Search

Plumbagin (PLB), a naphthoquinone compound, has been proven to have anti-cancer properties in different types of cancers. However, the anti-tumor actions as well as molecular processes in osteosarcoma (OS) remain unclear. This study investigates the underlying mechanisms of PLB in human OS cells in vitro. Our study showed that PLB significantly inhibited the proliferation of human OS cells in a time- and dosage-dependent manner. RNA sequencing data revealed that the efficacy of PLB is related to cell cycle, cell death, and p38 MAPK signaling pathway in KHOS-240S cells. Further studies indicated that PLB triggers G2/M phase arrest, mitochondrial-dependent apoptosis, as well as ferroptosis in human OS cells. Mechanistically, PLB treatment increased ROS generation that activates the p38 MAPK signaling pathway. BIRB 796, a p38 MAPK inhibitor, partly reversed PLB-induced phase arrest of G2/M and cell death. Furthermore, N-acetylcysteine (NAC), a ROS scavenger, significantly decreased G2/M phase arrest and cell death and reversed p38 MAPK activation caused by PLB. In conclusion, PLB induces arrest G2/M arrest, apoptosis as well as ferroptosis in human OS cells via ROS generation and p38 MAPK activation. There is potential for PLB to be an effective treatment for OS. • PLB induces G2/M arrest, apoptosis, and ferroptosis in human osteosarcoma cells. • The anti-osteosarcoma effect of Plumbagin is related to the ROS/p38 MAPK pathway. • PLB could be a promising therapeutic agent for osteosarcoma. [ABSTRACT FROM AUTHOR]

To demonstrate the effect of silicon dioxide, citric acid and sodium selenite combination vaginal gel (DeflaGyn®) on critical parameters in carcinogenesis in vitro HeLa cell culture medium. Various parameters including cell viability, intracellular reactive oxygen species, genotoxicity, apoptosis, mitochondrial membrane potential and glutathione levels were evaluated by applying varying doses of vaginal gel to HeLa cell culture medium. The vaginal gel showed a dose-dependent cytotoxic effect on HeLa cells. The IC50 (half maximal inhibitory concentration) gel concentration for HeLa cells at 24 h was calculated on the concentration-response curve and was found to be 80.15% of DeflaGyn®. Increasing DeflaGyn® concentrations (12.5–100%) increased iROS (intracellular reactive oxygen species) levels 1.3-fold on average compared to the control (0.1% DMSO (dimethyl sulfoxide)). DNA damage and apoptosis levels increased significantly with concentration in a dose-dependent manner. Similarly, a decrease was observed in the mitochondrial membrane potential (MMP levels decreased statistically significantly up to 70.14%) and intracellular glutathione levels, and all changes were proportional to the dose. Although it is known that the combination of vaginal gel facilitates the regression of cervical dysplasia and clearance of high-risk HPV (Human Papilloma Virus) types, there is no detailed information on the mechanism by which it provides these effects. In the present study, we found that the specific vaginal gel had a dose-dependent effect on various parameters thought to be important in the process of cervical carcinogenesis. Further studies are needed to reveal the pathways through which the gel is effective and whether it has similar effects in vivo. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Taibah University Medical Sciences is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Preeclampsia (PE) is a pregnancy-specific complication. Its etiology and pathogenesis remain unclear. Previous studies have shown that neutrophil extracellular traps (NETs) cause placental dysfunction and lead to PE. Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) have been widely used to treat different diseases. We investigated whether hUCMSC-EXOs can protect against NET-induced placental damage. NETs were detected in the placenta by immunofluorescence. The impact of NETs on cellular function and the effect of hUCMSC-EXOs on NET-induced placental damage were evaluated by 5-ethynyl-20-deoxyuridine (EdU) cell proliferation, lactate dehydrogenase (LDH), reactive oxygen species (ROS), and cell migration, invasion and tube formation assays; flow cytometry; and Western blotting. The number of placental NETs was increased in PE patients compared with control individuals. NETs impaired the function of endothelial cells and trophoblasts. These effects were partially reversed after N-acetyl-L-cysteine (NAC; ROS inhibitor) or DNase I (NET lysing agent) pretreatment. HUCMSC-EXOs ameliorated NET-induced functional impairment of endothelial cells and trophoblasts in vitro, partially reversed NET-induced inhibition of endothelial cell and trophoblast proliferation, and partially restored trophoblast migration and invasion and endothelial cell tube formation. Exosomes inhibited ROS production in these two cell types, suppressed p38 mitogen-activated protein kinase (p38 MAPK) signaling activation, activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, and modulated the Bax, Bim, Bcl-2 and cleaved caspase-3 levels to inhibit apoptosis. HUCMSC-EXOs can reverse NET-induced placental endothelial cell and trophoblast damage, possibly constituting a theoretical basis for the treatment of PE with exosomes. [Display omitted] • NETs impaire cellar function and lead to placental dysfunction. • HUCMSC-EXOs reduce NET-induced oxidative stress by inhibiting ROS production. • HUCMSC-EXOs can repair NET-induced cell damage and placental dysfunction. • The p38 MAPK and ERK1/2 signaling pathways play an important role in the above. [ABSTRACT FROM AUTHOR]

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF- β , secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF- β through TGF- β -TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF- β exhaustion alleviates the TGF- β -suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN- γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC. CCR1- and TGFBR2-expressed nanovesicles (C/T-NVs) target SMAD4 deficiency CRC tissue via the CCL9/CCR1 axis and trap intratumoral excessive TGF- β to alleviate liver metastasis. [Display omitted] [ABSTRACT FROM AUTHOR]

Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3–CHOP–DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM. Changes in phenylalanine serve as markers for multiple myeloma patients and predict a poor prognosis. Exogenous phenylalanine deprivation inhibits MM progression by perturbing endoplasmic reticulum homeostasis via the ATF3–CHOP–DR5 signaling axis. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Tartrazine (Tz) is one of the most commonly used colorants incorporated in the food manufacturing. Its toxicity is derived from metabolic byproducts representing health hazards to consumers. Gallic acid (GA) is known for its redox stabilizing, anti-apoptotic, and cytoprotective characteristics. Therefore, the aim of this study is to explore the possible defensive effect of GA against Tz-induced testicular dysfunction. To achieve this objective, 18 male Wistar adult rats were randomly and equally categorized into three groups for 30 days. The control group received no treatment. Tz at a dose of 30 mg/kg BW was administered to the Tz group. The Tz + GA group received GA at a dose of 200 mg/kg BW in concurrent with the previously described Tz dosage. Both Tz and GA were supplemented orally once daily by a stomach tube. Results: The marked decline in luteinizing hormone, follicle stimulating hormone, testosterone, and estradiol 17beta confirmed deviation in pituitary–gonadal axis of Tz-exposed rats. Imbalances in plasma redox equilibrium were evident, characterized by a notable increase in malondialdehyde and nitric oxide levels, along with a decrease in reduced glutathione and total antioxidant capacity. Deteriorations in histopathological features, fibrosis in testicular tissue, abnormalities in Sertoli cell, and up-regulation in caspase-3 were observed. Conversely, GA administration successfully reversed these issues. Conclusion: The ability of GA to counteract toxicological molecular targets in Tz-exposed testes is believed to be achieved through the restoration of oxidant/antioxidant balance and the prevention of the apoptotic cascade. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common female malignancy worldwide. Ubiquitin-specific peptidase 53 (USP53) has been shown to exert cancer-suppressing functions in several solid tumors, but its role and the underlying mechanism in breast cancer has not been clearly elucidated. Therefore, we have carried out a series of detailed studies on this matter at the levels of bioinformatics, clinical tissue, cell function and animal model. We found that USP53 expression was downregulated in breast cancer specimens and was negatively correlated with the clinical stages. Gain- and loss-of-function experiments demonstrated USP53 inhibited proliferation, clonogenesis, cell cycle and xenograft growth, as well as induced apoptosis and mitochondrial damage of breast cancer cells. Co-immunoprecipitation data suggested that USP53 interacted with zinc finger MYND-type containing 11 (ZMYND11), and catalyzed its deubiquitination and stabilization. The 33–50 amino acid Cys-box domain was key for USP53 enzyme activity, but not essential for its binding with ZMYND11. The rescue experiments revealed that the anti-tumor role of USP53 in breast cancer cells was at least partially mediated by ZMYND11. Both USP53 and ZMYND11 were prognostic protective factors for breast cancer. USP53-ZMYND11 axis may be a good potential biomarker or therapeutic target for breast cancer, which can provide novel insights into the diagnosis, treatment and prognosis. Keypoints: 1. USP53 has been shown to play an anticancer role in a variety of solid malignancies, but its role in breast cancer and its mechanism remain unclear. 2. Our results suggested that USP53 was low expressed in breast cancer and negatively correlated with TNM stage; USP53 suppressed proliferation and triggered apoptosis of breast cancer cells; USP53 inhibited breast cancer in vitro and in vivo by deubiquitinating ZMYND11. 3. USP53-ZMYND11 axis may be a potential breast cancer marker and therapeutic target. [ABSTRACT FROM AUTHOR]

The success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is lower and the risk for complications higher compared with other non-CTO PCI. Although interventionalists focus on intimal plaque characteristics, the coronary media is an important (especially for techniques involving antegrade dissection and re-entry) but poorly understood structure in CTO PCI. The aim of the present study was to investigate coronary medial wall thinning in CTO lesions and determine how this thinning might affect CTO PCI. A total of 2,586 sections were investigated, from arteries with evidence of CTO from 54 subjects (1,383 sections) and arteries without evidence of CTO from 54 subjects with non-coronary-related deaths (1,203 sections) after matching for age, gender, body weight, and body height. The medial thickness in subjects with CTO was lower than that in those with non-coronary-related death (P < 0.001). In subjects with CTO, CTO lesions had thinner medial walls compared with those with lower luminal narrowing (P < 0.001). At the CTO distal segments, the 6- to 12-mm distal segment from the distal end of the CTO had significantly less luminal narrowing (P < 0.001), and similar medial thickness, compared with the distal end of the CTO. Immunohistochemical analysis revealed that short-duration CTO had more cleaved caspase-3–positive cells in media and had significantly more CD3+, CD4+, CD8+, and CD4+CD28null T cells compared with long-duration CTO. CTO lesions demonstrated coronary medial thinning compared with non-CTO lesions. Further investigation of the cause-and-effect relationship among inflammation, apoptosis, and coronary medial wall thinning is warranted in future mechanistic studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Lung cancer causes a significant threat to human health. Despite considerable advancements in the treatment technologies in recent years, the five-year survival rate for lung cancer patients remains low. In this context, the discovery of pyroptosis, a unique cell death mechanism, offers a novel perspective for exploring new pathways of lung cancer treatment. Particularly, the role of gasdermin E (GSDME) in the process of pyroptosis reveals its tremendous potential in lung cancer therapy. Recent studies have made considerable progress in understanding the role of GSDME-mediated pyroptosis in lung cancer growth, the lung cancer microenvironment, and the effect of GSDME methylation on lung cancer treatment. This paper summarizes these research advancements and analyzes the potential and possible side effects of GSDME-mediated pyroptosis in lung cancer therapy, aiming to provide a theoretical foundation for developing more effective strategies for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Apoptosis generates plenty of membrane-bound nanovesicles, the apoptotic vesicles (apoVs), which show promise for biomedical applications. The liver serves as a significant organ for apoptotic material removal. Whether and how the liver metabolizes apoptotic vesicular products and contributes to liver health and disease is unrecognized. apoVs were labeled and traced after intravenous infusion. Apoptosis-deficient mice by Fas mutant (Fas mut ) and Caspase-3 knockout (Casp3 −/− ) were used with apoV replenishment to evaluate the physiological apoV function. Combinations of morphologic, biochemical, cellular, and molecular assays were applied to assess the liver while hepatocyte analysis was performed. Partial hepatectomy and acetaminophen liver failure models were established to investigate liver regeneration and disease recovery. We discovered that the liver is a major metabolic organ of circulatory apoVs, in which apoVs undergo endocytosis by hepatocytes via a sugar recognition system. Moreover, apoVs play an indispensable role to counteract hepatocellular injury and liver impairment in apoptosis-deficient mice upon replenishment. Surprisingly, apoVs form a chimeric organelle complex with the hepatocyte Golgi apparatus through the soluble N -ethylmaleimide–sensitive factor attachment protein receptor machinery, which preserves Golgi integrity, promotes microtubule acetylation by regulating α-tubulin N -acetyltransferase 1, and consequently facilitates hepatocyte cytokinesis for liver recovery. The assembly of the apoV-Golgi complex is further revealed to contribute to liver homeostasis, regeneration, and protection against acute liver failure. These findings establish a previously unrecognized functional and mechanistic framework that apoptosis through vesicular metabolism safeguards liver homeostasis and regeneration, which holds promise for hepatic disease therapeutics. [Display omitted] Apoptotic vesicles assemble with the recipient hepatocyte Golgi apparatus to form an apoptotic vesicle-Golgi complex, which is indispensable for the maintenance of liver homeostasis and regeneration. [ABSTRACT FROM AUTHOR]

