Activation Of Apoptosis Pathway Research Articles

Advanced oxidation protein products induce apoptosis in thyroid follicular epithelial cells through oxidative stress in Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder primarily driven by T cell. The apoptosis of the follicular thyroid cells plays an important role in HT apart from the lymphocyte-mediated cytotoxicity. Advanced oxidation protein products (AOPPs), resulting from oxidative stress, are known to be involved in various inflammatory diseases. However, their role in HT development has not been explored. Here, we discovered that AOPP levels were significantly elevated in thyroid tissues of both HT patients (Ctrl 4.12±0.56, HT 30.00±2.78; p<0.0001) and experimental autoimmune thyroiditis (EAT) mice (Ctrl 8.37±1.43, HT 55.82±2.87; p<0.0001), accompanied by extensive thyroid follicular epithelial cell apoptosis in HT patients (Ctrl 32.16±1.79, HT 147.10±13.32; p<0.0001) and EAT mice (Ctrl 66.78±6.72, HT 249.10±9.77; p<0.0001). In vitro study showed that AOPPs induced reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate oxidase (NOX), leading to apoptosis in human thyroid follicular epithelial cell (Nthy-ori 3-1). Treatment with apocynin, a NOX inhibitor, reduced AOPP-induced ROS production and apoptosis in Nthy-ori 3-1 cells, and in turn alleviated thyroid follicular epithelial cell apoptosis and autoimmune thyroiditis symptoms in mice. Mechanistically, AOPP treatment activated JNK pathway, leading to the downregulation of Bcl-2, upregulation of Bax, the mitochondrial membrane potential depolarization and consequently triggered the activation of mitochondria-dependent intrinsic apoptosis pathway. Collectively, our findings highlight the promotive roles of AOPP in HT and provide an attractive therapeutic target for HT therapy.

Fluoride-Induced Autophagy and Apoptosis in the Mouse Ovary: Genomic Insights into IL-17 Signaling and Gut Microbiota Dysbiosis.

Chronic fluoride (F) exposure is linked to gonadotoxicity in females, yet the underlying molecular mechanisms remain unclear. This study investigated fluoride-induced reprotoxicity using advanced genomic profiling. RNA-seq analysis identified significant activation of autophagy, apoptosis, and IL-17 signaling pathways in fluoride-exposed female mice. To explore these mechanisms, F0 pregnant mice were exposed to deionized water (control) or 100 mg/L sodium fluoride (NaF) during gestation and throughout the F1 generation (n = 16 females/group), covering puberty to weaning and maturity. NaF exposure caused significant reductions in body weight, organ coefficients, and pathological indices, with increased ovarian autophagic vacuoles, mitochondrial injuries, and elevated serum/ovary LPS levels in F1 females. qRT-PCR, fluorescent staining, biochemical assays, and Western blotting confirmed the activation of IL-17 signaling, apoptosis, and autophagy. Moreover, 16S rRNA sequencing revealed gut microbiota dysbiosis in NaF-exposed F1 females, potentially exacerbating ovary injury via serum LPS elevation. The gut dysbiosis could justify deteriorated serum LPS levels and its connection to F-induced ovary injury. These findings provide mechanistic insights into fluoride-induced reprotoxicity, emphasizing the interplay of IL-17 signaling, autophagy, and apoptosis in disrupting cellular homeostasis and suggesting potential therapeutic targets.

Expression of vesiculation-related genes is associated with a tumor-promoting microenvironment: a pan-cancer analysis.

Small extracellular vesicles (sEV) released by tumor cells (tumor-derived sEV; TEX) mediate intercellular communication between tumor and non-malignant cells and were shown to impact disease progression. This study investigates the relationship between the expression levels of the vesiculation-related genes linked to sEV production and the tumor microenvironment (TME). Two independent gene sets were analyzed, both previously linked to sEV production in various non-malignant or malignant cells. Expression profiles were compared among 28 tumor types listed in the Cancer Genome Atlas (TCGA). Gene expression and survival analysis (GEPIA2), immunogenomic analysis (TISIDB), and genomic analysis (GSCA) were performed. Vesiculation-related genes were overexpressed in tissues of most tumor types compared to healthy tissues, and high expression levels were associated with worse overall survival in cervical squamous cell carcinoma, kidney chromophobe, lower grade glioma, hepatocellular carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma but with improved overall survival in kidney renal clear cell carcinoma. Expression of these signatures correlated with an increased abundance of infiltrating CD4( +) T cells and dendritic cells, a decreased abundance of B cells and eosinophils, and activation of tumor cell apoptosis and epithelial-mesenchymal transition pathways in all tumor types. 17-AAG was identified as a potential drug candidate to target tumors with elevated expression of vesiculation-related genes. Vesiculation-related genes were associated with distinct immunological and genomic landscapes further emphasizing the important role of TEX in cancer progression.

