Activation Of Apoptosis Pathway Research Articles

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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.

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.

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.

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.

Intranuclear Irradiation Inhibits Solid Tumor Growth by Upregulating Caspase8 and Activating Apoptosis.

Radioimmunotherapy (RIT) is a novel and promising cancer treatment method, with ongoing research focusing on RIT antibody selection, radionuclides, treatment options, and benefited patient groups. As we dive into the mechanisms of tumor biology, a deeper exploration of how RIT affects tumor tissue is needed to provide new ways to improve clinical treatment outcome and patient prognosis. We labeled the anti-PD-L1 monoclonal antibody atezolizumab with iodine-131 (131I), separated and purified the labeled mAb with Sephadex G-25 medium gel filtration resin, and tested product stability. We detected the in vivo activity of 131I-PD-L1 mAb by analyzing its in vivo biodistribution and performing SPECT imaging and then set different treatment groups to study the effect of 131I-atezolizumab on the survival of tumor-bearing mice. Western blot, real-time quantitative PCR, and immunohistochemistry were used to detect the expression level of Caspase8 and Nlrp3 in tumor. TUNEL fluorescence staining was used to detect the apoptosis in the tumor. The radiopharmaceutical molecular probe 131I-atezolizumab showed high stability and in vivo biological activity. The treatment regimen adopted had a positive effect on the survival of tumor-bearing mice. 131I internal irradiation upregulated Caspase8 in tumor and ultimately inhibited solid tumor growth by activating apoptosis pathways. We also found a significant increase in the expression of NLRP3, which plays an important role in the pyroptosis pathway, in tumor. In summary, our data demonstrated that radiopharmaceuticals combined with immunotherapy affected tumor tissue by modulating relevant biological pathways, thereby achieving better antitumor effects compared with single therapy and providing new insights for promoting better patient prognosis and combination treatment strategies.

Electrical Stimulation Induces Activation of Mitochondrial Apoptotic Pathway and Down-Regulates Heat Shock Proteins in Pork: An Innovative Strategy for Enhancing the Ripening Process and Quality of Dry-Cured Loin Ham.

A fundamental regulatory framework to elucidate the role of electrical stimulation (ES) in reducing long production cycles, enhancing protein utilization, and boosting product quality of dry-cured ham is essential. However, how mitochondria and enzymes in meat fibers are altered by ES during post-processing, curing, and fermentation procedures remains elusive. This study sought to explore the impact of ES on the regulation of heat shock proteins (HSP27, HSP70), apoptotic pathways, and subsequent influences on dry-cured pork loin quality. The gathered data validated the hypothesis that ES notably escalates mitochondrial oxidative stress and accelerates mitochondrial degradation along the ripening process. The proapoptotic response in ES-treated samples was increased by 120.7%, with a cellular apoptosis rate 5-fold higher than that in control samples. This mitochondrial degradation is marked by increased ratios of Bax/Bcl-2 protein along the time course, indicating that apoptosis could contribute to the dry-cured ham processing. ES was shown to further down-regulate HSP27 and HSP70, establishing a direct correlation with the activation of mitochondrial apoptosis pathways, accompanied by dry-cured ham quality improvements. The findings show that ES plays a crucial role in facilitating the ripening of dry-cured ham by inducing mitochondrial apoptosis to reduce HSP expression. This knowledge not only explains the fundamental mechanisms behind myofibril degradation in dry-cured ham production but also offers a promising approach to enhance quality and consistency.

Self-assembled IR dye/mitoxantrone loaded Porphysomes nanosystem for enhanced combinatorial chemo-photothermal cancer therapy

Chemo-photothermal therapy (PTT) is an emerging non-invasive cancer treatment modality. Light-responsive porphysomes (DPP IR Mtx @Lipo NPs) nanosystems ablate breast cancer cells upon oxidative stress and hyperthermia. The unique self-assembled porphysomes were formed spherical shape in the size range of 150 ± 30 nm formed by the co-assembly of porphyrins along with IR 775 and chemotherapeutic drug, Mitoxantrone (Mtx), forming a camouflaged nanosystem (DPP IR Mtx @Lipo NPs, porphysomes). The advent of the prepared porphysomes aids in proper tuning of NIR absorbance improving singlet oxygen species generation among other anticancer drugs. The eminent release of DPP and adjuvant chemo-drug, Mitoxantrone from the self-assembled porphysomes is triggered by IR 775, a NIR photosensitizer upon laser irradiation. These multifunctional DPP IR Mtx @Lipo NPs have an efficient photothermal conversion efficiency of 65.8% as well as bioimaging properties. In-vitro studies in 2D and 3D models showed a significant cell death of 4T1 cells via the apoptotic pathway when irradiated with NIR laser, causing minimal damage to nearby healthy cells. DPP IR Mtx @Lipo NPs exhibited commingled PDT/PTT interdependent via NIR laser exposure, leading to mitochondrial disruption. Interestingly, the transient transfection using p53-GFP in cancer cells followed by DPP IR Mtx @Lipo NPs treatment causes rapid cell death. The activation of p53-dependent apoptosis pathways was vividly expressed, evidenced by the upregulation of Bax and increased pattern of Caspase-3 cleavage. This effect was pronounced upon transfection and induction with DPP IR Mtx @Lipo NPs, particularly in comparison to non-transfected malignant breast cancer 4T1 cells.

