Death Receptor-mediated Pathway Research Articles

Research progress on the regulatory cell death of osteoblasts in periodontitis

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of alveolar bone. The most critical mechanism underlying alveolar bone destruction is the imbalance of bone homeostasis, where osteoblast-mediated bone matrix synthesis plays an important role in regulating bone homeostasis. Regulated cell death is instrumental in both the inflammatory microenvironment and the regulation of bone homeostasis. Chronic inflammation, oxidative stress, and other factors can be directly involved in mitochondrial and death receptor-mediated signaling pathways, modulating B-cell lymphoma 2 family proteins and cysteine aspartic acid specific protease (caspase) activity, thereby affecting osteoblast apoptosis and alveolar bone homeostasis. Chronic inflammation and cellular damage induce osteoblast necroptosis via the RIPK1/RIPK3/MLKL signaling pathway, exacerbating the inflammatory response and accelerating alveolar bone destruction. Stimuli such as pathogenic microorganisms and cellular injury may also activate caspase-1-dependent or independent signaling pathways and gasdermin D family proteins, promoting osteoblast pyroptosis and releasing pro-inflammatory cytokines to mediate alveolar bone damage. Iron overload and lipid peroxidation in periodontitis can trigger ferroptosis in osteoblasts, impacting their survival and function, ultimately leading to bone homeostasis imbalance. This article focuses on the mechanism of periodontal disease affecting bone homeostasis through regulatory cell death, aiming to provide research evidence for the treatment of periodontitis and alveolar bone homeostasis imbalance.

An Insight Into Experimental and Theoretical Investigation of Structure, Photophysical Property by ESIPT Processes and Biological Activities of Schiff Base Copper Complex

ABSTRACTA novel Schiff base (BSSMO) and its copper complex have been synthesized, and their structure was delineated using single crystal XRD studies. Computational techniques were used to design and evaluate BSSMO‐based luminophores, revealing a significant intramolecular hydrogen bond within the molecule. Understanding ESIPT is crucial for optimizing photophysical and luminophore properties of organic molecules, especially for advancing optoelectronic devices. The study also explored the mechanisms of GSIPT and ESIPT for these BSSMO‐based luminophores using transition state theory, charge distribution, molecular orbital analysis, and quantum theory of atoms in molecules. Results advocated that BSSMO‐L2 exhibits higher absorption compared with BSSMO‐L1 and the same trend is observed in emission spectral studies. However, the intensity of enol emissions in BSSMO‐L2 is lower than that of keto (BSSMO‐L3) emissions and the S1 (Keto form) emission of BSSMO‐L3 shows significantly larger values, making it attractive for optoelectronic devices. The findings offer valuable insights for the development of ESIPT emitters with distinct photophysical properties. The in silico antidiabetic study of BSSMO‐L2 explores the interaction with PPAR‐γ protein, revealing a moderate affinity and stable complex, enhancing its bio‐potential for future applications. The in vitro anticancer study of Cu‐BSSMO‐L2 complex shows a potential anticancer effect through mitochondrial and extrinsic death receptor mediated pathways. These insights contribute to the design of novel benzenesulfonamide‐based bioactive molecules.

A Mutation Losing an RBP-Binding Site in the LncRNA NORSF Transcript Influences Granulosa Cell Apoptosis and Sow Fertility.

Sow fertility is an economically important quantitative trait. Hundreds of quantitative trait loci (QTLs) containing tens of thousands of potential candidate genes are excavated. However, among these genes, non-coding RNAs including long non-coding RNAs (lncRNAs) are often overlooked. Here, it is reported that NORSF is a novel causal lncRNA for sow fertility traits in QTLs. QTLs are characterized for sow fertility traits at the genome-wide level and identified 4,630 potential candidate lncRNAs, with 13 differentially expressed during sow follicular atresia. NORSF, a lncRNA that involved in sow granulosa cell (sGC) function, is identified as a candidate gene for sow fertility traits as a G to A transversion at 128nt in its transcript is shown to be markedly associated with sow fertility traits. Mechanistically, after forming the RNA:dsDNA triplexes with the promoter of Caspase8, NORSF transcript with allele G binds to an RNA-binding protein (RBP) NR2C1 and recruits it to the promoter of Caspase8, to induce Caspase8 transcription in sGCs. Functionally, this leads to a loss of inducing effect of NORSF on sGC apoptosis by inactivating the death receptor-mediated apoptotic pathway. This study identified a novel causal lncRNA that can be used for the genetic improvement of sow fertility traits.