Triphenylphosphine-modified cyclometalated iridiumIII complexes as mitochondria-targeting anticancer agents with enhanced selectivity.

This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridiumIII complexes as selective anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12-7.24μM) against A549 and HeLa cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for cancer cells over normal cells, achieving selectivity index in the range of 5.46-14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated reactive oxygen species (ROS) levels, and activation of intrinsic apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G2/M phase and suppress the migration of A549 cells.

Obeticholic acid aggravates liver fibrosis by activating hepatic farnesoid X receptor-induced apoptosis in cholestatic mice.

Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients. However, it can cause severe drug-induced liver injury (DILI), which may put PBC patients at risk of acute-on-chronic liver failure (ACLF) and even death. Farnesoid X receptor (FXR) is considered as the target of OCA for cholestasis, but there is still a lack of research on whether hepatic and ileal FXR have different effects after OCA treatment. The aim of this study was to investigate the mechanism of OCA aggravating liver fibrosis in cholestasis. The results showed that 40mg/kg OCA elevated serum AST, ALT, ALP and γ-GT levels in bile duct ligation (BDL) mice. Besides, severe fibrosis and necrosis were observed in the OCA-treated BDL mice, which was related to hepatic apoptosis pathway activation. Both hepatic and ileal FXR signaling could be significantly activated by OCA. However, ileum-specific knockout of Fxr aggravated OCA-induced liver injury in BDL mice. On the contrary, hepatic-specific knockout of Fxr structurally and functionally ameliorated liver pathological processes in the OCA-treated BDL mice, which was due to the blockade of hepatic FXR-induced apoptosis. In conclusion, the mechanism of OCA aggravating liver fibrosis in cholestasis was based on the activation of hepatic FXR-induced apoptosis. It was also indicated ileal FXR might be a safer pharmacological target for bile acids regulation.

Immunoregulatory Effects of Codonopsis pilosula Polysaccharide Modified Selenium Nanoparticles on H22 Tumor-Bearing Mice.

Codonopsis pilosula polysaccharide (CPP) and rare element selenium (Se) have been proved to exert various biological activities, and our previous study demonstrated that selenium nanoparticles modified with CPP (CPP-SeNPs) possessed significantly enhanced tumor cytotoxicity in vitro. This study aimed to investigated the inhibitory effects of CPP-SeNPs complex on H22 solid tumors via immune enhancement. In this study, the H22 tumor-bearing mice model was constructed, and the potential mechanisms of CPP-SeNPs antitumor effects were further explored by evaluating cytokines expression levels, immune cells activities and tumor cells apoptotic indicators in each group. The results demonstrated that CPP-SeNPs effectively exerted dose-dependent protective effects on the immune organs of tumor-bearing mice in vivo, leading to increase in peripheral white blood cell counts and inhibition of solid tumor growth with inhibitory rate of 47.18% in high-dose group (1.5 mg/kg). Furthermore, CPP-SeNPs treatment significantly elevated the levels of TNF-α, IFN-γ, and IL-2 in mice sera, enhanced NK cell cytotoxicity, augmented macrophage phagocytosis capacity, as well as increased both the amounts and proliferation activity of lymphocyte subsets. CPP-SeNPs improved the immune system's ability to clear tumor cells by up-regulating Bax expression while down-regulating Bcl-2 expression within solid tumors, indicating the potential activation of mitochondrial apoptosis pathway. Therefore, CPP-SeNPs administration can effectively inhibit tumor growth by enhancing immune response in tumor-bearing mice, which might be relevant to the regulation of gut microbiota short-chain fatty acids metabolisms. These findings could provide theoretical support and data foundation for further development of CPP-SeNPs as functional food and drug adjuvants.