The Antihypertensive Effects and Mechanisms of Huotan Jiedu Tongluo Decoction in Rats with H-Type Hypertension.

H-type hypertension, which is a specific form of hypertension characterized by elevated plasma homocysteine (Hcy) levels, has become a major public health challenge worldwide. This study investigated the hypotensive effects and underlying mechanisms of Huotan Jiedu Tongluo decoction (HTJDTLD), a highly effective traditional Chinese medicine formula commonly used to treat vascular stenosis. Methionine was used to induce H-type hypertension in rats, and HTJDTLD was administered intragastrically. Then, the systolic and diastolic blood pressures of the caudal artery of rats were measured by noninvasive rat caudal manometry. Histological assessment of the aorta was performed by hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to measure Hcy levels, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting were used to determine the mRNA and protein levels of Glucose regulatory protein 78 (GRP78), Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), c-Jun N-terminalkinases (JNK), and caspase-3. The results showed that HTJDTLD significantly lowered blood pressure, alleviated histopathological lesions, and decreased Hcy levels after methionine treatment. Moreover, HTJDTLD significantly inhibited the gene and protein expression of GRP78, JNK, TRAF2, and caspase 3, which are involved mainly in the endoplasmic reticulum (ER) stress-induced apoptosis pathway. Overall, the results indicated that HTJDTLD had effective antihypertensive effects in rats with H-type hypertension and revealed the antihypertensive mechanisms associated with inhibition of ER stress-induced apoptosis pathway activation.

Involvement of Inflammatory Cytokines, Renal NaPi-IIa Cotransporter, and TRAIL Induced-Apoptosis in Experimental Malaria-Associated Acute Kidney Injury.

The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA was used to investigate the relationship among pro-inflammatory cytokines, alterations in renal function biomarkers, and the induction of the TRAIL apoptosis pathway during malaria-associated acute kidney injury (AKI). Renal function was evaluated through the measurement of plasma creatinine and blood urea nitrogen (BUN). The mRNA expression of several cytokines and NaPi-IIa was quantified. Kidney sections were examined and cytokine levels were assessed using cytometric bead array (CBA) assays. The presence of glomerular IgG deposits and apoptosis-related proteins were investigated using in situ immunofluorescence assays and quantitative real-time PCR, respectively. NaPi-IIa downregulation in the kidneys provided novel insights into the pathogenesis of hypophosphatemia during CM. Histopathological analysis revealed characteristic features of severe malaria-associated nephritis, including glomerular collapse and tubular alterations. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, were upregulated. The TRAIL apoptosis pathway was significantly activated, implicating its role in renal apoptosis. The observed alterations in renal biomarkers and the downregulation of NaPi-IIa shed light on potential mechanisms contributing to renal dysfunction in ECM. The intricate balance between pro- and anti-inflammatory cytokines, along with the activation of the TRAIL apoptosis pathway, highlights the complexity of malaria-associated AKI and provides new therapeutic targets.

Omega-3 polyunsaturated fatty acids play a protective role in a mouse model of Parkinson's disease by increasing intestinal inducible Treg cells.

Parkinson's disease (PD) is defined as a progressive neurodegenerative disease in middle-aged and elderly people. The therapeutic effect of ω-3 PUFAs in several neurodegenerative diseases has been well recognized. Nevertheless, whether nutrition supplementing ω-3 PUFAs exerts a neuroprotective role in PD remains elusive. Bioinformatics revealed 2D chemical structural formula of three components. Mice received indicated treatment with saline, MPTP or ω-3 PUFAs according to grouping. Behavioral function of mice was measured through motor tests such as rearing, akinesia, and rotarod tests. OFT test measured anxiety-like behaviors of mice. Western blotting and TUNEL staining measured dopaminergic fibers and neurons of mice. Western blotting measured inflammation and apoptosis-related protein levels in mouse tissue. FACS measured iTreg cell proportion in colon and brain tissues of mice. ω-3 PUFAs repaired MPTP-stimulated motor function damage in PD mice. ω-3 PUFAs mitigated MPTP-stimulated comorbid anxiety in PD mice. ω-3 PUFAs relieved MPTP-stimulated deficits of dopaminergic fibers and neurons in PD mice. ω-3 PUFAs repressed MPTP-stimulated inflammation and apoptosis pathway activation in PD mice. ω-3 PUFAs repaired MPTP-stimulated immune function damage in PD mice. ω-3 PUFAs exert a protective role in PD mice through alleviating motor function impairment and neuroinflammation by increasing intestinal inducible Treg cells, which may provide a new direction for seeking targeted therapy plans for PD in humans.

Hypoxia-Induced Myocardial Hypertrophy Companies with Apoptosis Enhancement and p38-MAPK Pathway Activation.

Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 25:186-196, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dtmax were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dtmax, and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.