Biologic compounds have recently generated interest in cancer chemoprevention. Sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, has profound epigenetic actions. Since epigenetic aetiology is crucial for oral cancer, this study evaluated the role of SFN in oral cancer prevention. Oral squamous cell carcinoma cells (UPCI-SCC-172) were treated with SFN in three concentrations: 10 μM, 20 μM and 30 μM for two time periods: 24 h and 48 h. MTT assay assessed cell proliferation. Histone deacetylase (HDAC) enzyme activity was colorimetrically estimated in the nuclear extracts. Flow cytometry determined cell cycle stages, reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) changes. Extrinsic and intrinsic apoptotic pathways were evaluated from caspase enzyme assays. Cell proliferation and HDAC activity (44% in 24 h and 40% in 48 h) were significantly inhibited (p < 0.01). For 10 μM concentration, G2/M cell cycle arrest was found with a reduction in G1 phase cell population at 24 h and 48 h. Concentrations of 20 μM and 30 μM SFN presented cells in apoptosis marked by increased sub G1 cells at 48 h. Concentrations of 10 μM and 20 μM SFN showed a 1.3 to 2.8-fold increase in ROS generation at 24 h and 48 h. The concentration of 30 μM SFN showed a drop in ROS production, denoting cells already in apoptosis. Fall in MMP was also dose- and time-dependent. Caspase enzyme assays (p < 0.001) demonstrated activation of both extrinsic and intrinsic apoptotic pathways. Inhibitory action of SFN on oral cancer cell proliferation and HDAC activity led to cell cycle arrest and apoptosis. These effects marked by increase in ROS, a decrease in MMP and activation of apoptotic pathways offer exciting therapeutic options. [ABSTRACT FROM AUTHOR]

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics. Non-apoptotic RCD subroutines have been extensively studied in cancer, and related small-molecule compounds are continuously being developed to improve cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Nefrologia is the property of Revista Nefrologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Gambogenic acid (GNA), a bioactive compound derived from the resin of Garcinia hanburyi , has demonstrated significant antitumor properties. However, its mechanisms of action in oral squamous cell carcinoma (OSCC) remain largely unclear. This study aimed to elucidate the apoptotic effects of GNA on OSCC cell lines CAL-27 and SCC-15. Our results indicated that GNA induced apoptosis by upregulating the pro-apoptotic protein Noxa. Mechanistic investigations revealed that GNA treatment led to the generation of reactive oxygen species (ROS), which activated endoplasmic reticulum (ER) stress, culminating in cell apoptosis. Inhibition of ROS production and ER stress pathways significantly mitigated GNA-induced Noxa upregulation and subsequent apoptosis. Furthermore, in vivo studies using a murine xenograft model demonstrated that GNA administration effectively inhibited the growth of CAL-27 tumors. Collectively, these findings underscore GNA's potential as a therapeutic agent for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Extrachromosomal circular DNA (eccDNA) derived from linear chromosomes, are showed typical nucleosomal ladder pattern in agarose gel which as a known feature of apoptosis and demonstrated to be immunogenicity. In systemic lupus erythematosus (SLE) patients, elevated levels of cell-free DNA (cfDNA) can be found in either linear forms or circular forms, while circular ones are much less common and harder to detect. The molecular characteristics and function of circular forms in plasma SLE patients remains elusive. Herein, we characterized the hallmarks of plasma eccDNA in SLE patients, including the lower normalized number and GC content of eccDNA in SLE plasma than in the healthy, and SLE eccDNA number positively correlated with C3 and negatively with anti-dsDNA antibodies. The differential eccGenes (eccDNAs carrying the protein coding gene sequence) of SLE was significantly enriched in apoptosis-related pathways. The artificially synthesized eccDNA with sequences of the PRF1 exon region could promote transcriptional expression of PRF1, IFNA and IFIT3 and inhibit early-stage apoptosis. Plasma eccDNA can serve as a novel autoantigen in the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