Dynamics of changes in markers of apoptosis, circadian rhythms and antioxidant processes in the model of temporal lobe epilepsy in rats

Temporal lobe epilepsy is a common neurological disorder that in many cases is accompanied by drug resistance. The current approach to the treatment of patients with drug resistance includes surgical intervention, which does not guarantee full recovery. At present, new antiepileptic drugs that affect signaling cascades inherent in epileptogenesis are being developed. The development of such drugs requires knowledge of the basic mechanisms of epilepsy pathogenesis. The aim of the work was to investigate the dynamics of expression of proteins involved in the regulation of apoptosis, circadian rhythms and antioxidant response in the temporal cortex of the brain during prolonged kindling in the Krushinsky-Molodkina (KM) rat model with hereditary audiogenic epilepsy. The dynamics of expression of studied proteins – p53, CLOCK, Nrf2, p105 - was investigated in the temporal cortex (immunohistochemistry, Western blotting). It was found that p53 level was lower in KM control rats than in Wistar rats. In KM rats subjected to 21 days kindling, p53 content is increased compared to KM control. CLOCK level was downregulated in the KM control group compared to the negative control and elevated in the KM group after kindling 21 days relative to the KM group after 7 days kindling. No changes in Nrf2 and p105 production were detected. The data obtained suggest that the changes in the levels of the studied proteins in control KM rats compared to Wistar rats are genetically determined. Induced epileptogenesis (kindling) for 21 days leads to activation of p53-dependent apoptosis pathway and, possibly, to desynchronosis - change of circadian rhythms. The findings contribute to the study of temporal lobe epilepsy mechanisms and require further studies related to mitochondrial apoptosis and sleep-wake cycle shift in the pathogenesis of temporal lobe epilepsy.

Inside Cover Picture

A chemical investigation of the deep‐sea‐derived fungus Penicillium allii‐sativi resulted in the discovery of four new (1—4) and one known (5) meroterpenoids. Compound 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0‐G1 phase and triggering mitochondrial apoptosis in Hela cells. While macrophorin A effectively triggered cell death in MDA‐MB‐231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF. More details are discussed in the article by Yang et al. on pages 3283—3292. image

MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.

Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.

Fatty acid composition and anti-cancer activity of essential oil from Tenebrio molitor larvae in combination with zoledronic acid on prostate cancer

The essential oil extracted from Tenebrio molitor larvae (EOTM) is a natural product containing trace elements with potential therapeutic properties. This study aimed to assess the anticancer effects of EOTM and its synergistic interactions with zoledronic acid, a bisphosphonate drug, on prostate cancer cell lines. The chemical composition of EOTM was analyzed using GC-MS revealing a high concentration of fatty acids. The cytotoxicity of EOTM, both as a standalone treatment and in combination with zoledronic acid, was evaluated on prostate cancer cell lines (LNCaP, PC3) and normal hSKM using MTT assays. Results demonstrated that EOTM exhibited selective toxicity, inhibiting the growth of cancer cells in a dose-dependent manner while sparing normal cells. Morphological assessments and gene expression analyses of BCL2 and BAX were conducted through microscopy, Western blotting, and real-time RT-qPCR. These analyses indicated that EOTM induced apoptosis in cancer cells, as evidenced by cellular shrinkage, membrane blebbing, and nuclear fragmentation. Western blot results showed that EOTM downregulated the anti-apoptotic protein BCL2 and upregulated the proapoptotic protein BAX, suggesting activation of apoptosis pathways. Additionally, the combination of EOTM with zoledronic acid amplified these effects. Hoechst 33258 staining further confirmed the purity of cells following treatment. In conclusion, EOTM exhibits strong anticancer properties by inducing apoptosis in prostate cancer cells and demonstrates synergistic potential when combined with zoledronic acid. These findings warrant further investigation of EOTM as a natural and effective cancer treatment option.

Peptide-functionalized polymeric nanoparticles for delivery of curcumin to cancer cells