Behavioral and biochemical responses of the marine polychaete Perinereis aibuhitensis to 2-ethylhexyl-4-methoxycinnamate (EHMC) exposure

2-ethylhexyl-4-methoxycinnamate (EHMC) is a commonly used UV filter, and is receiving increasing concerns due to its ubiquitous occurrence in a variety of environmental media and potential adverse effects. This study was aimed to assess the ecotoxicological potentials of EHMC on the marine polychaete Perinereis aibuhitensis. To this end, ragworms were exposed to 2, 20, 200 μg/L EHMC for 14 days and multiple toxicological endpoints were investigated. The results showed that EHMC significantly reduced burrowing rate, but did not affect AChE activity. Exposure to EHMC significantly elevated the activities of SOD and CAT and decreased the levels of lipid peroxidation. Besides, the induction of AKP activity indicated a stimulated immune response in the ragworms when exposed to high concentration of EHMC. Furthermore, the upregulated expression of caspase-8 suggested that EHMC might induce apoptosis in ragworms via the death receptor-mediated extrinsic pathway. Our findings highlight the potential environmental risks of EHMC to marine ecosystems.

Optogenetic induction of caspase-8 mediated apoptosis by employing Arabidopsis cryptochrome 2

Apoptosis, a programmed cell death mechanism, is a regulatory process controlling cell proliferation as cells undergo demise. Caspase-8 serves as a pivotal apoptosis-inducing factor that initiates the death receptor-mediated apoptosis pathway. In this investigation, we have devised an optogenetic method to swiftly modulate caspase-8 activation in response to blue light. The cornerstone of our optogenetic tool relies on the PHR domain of Arabidopsis thaliana cryptochrome 2, which self-oligomerizes upon exposure to blue light. In this study, we have developed two optogenetic approaches for rapidly controlling caspase-8 activation in response to blue light in cellular systems. The first strategy, denoted as Opto-Casp8-V1, entails the fusion expression of the Arabidopsis blue light receptor CRY2 N-terminal PHR domain with caspase-8. The second strategy, referred to as Opto-Casp8-V2, involves the independent fusion expression of caspase-8 with the PHR domain and the CRY2 blue light-interacting protein CIB1 N-terminal CIB1N. Upon induction with blue light, PHR undergoes aggregation, leading to caspase-8 aggregation. Additionally, the blue light-dependent interaction between PHR and CIB1N also results in caspase-8 aggregation. We have validated these strategies in both HEK293T and HeLa cells. The findings reveal that both strategies are capable of inducing apoptosis, with Opto-Casp8-V2 demonstrating significantly superior efficiency compared to Opto-Casp8-V1.

Inhibition of Cell Proliferation and Cell Death by Apigetrin through Death Receptor-Mediated Pathway in Hepatocellular Cancer Cells.

Epidemiologic research recommends using flavonoids in the diet due to their overall health benefits. Apigetrin (Apigenin 7-O-glucoside) is a glycoside phytonutrient found in fruits and vegetables and known for different biological activities such as antioxidant and anti-inflammatory properties. Hepatocellular cancer (HCC) is a major health concern because of its adverse prognosis and side effects of chemotherapeutic agents. In the present study, we determine the impact of apigetrin on HepG2 cells and its cell death mechanism. Apigetrin reduced HepG2 cell proliferation with morphological changes and floating cells in treated cells. Colony formation and wound healing assays showed a reduced cell number in treatment groups. Further, we checked for the cell cycle through flow cytometry to understand the cell death mechanism. Apigetrin induced G2/M phase arrest in HepG2 cells by regulating Cyclin B1 and CDK1 protein levels in HepG2 cells. Annexin V and propidium iodide (PI) staining was performed to confirm the apoptotic cell population in treated groups. At the higher concentration, apigetrin showed a late apoptotic population in HepG2 cells. Chromatin condensation was also found in the treatment groups. Western blot analysis showed an increased expression of extrinsic apoptotic proteins such as FasL, Cleaved caspase 8, Cleaved caspase 3, and cleavage of PARP. In comparison, intrinsic apoptotic pathway markers showed no changes in Bax, Bcl-xL, and Cleaved caspase 9. Altogether, these findings strongly indicate that apigetrin causes cell death in HepG2 cells through the extrinsic apoptotic pathway, and that the intrinsic/mitochondrial pathway is not involved.