High intraocular pressure causes retinal ganglion cell injury in primary and secondary glaucoma diseases, yet the molecular landscape characteristics of retinal cells under high intraocular pressure remain unknown. Rat models of acute hypertension ocular pressure were established by injection of cross-linked hyaluronic acid hydrogel (Healaflow®). Single-cell RNA sequencing was then used to describe the cellular composition and molecular profile of the retina following high intraocular pressure. Our results identified a total of 12 cell types, namely retinal pigment epithelial cells, rod-photoreceptor cells, bipolar cells, Müller cells, microglia, cone-photoreceptor cells, retinal ganglion cells, endothelial cells, retinal progenitor cells, oligodendrocytes, pericytes, and fibroblasts. The single-cell RNA sequencing analysis of the retina under acute high intraocular pressure revealed obvious changes in the proportions of various retinal cells, with ganglion cells decreased by 23%. Hematoxylin and eosin staining and TUNEL staining confirmed the damage to retinal ganglion cells under high intraocular pressure. We extracted data from retinal ganglion cells and analyzed the retinal ganglion cell cluster with the most distinct expression. We found upregulation of the B3gat2 gene, which is associated with neuronal migration and adhesion, and downregulation of the Tsc22d gene, which participates in inhibition of inflammation. This study is the first to reveal molecular changes and intercellular interactions in the retina under high intraocular pressure. These data contribute to understanding of the molecular mechanism of retinal injury induced by high intraocular pressure and will benefit the development of novel therapies. [ABSTRACT FROM AUTHOR]

Background: There are many infectious diseases in the world caused by parasites. Among them, toxoplasmosis, American trypanosomiasis, African trypanosomiasis, leishmaniasis, neosporosis and malaria are more common and contribute to a majority of the affected individuals. Main body: Due to extensive use of antibiotics, antibiotic resistant strain of the parasites has developed. So, we need to develop a new metal ligand complexes which have many configurations, can overcome this drug resistance and also show significant results in elimination of the parasites. A series of anti-parasitic drugs have been formulated and tested for its activity. In this review, we have tried to see the interaction of different ruthenium drugs (arene ruthenium complex, ruthenium clotrimazole complex, etc.) on different parasites associated with the aforementioned diseases. Conclusion: Combination of ruthenium to any organic ligand shows synergistic effects against parasite either by overcoming the drug resistance of the parasite or by binding with new targets due to the presence of ruthenium ion. The multiple modes of action generate an effective drug exhibiting anti-parasitic activity at low concentration. [ABSTRACT FROM AUTHOR]

Background: Lysimachia ramosa (Wall. ex Duby) is a traditionally used medicinal plant in Meghalaya, a northeastern state of India. The people use the leaves of the plant to cure gastrointestinal worm infection. Kaempferol derivative, isolated from the leaves of the plant L. ramosa, was found to be the active anthelmintic compound in previous studies. The phytochemical present in the leaves causes alterations in the ultrastructure of the tegument of cestode, its glycogen content and tegumental enzymes. However, it has been found in the review of the literature that phytoproduct should be consumed in a limited dose during longtime treatment period to avoid any potential ill effects on the health of the consumers as many plant-based products are found to be toxic beyond a safe dose limit. Thereby, it becomes necessary to check the potential toxic effects of the active compound taking an animal model. Hence, the present study had been carried out to evaluate the toxicity of the active component on Wistar rats to find out the safe dose of the test compound for oral consumption through observations, if any, on chromosomal abnormalities, ultrastructural changes in bone marrow cells and apoptosis in liver and kidney. Results: The result shows kaempferol derivative causes a significant rise in chromosomal abnormalities (2.83 ± 0.19%, 3.83 ± 0.11%) and a significant decline in mitotic indices (3.17 ± 0.02%, 3.10 ± 0.01%) upon treatment with 500 mg and 1000 mg/kg b.w. dosages. At this level, the number of micronucleated erythrocytes increases significantly in the animals (2.33 ± 0.33%, 3.15 ± 0.24%). Intercellular integrity and eosinophil in the bone marrow are observed to be deformed and damaged on treatment with 1000 mg compound/kg b.w. of animals. Apoptotic indices are seen to be increased significantly (3.12 ± 0.18%, 6.17 ± 0.17%) and (2.43 ± 0.13%, 4.17 ± 0.17%) for the liver and kidney, respectively, in the animals of higher-dose treatment groups. Conclusions: The compound, kaempferol derivative in the present study, has been found to have cytotoxic and pro-apoptotic effects on the test animals beyond a certain dose, if consumed for longer period of time. Therefore, it can be concluded that kaempferol derivative extracted from Lysimachia ramosa should be tested for future trials on animals/humans at dose below 250 mg/kg body weight. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is a type of malignant tumor with increasing global incidence and mortality rates, especially in regions with high rates of obesity. Polygonatum sibiricum polysaccharide (PSP) has shown promise in addressing deficiencies associated with EC. While PSP has demonstrated anti-cancer properties across various cancer types, its efficacy in EC remains underexplored. This study investigates the inhibitory effects of PSP on EC cell proliferation and autophagy. Our data demonstrate that PSP effectively inhibits the growth of EC cells and induces apoptosis. Furthermore, PSP triggers autophagy in EC cells. Mechanistically, PSP suppresses the Toll-like receptors (TLR4)/Signal Transducer and Activator of Transcription 3 (STAT3) pathway, thereby inhibiting EC progression. In conclusion, our findings highlight the significant therapeutic potential of PSP in EC treatment by inhibiting cell growth, inducing apoptosis, and triggering autophagy via the TLR4/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Ovarian Cancer (OC) is a prevalent gynecological malignancy, underscoring the urgency to discover novel therapeutic approaches that enhance both clinical efficacy and safety. Taraxasterol (TA), an important component of dandelion, has been reported to exhibit inhibitory effects on the progression of various tumors. However, its specific role in OC is yet to be reported. In this present study, we observed that TA significantly inhibits the proliferation of OC cells, promotes apoptosis and reduces OC cell migration and angiogenesis. Mechanistically, TA targets the EPH receptor A2 (EphA2) receptor, thereby inhibiting OC progression. In conclusion, the ability of TA to suppress both cell proliferation and angiogenesis in OC through EphA2 targeting suggests its potential utility as a therapeutic agent for OC. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel HDACi with nanomolar activity against leukemic cells were synthesized. • HDACi of the KH-series are superior to a clinical grade HDACi. • HDACi of the KH-series modulate acetylation and phosphorylation of proteins. • The new HDACi KH16 regulates cell cycle arrest, apoptosis, and autophagy. • Apoptosis acts upstream of autophagy in KH16-treated cells. Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1,-2,-3,-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi SAHA (vorinostat). Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC 50 = 6 nM) and the most potent inducer of apoptosis (IC 50 = 110 nM; p < 0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in 115 human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces caspase-dependent processing of the autophagy proteins ULK1 and p62. These data reveal that HDACs are required to stabilize autophagy proteins through suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention. [ABSTRACT FROM AUTHOR]