Polymeric nanoparticles (NPs) have garnered significant interest due to their potential in drug delivery. Specifically, nanopolymers functionalized with molecules such as proteins or peptides serve as versatile vehicles for this purpose. Curcumin (Cur) is a widely studied anticancer compound known for its positive effects on human health. Nevertheless, its insolubility and low bio-distribution hinder the exploitation of its beneficial traits. In this study, our team developed a nanodelivery system using a nanopolymer called poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG), functionalized with A6 peptide to enable targeted delivery of Cur. The designed system exhibited favorable characteristics, including a stable zeta potential of −13.8 mV, a small size of 76.4 nm, uniform surface morphology, and high hydrophilicity with a contact angle of 31.53°. Additionally, the targeted delivery system demonstrated high encapsulation efficiency (EE%) (93 ± 0.89 %), drug loading (DL%) (16.7 ± 0.9 %), and a slow and gradual release profile with a release of approximately 83.1 ± 0.12 %. The MTT assay results showed significant cell death in MDA-MB-231 cancer cells (IC50 = 21.3 ± 1.57 μM) when treated with the Cur-NPs-A6 formulation, while the toxicity of the designed NPs was reduced on non-cancerous MCF-10A cells. Moreover, both the RT-qPCR and invasion assays demonstrated the system's effectiveness in activating apoptosis pathways and inhibiting cell invasion. These findings suggest that the engineered intelligent delivery system, equipped with the A6 peptide, which has a strong affinity for CD44 (a protein with increased expression in malignancy), could be an exceptionally effective strategy for cancer treatment.

Japanese encephalitis virus infection induces mitochondrial-mediated apoptosis through the proapoptotic protein BAX.

The Japanese encephalitis virus (JEV), a zoonotic flavivirus, is Asia's primary cause of viral encephalitis. JEV induces apoptosis in a variety of cells; however, the precise mechanisms underlying this apoptosis resulting from JEV infection remain to be elucidated. Our previous studies showed that the proapoptosis gene BAX may have a role in JEV proliferation. In this study, we constructed a PK-15 cell line (BAX.KO) with a knockout of the BAX gene using CRISPR/Cas9. The knockout of the BAX gene effectively inhibited the proliferation of JEV, resulting in a 39.9% decrease in viral protein levels, while BAX overexpression produced the opposite effect. We confirmed that JEV induces apoptosis of PK-15 using 4',6-diamidino-2-phenylindole (DAPI) staining and Annexin V-FITC/PI staining. Furthermore, we found that the phosphorylation of P53 and the expression levels of BAX, NOXA, PUMA, and cleaved-caspase-3/9 were significantly upregulated after JEV infection. Moreover, we found that JEV infection not only caused mitochondrial damage, the release of mitochondrial cytochrome C (Cyt C), and the downregulation of the apoptosis-inhibiting protein BCL-2 but also reduced the mitochondrial membrane potential (MOMP) and the accumulation of intracellular reactive oxygen species (ROS). These factors collectively encourage the activation of the mitochondrial apoptosis pathway. In contrast, BAX gene knockout significantly reduces the apoptotic changes caused by JEV infection. Treatment with the caspase3 inhibitor attenuated JEV-induced viral proliferation and release, leading to a decrease in viral protein levels of 46% in PK-15 cells and 30% in BAX.KO cells. In conclusion, this study clarified the molecular mechanisms of JEV-induced apoptosis and provided a theoretical basis for revealing the pathogenic mechanisms of JEV infection.

Biogenic silver nanoparticles synthesized using bracken fern inhibits cell proliferation in HCT-15 cells through induction of apoptosis pathway and overexpression of heat shock proteins

BackgroundIn recent years, biosynthesized nanoparticles has shown a promise as alternative avenue for improving the effectiveness of conventional chemotherapy. Despite, there is a significant gap in existing literature concerning the comprehensive study of biogenic silver nanoparticles derived from terrestrial fern species and their potential effects on cancer cells. This study is aiming to investigate effects of biogenic silver nanoparticles synthesized using aqueous extract of bracken fern Pteridium revolutum on inhibiting cell proliferation and inducing apoptosis in HCT-15 cells. MethodsBiogenic silver nanoparticles synthesized using aqueous extract of Pteridum revolutum followed by their characterization (UV–Visible spectroscopy, TEM, XRD and FTIR). The impact on cell proliferation of HCT-15 cells was assessed by MTT assay while induction of apoptosis was demonstrated via DNA fragmentation, caspase-3 assay, cell cycle arrest, FITC V- Annexin assay and evaluation of expression of apoptotic genes using real time PCR and western blotting techniques. ResultsResults of UV–Vis spectrum of colloidal solution of CW-AgNPs showed surface plasmon resonance peak at 430 nm. TEM and XRD results confirmed synthesis of spherical shaped, 20–40 nm sized nanoparticles. The results elucidate cytotoxic effect of PR-AgNPs against HCT-15 cells in time and dose dependent manner with IC50 observed at 5.79 ± 0.58 µg /mL after 24 h of exposure. Furthermore, PR-AgNPs induce significant alterations in cellular morphology, elevate DNA DNA fragmentation and enhance expression of p53 and caspase-3 in HCT10 cells. ConclusionThe findings from this study address the noteworthy antiproliferative effects of PR-AgNPs in cancer cells primarily mediated through activation of intrinsic apoptosis pathway by inducing p53 and caspase-3 genes.