The cellular uptake of Cordyceps sinensis exopolysaccharide‑selenium nanoparticles and their induced apoptosis of HepG2 cells via mitochondria- and death receptor-mediated pathways

This wok investigated the effects of Cordyceps sinensis exopolysaccharide‑selenium nanoparticles (EPS-SeNPs), EPS-Se-1, EPS-Se-2, EPS-Se-3, and EPS-Se-4) with particle sizes (79–124 nm) and Se contents (20.11–40.80 μg/mg) on endocytosis and antitumor activity against human hepatocellular carcinoma (HepG2) cells and revealed the apoptosis-related mechanisms. EPS-SeNPs inhibited HepG2 cells proliferation in a dose and Se content-dependent manner by disrupting cell membrane and mitochondrial integrity, promoting reactive oxygen species production. EPS-SeNPs were endocytosed by HepG2 cells through a clathrin-mediated pathway and followed the quasi-first-order kinetics model, indicating physical adsorption played a dominant role in cellular uptake behavior of EPS-SeNPs. Notably, EPS-Se-3 with the lowest particle size (79 nm) showed the highest antitumor activity and the strongest ability to promote cell apoptosis. Western blotting results revealed that EPS-Se-3 increased expressions of Bax, Cytochrome c, cleaved caspase-9, cleaved caspase-3, Fas, p53, and cleaved caspase-8, while decreased the expressions of Bcl-2 and PARP, as contrast to that of control. Overall, EPS-SeNPs induced cell apoptosis through intrinsic mitochondria-mediated and extrinsic death receptor-mediated pathways.

The apoptotic effects of soybean agglutinin were induced through three different signal pathways by down-regulating cytoskeleton proteins in IPEC-J2 cells

Soybean agglutinin (SBA) is a main anti-nutritional factor in soybean. SBA exhibits its anti-nutritional functions by binding to intestinal epithelial cells. Keratin8 (KRT8), Keratin18 (KRT18) and Actin (ACTA) are the representative SBA-specific binding proteins. Such cytoskeletal proteins act a crucial role in different cell activities. However, limited reports reveal what the signal transduction pathway of apoptosis caused by SBA when binding to KRT8, KRT18 and ACTA. We aimed to evaluate the effects of SBA on cell apoptosis and the expression of the cytoskeletal protein (KRT8, KRT18 and ACTA), reveal the roles of these cytoskeletal proteins or their combinations on SBA-induced cell apoptosis in IPEC-J2 cell line, evaluate the influences of SBA on the mitochondria, endoplasmic reticulum stress and death receptor-mediated apoptosis signal pathway and to show the roles of KRT8, KRT18 and ACTA in different apoptosis signal pathways induced by SBA. The results showed that SBA induced the IPEC-J2 cell apoptosis and decreased the mRNA expression of KRT8, KRT18 and ACTA (p < 0.05). The degree of effect of three cytoskeleton proteins on cell apoptosis was ACTA > KRT8 > KRT18. The roles of these three cytoskeletal proteins on IPEC-J2 apoptotic rates had a certain accumulation effect. SBA up-regulated mitochondrial fission variant protein (FIS1) and fusion protein (Mfn2) promoted CytC and AIF in mitochondria to enter the cytoplasm, activated caspase-9 and caspase-3, damaged or declined mitochondrial function and reduced ATP synthesis (p < 0.05). Also, SBA up-regulated the expression of GRP78, XBP-1, eIF2α, p-eIF2α and CHOP (p < 0.05), down-regulated the expression level of ASK1 protein (p < 0.05). SBA led to the recruitment of FADD to the cytoplasmic membrane and increased the expression of FasL, resulting in caspase-8 processing. SBA up-regulated the expression level of Bax protein and decreased cytosolic Bcl-2 and Bid (p < 0.05). In addition, there was a significant negative correlation between the gene expression of cytoskeleton proteins and apoptosis, as well as the expression of key proteins of apoptosis-related signal transduction pathways. In conclusion, SBA induced the activation of the mitochondria, endoplasmic reticulum stress and the death receptor-mediated apoptosis signal pathway and the crosstalk between them. The effect of SBA on these three pathways was mainly exhibited via down-regulation of the mRNA expression of the three cytoskeletal expressions. This study elucidates the molecular mechanism and signaling pathway of SBA that lead to apoptosis from the perspective of cell biology and molecular biology and provides a new perspective on the toxicity mechanism of other food-derived anti-nutrients, medical gastrointestinal health and related cancer treatment.