The huge diversity of secondary bioactive metabolites, such as antibiotic and anticancer compounds produced by Micromonospora sp., makes it an attractive target for study. Here, we explored the anti-proliferative activities of Micromonospora sp. M2 extract (MBE) in relation to its pro-oxidative activities in A549 and MCF7 cell lines. Anti-proliferative effects were assessed by treating cells with MBE. We found that treatment with MBE decreased cell proliferation and increased intracellular reactive oxygen species, and that these observations were facilitated by the suppression of the PI3K-AKT pathway, alterations to the Bcl/Bad ratio, and increased caspase activity. These observations also demonstrated that MBE induced apoptotic cell death in cell lines. In addition, the phosphorylation of P38 and c-Jun N-terminal kinase (JNK) were upregulated following MBE treatment in both cell lines. Collectively, these results indicate that MBE acts as an anticancer agent via oxidative stress and JNK/mitogen-activated protein kinase pathway activation, enhancing apoptotic cell death in cell lines. [ABSTRACT FROM AUTHOR]

The regulation of the cell cycle is essential for maintaining normal cellular function, especially in the development of diseases such as lung cancer. The cell cycle consists of four major phases (G1, S, G2 and M phases), which are characterized by a series of precise molecular events to ensure proper cell proliferation and division. In lung cancer cells, cell cycle dysregulation can lead to disordered proliferation and increased invasiveness of cancer cells. G2 and S-phase expressed 1 (GTSE1) is a regulatory protein found in the cytoplasm of the cell, which plays a key role in the cell cycle distribution of a wide range of cancer cells and is involved in life processes such as cell proliferation and apoptosis. GTSE1 affects cell cycle progression by interacting with cyclin-dependent kinase inhibitor 1A (p21) and maintaining the stability of p21, which in turn inhibits the activity of cyclin-dependent kinase 1/2 (CDK1/2). In addition, GTSE1 is also involved in the regulation of tumor protein 53 (p53) signaling pathway. With the assistance of mouse double minute 2 homolog (MDM2), GTSE1 is able to transport p53 from the nucleus to the cytoplasm and promote its ubiquitination and degradation, thus affecting cell cycle and cell deathrelated signaling pathways. This paper reviews the expression of GTSE1 in lung cancer cells and its effects on lung cancer, as well as its potential mechanisms involved in cell cycle regulation. [ABSTRACT FROM AUTHOR]

Cinnamomi cortex was applied to mitigate joint injury since ancient China. However, the effect of Cinnamomi cortex on gouty arthritis (GA) was rarely reported. This study aimed to explore the effect of Cinnamomi cortex on monosodium urate (MSU)-induced acute GA (AGA) in rats, and clarify the underlying mechanism. The results showed that Cinnamomi cortex extract (CE) containing rich polyphenols and flavonoids alleviated joint swelling and inflammation by reducing programmed cell death in MSU-induced AGA rats. Network pharmacology analysis showed that CE's predictive inflammatory pathways included nuclear factor-κB (NF-κB) and necroptosis pathways. CE reduced expression of pyroptosis-related regulators including Gasdermin D and Caspase 1 via regulating NF-κB/NOD-like receptor thermal protein domain associated protein 3 signaling pathway in AGA rats. In conclusion, this study provided a theoretical basis for Cinnamomi cortex applied as a new veterinary medicine to protect against GA. [ABSTRACT FROM AUTHOR]

For over two decades, the development of B-cell lymphoma-2 (Bcl-2) family therapeutics has primarily focused on anti-apoptotic proteins, resulting in the first-in-class drugs called BH3 mimetics, especially for Bcl-2 inhibitor Venetoclax. The pro-apoptotic protein Bcl-2-associated X protein (BAX) plays a crucial role as the executioner protein of the mitochondrial regulated cell death, contributing to organismal development, tissue homeostasis, and immunity. The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death, such as cancer, neurodegeneration, and heart failure. In addition to conducting thorough investigations into the physiological modulation of BAX, research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX, as well as diverse all-molecule BAX modulators. This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX. Furthermore, it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX, offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX. The elucidation of the physiologic and pharmacologic regulatory mechanisms of BAX and characterization of potential druggable binding sites offer an innovative avenue for developing next-generation apoptosis modulators to treat a wide range of diseases in the context of dysregulated cell death by directly targeting BAX. [Display omitted] [ABSTRACT FROM AUTHOR]

Corneal injuries are the major cause of blindness and visual impairment. Available treatments are limited by their efficacy and side effects. Mesenchymal stem cell‐derived extracellular vesicles are presumed as functional equivalents and potential candidates for cell‐free therapy. This study reports isolation and characterization of extracellular vesicles from human bone marrow mesenchymal stem cells and evaluates their role in mediating epithelial repair and apoptosis in cultured corneal epithelial cells through scratch assay, PCR, immunofluorescence, and flow cytometry in vitro. The isolated extracellular vesicles were spherical, < 150 nm in diameter, and characterized as CD9+, CD63+, CD81+, TSG101+, and Calnexin−. Further, these vesicles promoted corneal epithelial repair by enhancing proliferation and suppressed apoptosis by regulating the expression of BAD, P53, BCL‐2, and cleaved CASPASE‐3. Thus, our results suggest that BM‐MSC‐EVs might have the potential to be used for the treatment of injury‐induced corneal epithelial defects. Clinical translation of this work would require further investigations. [ABSTRACT FROM AUTHOR]