Intestinal inflammation, oxidative damage, and pathogenesis of intestinal Cryptosporidium in juvenile Asian sea bass (Lates calcarifer)

AbstractPiscine intestinal Cryptosporidium infection is a known cause of severe illness and mortality in juvenile Asian sea bass, with inflammation playing a central role. This inflammation triggers the generation of reactive oxygen species (ROS), leading to irreversible DNA damage and activation of apoptosis pathways. However, the specific impact of inflammation on ROS production, DNA damage, and apoptosis in this context remains unclear. This study investigated the pathogenic role of inflammation and ROS in causing DNA damage and cell apoptosis in piscine intestinal cryptosporidiosis. Forty‐four intestinal samples from 60‐ and 90‐day juvenile Asian sea bass were divided into four groups based on Cryptosporidium infection status. Histopathological evaluation and immunofluorescent analysis were conducted to assess ROS production, DNA damage, and cellular apoptosis markers. Results showed significantly higher inflammatory cell infiltration, intracellular ROS production, DNA damage, and cellular apoptosis in 60‐day infected fish compared to 90‐day infected fish. These findings underscore distinct responses in juvenile Asian sea bass to piscine intestinal cryptosporidiosis, highlighting severe inflammation, oxidative DNA damage, and cellular apoptosis, particularly in younger fish.

Redox Status and Protein Glutathionylation in Binase-Treated HPV16-Positive SiHa Carcinoma Cells

Human papillomavirus type 16 (HPV16) belongs to viruses of the high-risk type and is associated by overexpression of E6 and E7 oncoproteins, which determine the oncogenic properties of the virus, such as immortalization and malignant transformation of proliferating epithelial cells. The biogenesis of redox-sensitive proteins E6 and E7 at the early stages of viral infection leads to blocking of the cell antioxidant defense system and ubiquintin-dependent degradation of p53 and Rb tumor suppressors. Maintaining high rates of tumor cell proliferation contributes to an increase in the level of reactive oxygen species (ROS) and a shift in the redox balance towards oxidative processes. Reduced glutathione (GSH) provides antioxidant protection to tumor cells through S-glutathionylation of thiol groups of redox-sensitive proteins, which leads to the appearance of multidrug-resistant forms of cancer. In this regard, drugs restoring redox balance and increasing susceptibility to antitumor therapy are of particular importance. We have established that, Bacillus pumilus RNase (binase) modulates the redox-dependent regulatory mechanisms that ensure tumor cell resistance to apoptosis in HPV-16-positive SiHa cells of cervical squamous cell carcinoma,. Binase in nontoxic concentrations initiates a number of pre-apoptogenic changes, i.e., decreases ROS and reduced glutathione (GSH) levels, suppresses the expression of the E6 oncoprotein, activates the expression of the p53 tumor suppressor, and reduces the mitochondrial potential of tumor cells. Binase-induced disruption of the integrity of the mitochondrial membrane is a signal for activation of the mitochondrial apoptosis pathway.

The G-Protein-Coupled Estrogen Receptor Agonist G-1 Mediates Antitumor Effects by Activating Apoptosis Pathways and Regulating Migration and Invasion in Cervical Cancer Cells.

Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia.

Therapeutic potential of aquatic Stevia extract in alleviating endoplasmic reticulum stress and liver damage in streptozotocin-induced diabetic rats.