Abstract 2739: Genetic modification of mesothelial cells with full length membrane-bound TRAIL for ovarian cancer treatment

Abstract Mesothelial cells lining the peritoneum play an important role in epithelial ovarian cancer (EOC) locoregional spreading by promoting cancer cell proliferation, adhesion, and invasion into the peritoneal wall and organs. Peritoneal dissemination represents a critical first step in EOC progression, and we posit that genetic modification of mesothelial cells with full length membrane-bound TRAIL is a practical approach to intervention and will provide local control of EOC progression. Here, we stably overexpressed full length tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with a lentiviral vector in the immortalized mesothelial cell line, MeT5A. Overexpression of TRAIL on the cell surface of MeT5A was confirmed by flow cytometry, and no obvious changes in proliferation or morphology were observed when MeT5A/TRAIL cells were grown in culture. In co-culture experiments, however, MeT5A/TRAIL cells induced apoptosis of surrounding cancer cells and continued proliferating until the culture surface was confluent with mesothelial cells alone. Interestingly, MeT5A/TRAIL not only induced cell death of TRAIL-sensitive cancer cells, such as OVCAR3 and H460, but it also induced significant apoptosis of cancer cells previously deemed resistant to soluble TRAIL, such as A2780, and OVCAR8. This finding suggests that full length TRAIL (amino acid 1-281) expressed on the cell surface is capable of activating death receptor-mediated apoptotic pathways that are not reactive to the soluble form of TRAIL (amino acid 114-281), which was previously developed as a cancer therapeutic and thoroughly evaluated in animal models and clinical trials. When co-cultured with MeT5A/TRAIL, primary ovarian cancer cells from patients also underwent apoptosis as detected by flow cytometry and the upregulation of cleaved caspase-3, caspase-8, caspase-9, PARP, and Bid on Western blots. Next, we assessed the anticancer potential of mesothelial cells expressing membrane-bound TRAIL in a NSG xenograft mouse model of ovarian cancer. Intraperitoneal inoculation of MeT5A/TRAIL cells significantly reduced overall cancer burden in mice where OVCAR3, A2780, and OVCAR8 cancer cells were pre-established. Intraperitoneal gene delivery of TRAIL to resident peritoneal mesothelial cells utilizing a conditionally replicative adenovirus vector also prolonged survival of NSG mice bearing A2780 xenografts. Our data suggest that genetic modification of mesothelial cells with full length membrane-bound TRAIL is feasible and has therapeutic potential for disrupting EOC progression. Citation Format: Er Yue, Tonya Walser, Tamara Mirzapoiazova, Ravi Salgia, Edward W. Wang. Genetic modification of mesothelial cells with full length membrane-bound TRAIL for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2739.