Objective: To investigate the cardioprotective potential of betulin in isoproterenol (ISO)-induced myocardial injury in rats. Methods: Wistar rats were divided into five groups (n=10): normal, ISO, nebivolol 5 mg/kg, and betulin (20 & 40 mg/kg). Nebivolol and betulin were administered orally for 29 days. ISO (85 mg/kg) was administered subcutaneously on day 27 and day 28 to induce myocardial injury. On day 29, blood was collected for determination of cardiac markers, and hemodynamic parameters were investigated. The levels of oxidative stress markers and the gene expressions of apoptotic markers and inflammatory mediators were evaluated. Moreover, 2,3,5-triphenyltetrazolium chloride staining and histopathological analysis were also performed. Results: Betulin reduced the size of myocardial infarction, decreased elevated levels of cardiac enzymes, and maintained hemodynamic functions. It also inhibited ISO-induced upregulation of Bax, caspase-3, NF-κB, and IL-6, enhanced endogenous antioxidant enzymes, and reduced lipid peroxidation. Additionally, pretreatment with betulin alleviated myocardial ischemic damage, as reflected by reduced myonecrosis, edema, and inflammatory changes. Conclusions: Betulin exhibits strong cardioprotective activity against ISO-induced myocardial injury by anti-inflammatory, antiapoptotic, and antioxidant activities. [ABSTRACT FROM AUTHOR]

Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double‐strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells. [ABSTRACT FROM AUTHOR]

Warming Yang promoting blood circulation and diuresis (WYPBD) has been proven effective in treating some diseases. This study aimed to evaluate therapeutic effect of WYPBD in treating chronic heart failure (CHF). CHF rats were established by intraperitoneally injecting doxorubicin (DOX). Therapeutic effects of WYPBD on cardiac function and hemodynamic parameters of myocardial tissues were analyzed. Collagen fiber production and myocardial fibrosis were evaluated. Transcriptions of COL1A1 gene, COL3A1 gene, and TGFB1 gene were evaluated with RT-PCR. Expression of BNP, AVP, PARP, caspase-3, and Bcl-2 in myocardial tissues were evaluated. TUNEL assay was used to identify apoptosis of cardiomyocytes. WYPBD alleviated degree of myocardial hypertrophy in CHF rats compared to the rats in CHF model group (P < 0.05). WYPBD significantly improved cardiac hemodynamics (increased LVEF and LVSF) of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD protected myocardial structure and inhibited collagen fiber production in myocardial tissues of CHF rats. WYPBD markedly decreased myocardial fibrosis mediators (Col1a, Col3a, TGF-ß 1) transcription in myocardial tissues of CHF rats compared to rats in CHF model group (P < 0.05). WYPBD significantly reduced BNP and AVP expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). WYPBD markedly reduced the expression of PRAP and caspase-3, and increased Bcl-2 expression in myocardial tissues of CHF rats compared to rats in the CHF model group (P < 0.05). In conclusion, WYPBD alleviated CHF myocardial damage by inhibiting collagen fiber and myocardial fibrosis, attenuating apoptosis associated with the mitochondria signaling pathway of cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background: Cyclophosphamide (CP) is a chemotherapeutic and immunosuppressive agent that induces oxidative stress, causing lung tissue damage. Aim: The study aims to explore the antioxidant role of tert-butylhydroquinone (TBHQ) in ameliorating CP-induced lung toxicity exhibited as oxidative stress and programmed cell death. Methods: Thirty-two adult male rats were allocated randomly into four groups: group 1 (control), group 2 TBHQ 50 mg/kg orally for 14 days, and group 3 single dose of (200 mg/kg, CP, i.p.) on the 9th day. In group 4, TBHQ (50 mg/kg, orally) was provided for 14 days, and (200 mg/kg, CP, i.p.) was administrated on the 9th day. Rats' body and lung weight were measured. Oxidative stress marker malondialdehyde (MDA) and pulmonary tissue enzymatic antioxidant levels were assessed: glutathione S transferase, catalase, superoxide dismutase, and glutathione peroxidase. Additionally, glutathione level was measured. Assessment of the levels of TNF-α, IL-1β, and IL-6 were done as well as histopathological and immunohistochemistry investigations. Molecular docking studies of the protein structures of p53-MDM2, IL-6, and IL-1β were performed. Results: CP-intoxicated rats demonstrated a significant decline (CAT, GPx, SOD, GST, and GSH) levels and a significant increase in MDA levels. The proinflammatory parameters (TNF-α, IL-6, IL-1ß) were significantly elevated in group 3. The noted biochemical changes, accompanied by histopathological destruction, indicate CP-induced pulmonary tissue injury. TBHQ played a protective role by attenuating most of the aforementioned biochemical alterations and histopathological distortions in rats' lungs. Conclusions: TBHQ might be utilized as a potential ameliorative agent to inhibit CP-induced pulmonary toxicity via TBHQ's antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Cinnamomi cortex was applied to mitigate joint injury since ancient China. However, the effect of Cinnamomi cortex on gouty arthritis (GA) was rarely reported. This study aimed to explore the effect of Cinnamomi cortex on monosodium urate (MSU)-induced acute GA (AGA) in rats, and clarify the underlying mechanism. The results showed that Cinnamomi cortex extract (CE) containing rich polyphenols and flavonoids alleviated joint swelling and inflammation by reducing programmed cell death in MSU-induced AGA rats. Network pharmacology analysis showed that CE's predictive inflammatory pathways included nuclear factor-xB (NF-kB) and necroptosis pathways. CE reduced expression of pyroptosis-related regulators including Gasdermin D and Caspase 1 via regulating NF-xB/NOD-like receptor thermal protein domain associated protein 3 signaling pathway in AGA rats. In conclusion, this study provided a theoretical basis for Cinnamomi cortex applied as a new veterinary medicine to protect against GA. [ABSTRACT FROM AUTHOR]