Misfolded proteins accumulate in the liver due to endoplasmic reticulum stress (ERS) caused by high blood glucose levels in diabetes. This triggers the unfolded protein response (UPR), which if persistently activated, results in cellular dysfunction. Chronic ER stress increases inflammation, insulin resistance, and apoptosis. There is growing interest in using native plants and traditional medicine for diabetes treatment. The stevia plant has recently gained attention for its potential therapeutic effects. This study investigates the protective effects of aquatic stevia extract on liver damage, ER stress, and the UPR pathway in streptozotocin (STZ)-induced diabetic rats. Rats were randomly divided into four groups: a control group that received 1ml of water; a diabetic group induced by intraperitoneal injection of STZ (60mg/kg); a diabetic group treated with metformin (500mg/kg); and a diabetic group treated with aquatic extracts of stevia (400mg/kg). After 28 days, various parameters were assessed, including inflammatory markers, oxidative stress indices, antioxidant levels, gene expression, stereology, and liver tissue pathology. Compared to the diabetic control group, treatment with stevia significantly decreased serum glucose, liver enzymes, inflammatory markers, and oxidative stress while increasing body weight and antioxidant levels. Additionally, stevia extract manipulated UPR gene expression and reduced apoptosis pathway activation. Histological examination revealed improved liver tissue morphology in stevia-treated diabetic rats. These findings suggest that aquatic stevia extract mitigates ER stress in diabetic rats by modulating the IRE-1 arm of the UPR and apoptosis pathways, highlighting its potential therapeutic benefits for diabetes-related liver complications.

Unveiling the Mechanisms of Apoptosis Induction by Deep‐Sea‐Derived Polyketide‐Terpenoid Hybrids from Penicillium allii‐sativi: A Focus on Mitochondrial and mTOR Pathways

Comprehensive SummaryA chemical investigation of the deep‐sea‐derived fungus Penicillium allii‐sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids (1—4) and one related known co‐metabolite (5). These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units. Particularly, compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part. The structures of new compounds were assigned by extensive spectroscopic analysis, quantum calculations, and biogenetic considerations. Notably, 3 significantly blocked the mTOR signaling pathway, resulting in the arrest of cell cycle at G0‐G1 phase and triggering mitochondrial apoptosis in Hela cells. While the previously reported co‐metabolite macrophorin A (MPA) effectively triggered cell death in MDA‐MB‐231 cancer cells by activating apoptosis pathways involving death receptors, mitochondria, mTOR, and TNF.

Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia.

Protein arginine methyltransferase 3 (PRMT3) plays an important role in gene regulation and a variety of cellular functions, thus, being a long sought-after therapeutic target for human cancers. Although a few PRMT3 inhibitors are developed to prevent the catalytic activity of PRMT3, there is little success in removing the cellular levels of PRMT3-deposited ω-NG,NG-asymmetric dimethylarginine (ADMA) with small molecules. Moreover, the non-enzymatic functions of PRMT3 remain required to be clarified. Here, the development of a first-in-class MDM2-based PRMT3-targeted Proteolysis Targeting Chimeras (PROTACs) 11 that selectively reduced both PRMT3 protein and ADMA is reported. Importantly, 11 inhibited acute leukemia cell growth and is more effective than PRMT3 inhibitor SGC707. Mechanism study shows that 11 induced global gene expression changes, including the activation of intrinsic apoptosis and endoplasmic reticulum stress signaling pathways, and the downregulation of E2F, MYC, oxidative phosphorylation pathways. Significantly, the combination of 11 and glycolysis inhibitor 2-DG has a notable synergistic antiproliferative effect by further reducing ATP production and inducing intrinsic apoptosis, thus further highlighting the potential therapeutic value of targeted PRMT3 degradation. These data clearly demonstrated that degrader 11 is a powerful chemical tool for investigating PRMT3 protein functions.

Cimicifugin, a broad-spectrum inhibitor of Theileria annulata and Plasmodium falciparum CDK7.

Cyclin-dependent kinase 7 is an attractive therapeutic target for the treatment of cancers, and a previous report suggested that Plasmodium falciparum CDK7 is a potential drug target for developing new anti-malarial drugs. In this study, we aimed to characterize and evaluate the drug target potential of Theileria annulata CDK7. Theileria annulata is responsible for tropical theileriosis, which induces a phenotype similar to cancerous cells like immortalization, hyperproliferation, and dissemination. Virtual screening of the MyriaScreen II library predicted 14 compounds with high binding energies to the ATP-binding pocket of TaCDK7. Three compounds (cimicifugin, ST092793, and ST026925) of these 14 compounds were non-cytotoxic to the uninfected bovine cells (BoMac cells). Cimicifugin treatment led to the activation of the extrinsic apoptosis pathway and induced autophagy in T. annulata-infected cells. Furthermore, cimicifugin also inhibited the growth of P. falciparum, indicating that it has both anti-theilerial and anti-malarial activities and that TaCDK7 and PfCDK7 are promising drug targets.