Toxic effects of zinc oxide nanoparticles as a food additive in goat mammary epithelial cells

Zinc oxide nanoparticles (ZnO NPs) have recently been used as food preservatives and additives because of their good antibacterial and nutritional functions. This study performed RNA-seq analyses to evaluate the potential toxicity of ZnO NPs on goat mammary epithelial cells (GMECs) in vitro. Our results suggested that the ZnO NP treatment significantly reduced GMEC viability in a time- and dose-dependent manner. Transcriptomic analysis showed that ZnO NP exposure changed the expression levels of more than 500 genes in GMECs, including various biological pathways. We observed that decreased mitochondrial membrane potential caused mitochondrial dysfunction. Further study indicated that the treatment of cells with ZnO NPs resulted in the accumulation of reactive oxygen species (ROS), which led to oxidative stress. Meanwhile, the expression of genes (TNFα, TNFR1, FADD, Caspase 8 and Caspase 6) associated with the death receptor pathway was upregulated, which indicated the death receptor-mediated extrinsic apoptosis pathway was activated. Moreover, the expression levels of Bax, Cytc, Caspase 3 and Caspase 9 were upregulated, while the expression levels of Bcl2 were downregulated, which indicated mitochondria-mediated intrinsic apoptosis pathway was activated. More notably, ZnO NP exposure increased the expression levels of ER stress-related genes (PERK, ATF4, eIF2α and CHOP) and proteins (p-PERK, p-eIF2α, PERK and CHOP). Furthermore, gene ontology (GO) terms and genes related to autophagy were altered, suggesting that exposure to ZnO NPs might activate autophagy in GMECs. In summary, our findings showed that ZnO NPs could exert significant toxic effects on GMECs through multiple mechanisms. These pathways are related to each other and influence each other to participate in ZnO NPs-induced the damage of GMECs. Thus, their safe use in the feed and food industry should be considered. Meanwhile, RNA-seq might represent a new method of assessing the toxicity mechanisms of nanomaterials.

Arctigenin induces caspase-dependent apoptosis in FaDu human pharyngeal carcinoma cells.

The present study was carried out to investigate the effect of Arctigenin on cell growth and the mechanism of cell death elicited by Arctigenin were examined in FaDu human pharyngeal carcinoma cells. To determine the apoptotic activity of Arctigenin in FaDu human pharyngeal carcinoma cells, cell viability assay, DAPI staining, caspase activation analysis, and immunoblotting were performed. Arctigenin inhibited the growth of cells in a dose-dependent manner and induced nuclear condensation and fragmentation. Arctigenin-treated cells showed caspase-3/7 activation and increased apoptosis versus control cells. FasL, a death ligand associated with extrinsic apoptotic signaling pathways, was up-regulated by Arctigenin treatment. Moreover, caspase-8, a part of the extrinsic apoptotic pathway, was activated by Arctigenin treatments. Expressions of anti-apoptotic factors such as Bcl-2 and Bcl-xL, components of the mitochondria-dependent intrinsic apoptosis pathway, significantly decreased following Arctigenin treatment. The expressions of pro-apoptotic factors such as BAX, BAD and caspase-9, and tumor suppressor -53 increased by Arctigenin treatments. In addition, Arctigenin activated caspase-3 and poly (ADP-ribose) polymerase (PARP) induced cell death. Arctigenin also inhibited the proliferation of FaDu cells by the suppression of p38, NF-κB, and Akt signaling pathways. These results suggest that Arctigenin may inhibit cell proliferation and induce apoptotic cell death in FaDu human pharyngeal carcinoma cells through both the mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway.

Carboxyl Group-Modified Myoglobin Induces TNF-α-Mediated Apoptosis in Leukemia Cells.