Sixteen new dammarane-type triterpenoid saponins (1–16) featuring diverse structural variations in the side chain at C-17, along with twenty-one known analogues (17–37), have been isolated from the rhizomes of Gynostemma longipes C. Y. Wu, a plant renowned for its medicinal and edible properties. The structural elucidation of these compounds was accomplished through comprehensive analyses of 1D and 2D NMR and HRMS spectroscopic data, supplemented by comparison with previously reported data. Subsequent assays on the isolates for their protective effects against hypoxia-induced damage in pheochromocytoma cells (PC12 cells) revealed that nine saponins exhibited significant anti-hypoxic activities. Further investigation into the anti-hypoxia mechanisms of the representative saponins demonstrated that compounds 22 and 36 markedly reduced the levels of hypoxia-induced apoptosis. Additionally, these compounds were found to decrease the release of lactate dehydrogenase (LDH) and malondialdehyde (MDA), while increasing the activity of superoxide dismutase (SOD), thereby indicating that the saponins could mitigate hypoxia-induced injuries by ameliorating apoptosis and oxidative stress. These findings offer substantial evidence for the future utilization and development of G. longipes , identifying dammarane-type triterpenoid saponins as its active anti-hypoxic constituents. [ABSTRACT FROM AUTHOR]

Bazi Bushen (BZBS), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy in testicular dysfunction within D-galactose and NaNO 2 mouse models. This study aimed to ascertain if BZBS could also mitigate the decline in testicular function associated with natural aging. Therefore, male aged mice were employed to evaluate the preventive effects of BZBS on male reproductive aging. This was achieved by assessing sex hormone production, testicular histomorphology, and spermatogenesis. Relative to the untreated aged control group, BZBS administration elevated the levels of sex hormones and spermatocyte populations and preserved normal testicular structure in aged mice. Notably, spermatogenesis was maintained. Further analyses, including malondialdehyde (MDA) assays and real-time PCR, indicated that BZBS diminished testicular oxidative stress and the inflammatory burden. Corroborating these findings, mice treated with BZBS exhibited reductions in the populations of senescent and apoptotic cells within the seminiferous tubules, suggesting alleviated cellular damage. In contrast, we observed that rapamycin, a drug known for its longevity benefits, induced excessive testicular apoptosis and did not decrease lipid peroxidation. Collectively, our results highlight BZBS's promising clinical potential in counteracting male reproductive aging, underlining its mechanisms of action. [ABSTRACT FROM AUTHOR]

Hernandezine (Her), a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum , is recognized for its range of biological activities inherent to this herbal medicine. Despite its notable properties, the anti-cancer effects of Her have remained largely unexplored. In this study, we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms. Furthermore, Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems, leading to LC3 lipidation. Our findings revealed that Her caused damage to the mitochondrial membrane, with the damaged mitochondria undergoing mitophagy, as evidenced by the elevated expression of mitophagy markers. Conversely, Her disrupted autophagic flux, demonstrated by the upregulation of p62 and accumulation of autolysosomes, as observed in the RFP-GFP-LC3 reporter assay. Initially, we determined that Her did not prevent the fusion of autophagosomes and lysosomes. However, it inhibited the maturation of cathepsin D and increased lysosomal pH, indicating an impairment of lysosomal function. The use of the early-stage autophagy inhibitor, 3-methyladenine (3-MA), did not suppress LC3II, suggesting that Her also induces noncanonical autophagy in autophagosome formation. The application of Bafilomycin A1, an inhibitor of noncanonical autophagy, diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her, thereby augmenting Her-induced cell death. These observations imply that while autophagy initially plays a protective role, the disruption of the autophagic process by Her promotes programmed cell death. This study provides the first evidence of Her's dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death. These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death, offering potential avenues for enhancing cancer prevention and therapeutic strategies. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1β, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5 -induced lung injury. [ABSTRACT FROM AUTHOR]

In rheumatoid arthritis (RA), macrophages infiltrate joints, while fibroblast-like synovial cells proliferate abnormally, forming a barrier against drug delivery, which hinders effective drug delivery to joint focus. Here we firstly designed a pH-responsive size-adjustable nanoparticle, composed by methotrexate (MTX)-human serum albumin (HSA) complex coating with pH-responsive liposome (Lipo/MTX-HSA) for delivering drugs specifically to inflamed joints in acidic environments. We showed in vitro that the nanoparticles can induce mitochondrial dysfunction, promote apoptosis of fibroblast-like synoviocytes and macrophages, further reduce the secretion of inflammatory factors (TNF-α, IL-1β, MMP-9), and regulate the inflammatory microenvironment. We also demonstrated similar effects in a rat model of arthritis, in which Lipo/MTX-HSA accumulated in arthritic joints, and at low pH, liposome phospholipid bilayer cleavage released small-sized MTX-HSA, which effectively reduced the number of fibroblast-synoviocytes and macrophages in joints, alleviated joint inflammation, and repaired bone erosion. These findings suggest that microenvironment-responsive size-adjustable nanoparticles show promise as a treatment against rheumatoid arthritis. Abnormal proliferation of fibroblast synoviocytes poses a physical barrier to effective nanoparticle delivery. We designed size-adjustable nano-delivery systems by preparing liposomes with cholesterol hemisuccinate (CHEM), which were subsequently loaded with small-sized albumin nanoparticles encapsulating the cytotoxic drug MTX (MTX-HSA), termed Lipo/MTX-HSA. Upon tail vein injection, Lipo/MTX-HSA could be aggregated at the site of inflammation via the ELVIS effect in the inflamed joint microenvironment. Specifically, intracellular acidic pH-triggered dissociation of liposomes promoted the release of MTX-HSA, which was further targeted to fibroblasts or across fibroblasts to macrophages to exert anti-inflammatory effects. The results showed that liposomes with adjustable particle size achieved efficient drug delivery, penetration and retention in joint sites; the strategy exerted significant anti-inflammatory effects in the treatment of rheumatoid arthritis by inducing mitochondrial dysfunction to promote apoptosis in fibrosynoviocytes and macrophages. [Display omitted] [ABSTRACT FROM AUTHOR]

