Periodontite/complicações , Periodontite/epidemiologia , Pessoa de Meia-Idade , Depressão/epidemiologia , Depressão/complicações , Depressão/mortalidade , Adulto , Modelos de Riscos Proporcionais , Causas de Morte , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Fatores de Risco , Inquéritos Nutricionais , Idoso , Neoplasias/mortalidade , Neoplasias/complicações

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Renewable feedstocks are sought for clean technology applications, including energy storage applications. In this study, LignoForce™ lignin, a biobased aromatic polymer commercially isolated from wood, was fractioned into two parts using acetone, and the resulting lignin fractions had distinct thermo-rheological behavior. These two fractionated lignins were combined in various ratios and transformed into nanofibers by electrospinning. Subsequently, electrospun fiber materials were disrupted by agitating the mats in water, and the materials were transformed into ultralight 3D aerogels through lyophilization and post-process controlled heating. Using only this combination of two fractions, the morphology of lignin nanofibers was tailored by heat treatment, resulting in lignin aerogels with high flexibility and significant shape recovery properties. Various microscale structures of lignin fibers impacted the resulting physical properties of the elastic aerogel materials, such as resilience, compressive strength, and electrical conductivity for the corresponding carbonized samples. By exploiting lignin's sensitivity to heat and tailoring the thermal properties of the lignin through fractionation, the work provided an interesting path to form robust lignin-derived functional materials without any toxic chemical additives and significant ability to serve as free-standing electrodes with specific capacitance values better than some graphene-based supercapacitors.

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This study aimed to investigate the potential cardioprotective effects of sacubitril/valsartan (Sac/Val) in mice with doxorubicin (DOX)-induced cardiomyopathy, a common manifestation of cancer therapy-related cardiac dysfunction (CTRCD) associated with DOX. A total of thirty-two mice were equally classified into 4 groups: control group, DOX (total 24 mg/kg), Sac/Val (80 mg/kg), and Sac/Val + DOX (Sac/Val was given from seven days before doxorubicin administration). Neonatal rat ventricular myocytes was exposed to 5 µM of DOX for 6 h in vitro to mimic the in vivo conditions. A variety of techniques were used to investigate cardiac inflammation, fibrosis, apoptosis, and autophagy, including western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry, and fluorescence. Mice with DOX-induced cardiotoxicity displayed impaired systolic and diastolic function, characterized by elevated levels of cardiac inflammation, fibrosis, cardiomyocyte hypertrophy, apoptosis, and autophagy inhibition in the heart. Treatment with Sac/Val partially reversed these effects. In comparison to the control group, the protein expression of NLRP3, caspase-1, collagen I, Bax, cleaved caspase-3, and P62 were significantly increased, while the protein expression of Bcl-2 and LC3-II were significantly decreased in the myocardial tissues of the Dox-induced cardiomyopathy group. The administration of Sac/Val demonstrated the potential to partially reverse alterations in protein expression within the myocardium of mice with DOX-induced cardiotoxicity by modulating the AMPKα-mTORC1 signaling pathway and suppressing oxidative stress. Additionally, Sac/Val treatment may mitigate Dox-induced apoptosis and inhibition of autophagy in primary cardiomyocytes. Sac/Val seems to be cardioprotective against DOX-induced cardiotoxicity in the pre-treatment mice model. These findings could be attributed to the anti-inflammatory, antioxidant, anti-apoptotic, and de-autophagy effects of Sac/Val through regulation of the AMPKα-mTORC1 signaling pathway.

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The approval of anti-amyloid ß (Aß) monoclonal antibodies (lecanemab) for the treatment of patients with early preclinical stage of Alzheimer's disease (AD) by the Food and Drug Administration, suggests the reliability and importance of brain Aß clearance for AD therapy. Microglia are the main phagocytes that clear Aß in the brain, but the underlying regulatory mechanism is unclear. Here, we investigate the critical role of cathepsin B (CatB) in modulating microglial Aß clearance from mouse brain. Wild-type or CatB-/- mice were injected with Aß into the hippocampus from 1 to 3 weeks. Mice were evaluated for cognitive change, Aß metabolism, neuroinflammation. Microglia and neuron cultures were prepared to verify the in vivo results. The statistical analyses were performed by student's t test, one-way ANOVA with a post hoc Tukey's test using the GraphPad Prism software package. CatB deficiency significantly reduces Aß clearance efficiency and aggravates mouse cognitive decline. Exogenous Aß markedly increases CatB expression in activated microglia. Transcriptome analysis and in vitro cell culture experiments demonstrate that CatB is associated with gene clusters involved in migration, phagocytosis, and inflammation. In addition, transcriptome analysis and immunoblotting suggest that CatB modulates microglial Aß clearance via PI3K-AKT activation. Our study unveils a previously unknown role of CatB in promoting microglial functionality during Aß clearance.

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Tamoxifen (TAM), a selective estrogen receptor (ER) modulator, has received approval for use in patients with breast cancer (BC) exhibiting positive ER expression. Given the widespread clinical use of TAM, a comprehensive real-world study of its adverse events (AEs) is warranted. The database for analysis, sourced from the Food and Drug Administration Adverse Event Reporting System (FAERS), covers the period from the first quarter of 2014 to the third quarter of 2023. A disproportionality analysis was conducted to quantify the correlation between TAM and AEs. Subgroup analyses were performed to identify differences between BC AEs in males and females receiving TAM, aiming to assess the risk factors of male BC AEs. Total 4890 reports indicated BC, with 91 and 4190 specifically linked to AEs in male and female patients with BC, respectively. Male-specific AE was libido decreased (reporting odds ratio [ROR]: 43.33), and female-specific AE was uterine disease, including sarcoma uterus (ROR: 519.51), endometrial cancer (ROR: 131.26), uterine polyp (ROR: 40.83), endometriosis (ROR: 11.39), among others. A notably higher risk of AEs in male patients with BC was observed in individuals aged >65 years (χ2 = 20.83, p < .001). Male patients with BC had a relatively higher risk of hospitalization (χ2 = 4.83, p = .03) and a lower risk of deaths (χ2 = 5.32, p = .02). Theses finding may assist healthcare professionals in recognizing the TAM-associated AEs and understanding gender differences, potentially improving safety in clinical applications.

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The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.

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Glioblastoma (GBM) was the most malignant intracranial tumor with high mortality rates and invariably poor prognosis due to its limited clinical treatments. The urgent need to develop new therapeutic drugs for GBM treatment is evident. As a coumarin derivative, daphnoretin's favorable pharmacological activities have been widely documented. However, the potential inhibitory effects of daphnoretin on GBM have not been explored. In this study, we aimed to investigate the effects of daphnoretin on GBM and elucidate its anti-GBM mechanisms for the first time. It was observed that daphnoretin inhibited GBM cell proliferation, migration, and invasion in vitro and suppressed tumor growth without significant drug toxicity in GBM xenograft tumor models in vivo. Mechanistically, daphnoretin was predicted to target the PI3K/AKT signaling pathway through network pharmacology and molecular docking analysis. Subsequently, it was further verified by Biacore assay for surface plasmon resonance (SPR) experiments. Experimentally, daphnoretin induced apoptosis in GBM cells via the PI3K/AKT signaling pathway. Moreover, the effects of daphnoretin on GBM cells could be reversed by the AKT activator SC79. These results suggest that daphnoretin holds potential as a therapeutic drug against GBM and provides new insights into GBM treatment.