Previous studies have shown that chemical modification may increase the activity of proteins or confer novel activity to proteins. Some studies have indicated that myoglobin (Mb) is cytotoxic; however, the underlying mechanisms remain unclear. In this study, we investigated whether chemical modification of the carboxyl group by semicarbazide could promote the Mb cytotoxicity in human leukemia U937 cells and the underlying mechanism of semicarbazide-modified myoglobin (SEM-Mb)-induced U937 cell death. The semicarbazide-modified Mb (SEM-Mb) induced U937 cell apoptosis via the production of cleaved caspase-8 and t-Bid, while silencing of FADD abolished this effect. These findings suggest that SEM-Mb can induce U937 cell death by activating the death receptor-mediated pathway. The SEM-Mb inhibited miR-99a expression, leading to increased NOX4 mRNA and protein expression, which promoted SIRT3 degradation, and, in turn, induced ROS-mediated p38 MAPK phosphorylation. Activated p38 MAPK stimulated miR-29a-dependent tristetraprolin (TTP) mRNA decay. Downregulation of TTP slowed TNF-α mRNA turnover, thereby increasing TNF-α protein expression. The SEM-Mb-induced decrease in cell viability and TNF-α upregulation were alleviated by abrogating the NOX4/SIRT3/ROS/p38 MAPK axis or ectopic expression of TTP. Taken together, our results demonstrated that the NOX4/SIRT3/p38 MAPK/TTP axis induces TNF-α-mediated apoptosis in U937 cells following SEM-Mb treatment. A pathway regulating p38 MAPK-mediated TNF-α expression also explains the cytotoxicity of SEM-Mb in the human leukemia cell lines HL-60, THP-1, K562, Jurkat, and ABT-199-resistant U937. Furthermore, these findings suggest that the carboxyl group-modified Mb is a potential structural template for the generation of tumoricidal proteins.

The myth of cobra venom cytotoxin: More than just direct cytolytic actions.

Cobra venom cytotoxin (CTX) is a non-enzymatic three-finger toxin that constitutes 40–60% of cobra venom. Thus, it plays an important role in the pathophysiology of cobra envenomation, especially in local dermonecrosis. The three-finger hydrophobic loops of CTX determine the cytotoxicity. Nevertheless, the actual mechanisms of cytotoxicity are not fully elucidated as they involve not only cytolytic actions but also intracellular signalling-mediated cell death pathways. Furthermore, the possible transition cell death pattern remains to be explored. The actual molecular mechanisms require further studies to unveil the relationship between different CTXs from different cobra species and cell types which may result in differential cell death patterns. Here, we discuss the biophysical interaction of CTX with the cell membrane involving four binding modes: electrostatic interaction, hydrophobic partitioning, isotropic phase, and oligomerisation. Oligomerisation of CTX causes pore formation in the membrane lipid bilayer. Additionally, the CTX-induced apoptotic pathway can be executed via death receptor-mediated extrinsic pathways and mitochondrial-mediated intrinsic pathways. We also discuss lysosomal-mediated necrosis and the occurrence of necroptosis following CTX action. Collectively, we provided an insight into concentration-dependent transition of cell death pattern which involves different mechanistic actions. This contributes a new direction for further investigation of cytotoxic pathways activated by the CTXs for future development of biotherapeutics targeting pathological effects caused by CTX.

Dehydrocrenatidine Induces Liver Cancer Cell Apoptosis by Suppressing JNK-Mediated Signaling

Liver cancer is a leading cause of death worldwide. Despite advancement in therapeutic interventions, liver cancer is associated with poor prognosis because of highly lethal characteristics and high recurrence rate. In the present study, the anticancer potential of a plant-based alkaloid namely dehydrocrenatidine has been evaluated in human liver cancer cells. The study findings revealed that dehydrocrenatidine reduced cancer cell viability by arresting cell cycle at G2/M phase and activating mitochondria-mediated and death receptor-mediated apoptotic pathways. Specifically, dehydrocrenatidine significantly increased the expression of extrinsic pathway components (FAS, DR5, FADD, and TRADD) as well as intrinsic pathway components (Bax and Bim L/S) in liver cancer cells. In addition, dehydrocrenatidine significantly increased the cleavage and activation of PARP and caspases 3, 8, and 9. The analysis of upstream signaling pathways revealed that dehydrocrenatidine induced caspase-mediated apoptosis by suppressing the phosphorylation of JNK1/2. Taken together, the study identifies dehydrocrenatidine as a potent anticancer agent that can be use clinically to inhibit the proliferation of human liver cancer cells.

Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated, and cell cycle arrest pathways.

The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 >180μM in the dark to 1.3± 0.7μM following 10 min of light irradiation (425nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death.

Natural Products Modulate Cell Apoptosis: A Promising Way for the Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease impacting patients’ quality of life and imposing heavy societal and economic burdens. Apoptosis of intestinal epithelial cells (IECs) has been considered an early event during the onset of UC and plays a crucial role in disease development. Thus, effectively inhibiting apoptosis of IECs is of critical significance for the clinical management of UC, presenting a potential direction for the research and development of pharmacotherapeutic agents. In recent years, research on the ameliorative effects of natural products on UC through inhibiting IECs apoptosis has attracted increasing attention and made remarkable achievements in ameliorating UC. In this review, we summarized the currently available research about the anti-apoptotic effects of natural products on UC and its mechanisms involving the death-receptor mediated pathway, mitochondrial-dependent pathway, ERS-mediated pathway, MAPK-mediated pathway, NF-κB mediated pathway, P13k/Akt pathway, JAK/STAT3 pathway, and NLRP3/ASC/Caspase-1 pathway. Hopefully, this review may yield useful information about the anti-apoptotic effects of natural products on UC and their potential molecular mechanisms and provide helpful insights for further investigations.

Ginsenoside Rb1 Attenuates Triptolide-Induced Cytotoxicity in HL-7702 Cells via the Activation of Keap1/Nrf2/ARE Pathway

Triptolide (TP) is the major bioactive compound extracted from Tripterygium wilfordii Hook F. It exerts anti-inflammatory, antirheumatic, antineoplastic, and neuroprotective effects. However, the severe hepatotoxicity induced by TP limits its clinical application. Ginsenoside Rb1 has been reported to possess potential hepatoprotective effects, but its mechanism has not been fully investigated. This study was aimed at investigating the effect of ginsenoside Rb1 against TP-induced cytotoxicity in HL-7702 cells, as well as the underlying mechanism. The results revealed that ginsenoside Rb1 effectively reversed TP-induced cytotoxicity in HL-7702 cells. Apoptosis induced by TP was suppressed by ginsenoside Rb1 via inhibition of death receptor-mediated apoptotic pathway and mitochondrial-dependent apoptotic pathway. Pretreatment with ginsenoside Rb1 significantly reduced Bax/Bcl-2 ratio and down-regulated the expression of Fas, cleaved poly ADP-ribose polymerase (PARP), cleaved caspase-3, and -9. Furthermore, ginsenoside Rb1 reversed TP-induced cell cycle arrest in HL-7702 cells at S and G2/M phase, via upregulation of the expressions of cyclin-dependent kinase 2 (CDK2), cyclin E, cyclin A, and downregulation of the expressions of p53, p21, and p-p53. Ginsenoside Rb1 increased glutathione (GSH) and superoxide dismutase (SOD) levels, but decreased the reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Pretreatment with ginsenoside Rb1 enhanced the expression levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), total Nrf2, NAD(P)H: quinone oxidoreductases-1 (NQO-1), heme oxygenase-1 (HO-1), and Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex. Therefore, ginsenoside Rb1 effectively alleviates TP-induced cytotoxicity in HL-7702 cells through activation of the Keap1/Nrf2/ARE antioxidant pathway.

Health promoting effects of fermented foods against cancer: an updated concise review

The global cancer burden has increased, and about 9.6 million cancer-related deaths were recorded in 2018. Genetic makeup, unhealthy lifestyle, urbanization, obesity, and dietary preferences are key risk factors associated with cancer incidence and development. Next to lung cancer, colorectal cancer is the most perilous cancer type in terms of mortality rate. Diet plays a major role in colorectal cancer risk. The consumption of vegetables, unprocessed cereals, fish product, and fermented foods are associated with lower cancer risk, while raw and processed red meats and refined foods are associated with increased cancer risk. The anti-cancer properties of fermented foods and their possible mechanisms are summarized in this review. Some studies indicated that the consumption of fermented foods reduced the risk of cancer and improved the health status of cancer patients. However, some other research findings suggested that the intake of fermented foods was not associated with reduced cancer risk. Several signaling pathways (p38 MAPK, ERK1/2, energy deprivation, and death-receptor mediated pathways) are involved in the anti-proliferative and growth suppressive properties of fermented foods. Overall, the literature survey suggested that the consumption of fermented foods might reduce cancer risk and improve health status in association with other factors, such as genetics and healthy lifestyle.