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases. [ABSTRACT FROM AUTHOR]

Breast cancer is a females' prevalent malignancy, resulting in higher mortality rates than other cancers. Therefore, exploring effective therapeutic targets and diagnostic biomarkers is critical for improving drugs' curative effect in treating breast cancer patients. The MDA-MB-231 and Michigan Cancer Foundation-7 (MCF-7) cells were transfected by pc-CDCA2, Small interfering RNA Negative Control (siNC), siCDCA2, and pc-KISS1 to investigate the effects of cell division cycle associated 2 (CDCA2) and kisspeptin 1 (KISS1) protein on breast cancer cell's viability, migration and invasion. Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) was used to examine the CDCA2 mRNA expression. Impact of CDCA2 and KISS1 on invasion ability, motility and viability of breast cancer cells were detected via colony-forming unit, Cell Counting Kit-8 (CCK-8) and transwell assay. The Annexin V-Fluorescein Isothiocyanate (annexin V-FITC) staining was employed to determine the cellular apoptosis ratio based on flow cytometry. Findings indicated that CDCA2 expression got increased in breast cancer tissues, which greatly enhanced the cell proliferation, migration and invasion ability. Moreover, the regulation of CDCA2 may suppress the activation of KISS1 in breast cancer cells. In summary, the findings depicted that in breast cancer cells, the CDCA2 expression was enhanced to promote cells motility, invasiveness and viability through inhibition of KISS1 expression. Therefore, targeted gene therapy to suppress the expression levels of CDCA2 and upregulation of the KISS1 have the potential to be promising therapeutic strategies for treating breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Purpose: In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic thirdtrimester maternal COVID-19 infection. Materials and Methods: This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area’s inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick- End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status. Results: Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group (p<0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group (p>0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis (p<0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process. Conclusion: The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether the exposure to radiofrequency emitted by wireless internet providers (2450 MHz) throughout the day during rats’ pregnancy causes a problem in the thyroid tissues of their offspring. The pregnant rats in the experimental group were exposed to radiofrequency radiation (RFR) (24 hours/day) at a 2450 MHz frequency in pulse wave mode with 1 W output strength by a generator simulating Wi-Fi waves. The offspring in the control and experimental groups were randomized selected (n:8). At the end of the sixth month, the thyroid tissues were removed and evaluated histopathologically and biochemically. Mann‒Whitney U-tests and T-tests were used for statistical analysis. The threshold for statistical significance was p <0.05. There was a significant difference in mononuclear cell infiltration (p=0.03) and vascular increase in congestion (p<0.001). There was no difference in the TUNEL-positive cell percentage (p=0.62) and H2A.X antibody levels (p=0.68) between the rats in the control and experimental groups. In this study, 2450 MHz RFR exposure during the prenatal period did not cause a statistically significant difference in terms of H2A.X levels and TUNEL-positive cell percentages in the thyroid tissue of rats. [ABSTRACT FROM AUTHOR]

Dental caries can lead to inflammation or necrosis of the pulp, necessitating root canal treatment. However, this treatment carries the risk of pain, with its incidence influenced by the condition and quality of the pulp tissue. Immunologic and microbiologic factors play significant roles in determining the quality of the pulp tissue, thereby impacting the diagnosis of pulp tissue health. To elucidate the reduction in cell count resulting from the intrinsic apoptosis pathway of dental pulp nerve cells subsequent to lipopolysaccharide (LPS) administration, based on the expression levels of nitrotyrosine and F2-isoprostane. Thirty-two Sprague Dawley rats were divided into two groups. In the control group, only access opening was performed on the mandibular incisors of the rats. Conversely, in the treatment group, access opening was performed, and lipopolysaccharide (LPS) from Porphyromonas gingivalis was induced, left for 48 hours to induce an inflammatory condition, and subsequently terminated. Immunohistochemical staining was then employed to assess the expression of nitrotyrosine and F2-isoprostane. Additionally, the number of dental pulp nerve cells was observed using hematoxylin and eosin (HE) staining. Significant differences were observed in the expression levels of nitrotyrosine and F2- isoprostane, as well as in the number of nerve cells, between the control and treatment groups. Administration of lipopolysaccharide (LPS) leads to increased expression of nitrotyrosine and F2- isoprostane, while concurrently decreasing the number of dental pulp nerve cells affected by inflammation. [ABSTRACT FROM AUTHOR]

One of the most common cancers in the world is oral squamous cell carcinoma. Increasing apoptotic activity is one method of treating cancer by reducing or stopping the uncontrolled growth of cancer cells. Known for its many health advantages and anti-tumor capabilities, Ant's Nest (Myrmecodia pendans) is a native of Papua, Indonesia. This study aimed to analyze the therapeutic effects of Ant's Nest extract on epithelial dysplasia in a carcinoma model through the immunoexpression of Caspase-3, Bax, and Bcl-2. The research was a pure experimental study using male Sprague Dawley rats, divided into control and treatment groups. The experimental animals were induced with 0.5% dimethylbenz(a)anthracene (DMBA) for 4 weeks, resulting in epithelial dysplasia. Subsequently, Ant's Nest water and ethanol extracts were administered orally at a dose of 6.3 mg dissolved in 0.5% CMC once a day for 4 weeks. Immunohistochemical examinations were conducted for Caspase-3, Bax, and Bcl-2 immunoexpression. The results of the study showed that there were notable variations in the immunoexpression of Bcl-2, Bax, and Caspase-3 between the treatment and control groups. The group that was given Ant's Nest water and ethanol extracts showed a decrease in Bcl-2 immunoexpression and an increase in Caspase-3 and Bax immunoexpression. We find that via modulating the immunoexpression of Caspase-3, Bax, and Bcl-2, Ant's Nest extract treatment promotes the process of apoptosis. [ABSTRACT FROM AUTHOR]