Circ_0005033 is an oncogene in laryngeal squamous cell carcinoma and regulates cell progression and Cisplatin sensitivity via miR-107/IGF1R axis.

Transcriptome expression profiles of laryngeal squamous cell carcinoma (LSCC) are altered, and we aimed to investigate expression and role of hsa_circ_0005033 (circ_0005033), microRNA (miR)-107 and insulin-like growth factor 1 receptor (IGF1R) in LSCC. Real-time PCR, western blotting and immunohistochemistry detected RNA and protein expression levels. Functional assays were performed using MTT assay, EdU assay, apoptosis assay, flow cytometry, Transwell assay, and xenograft tumor model. Direct interaction was predicted by Starbase algorithm and validated by dual-luciferase reporter assay and RNA immunoprecipitation. Expression of circ_0005033 was substantially upregulated in LSCC tissues and cells, and allied with miR-107 downregulation and IGF1R upregulation. Circ_0005033 showed a closed-loop structure and long half-life. Essentially, circ_0005033 and IGF1R were competing endogenous RNAs for miR-107 via target binding. Silencing circ_0005033 facilitated apoptosis rate and lowered cell viability, proliferation, migration and invasion of LSCC cells, as well as delayed xenograft tumor growth. Allied with that, cleaved-caspase 3/8/9 expression was elevated via death receptor-mediated and mitochondrial pathways, and expression of matrix metalloproteinase-2 (MMP2), MMP9, cyclin D1 and proliferating cell nuclear antigen was decreased. Moreover, Cisplatin-induced inhibition of cell viability was exacerbated by inhibiting circ_0005033. These functional effects of circ_0005033 depression were consistent with those of miR-107 overexpression. Furthermore, depleting miR-107 and restoring IGF1R abated the effects of circ_0005033 knockdown and miR-107 overexpression, respectively. Circ_0005033 was oncogenic in LSCC by regulating cell progression and Cisplatin sensitivity at least via miR-107/IGF1R axis.

Calcium alleviates fluoride-induced kidney damage via FAS/FASL, TNFR/TNF, DR5/TRAIL pathways in rats

Long-term excessive intake of fluoride (F) can cause osseous and non-osseous damage. The kidney is the main fluoride excretion organ of the body. This study aimed to explore whether dietary calcium (Ca) supplementation can alleviate kidney damage caused by fluorosis and to further investigate the effects of Ca on the mitigation mechanism of renal cell apoptosis triggered by F. We evaluated the histopathological structure, renal function indicators, and gene and protein expression levels of death receptor-mediated apoptosis pathways in Sprague Dawley (SD) rats treated with sodium fluoride (NaF) and/or calcium carbonate (CaCO3) for 120 days. The results showed that 100 mg/L NaF induced kidney histopathological injury and apoptosis, increased the concentrations of Creatinine (CRE), uric acid (UA), blood urea nitrogen (BUN), potassium (K), phosphorus (P) and F (p < 0.05), and decrease the level of serum magnesium (Mg) (p < 0.05). Moreover, NaF increased the mRNA and protein expression levels of Fas cell surface death receptor (FAS), tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Caspase 8, Caspase 3 and poly ADP-ribose polymerase (PARP) (p < 0.01), which finally activated the death receptor pathway. Inversely, Ca supplementation reversed the decrease of CRE, BUN, UA, F and P levels induced by F, alleviated histopathological damage and apoptosis, and reduced the gene and protein expression levels of death receptor pathway-related markers. In conclusion, 1% Ca alleviates F-induced kidney apoptosis through FAS/FASL, TNFR/TNF, DR5/TRAIL signaling pathways.