Trends in Biochemical Sciences
ReviewCaspases: killer proteases
Abstract
Caspases (ysteinyl artate-specific protein) mediate highly specific proteolytic cleavage events in dying cells, which collectively manifest the apoptotic phenotype. The key and central role that these enzymes play in a biochemical cell-suicide pathway has been conserved throughout the evolution of multicellular eukaryotes.
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Cited by (2213)
Resveratrol alleviates heat-stress-induced impairment of the jejunal mucosa through TLR4/MAPK signaling pathway in black-boned chicken
2024, Poultry ScienceHeat stress in chickens caused by high temperatures in summer is a serious issue faced by the poultry industry globally, which reduces product quality. The aim of this study is to investigate the role of resveratrol in alleviating heat stress injury and inflammatory response of jejunal mucosa in black-boned chickens through TLR4/MAPK signaling pathway. In total, 240 black-boned chickens (28-day old) were randomly divided into 4 treatment groups as follows. The normal temperature (NT) and normal temperature with resveratrol (NT+Res) groups received a basal diet without and with 400 mg/kg resveratrol, respectively, and treated at 24℃ ± 2℃, 24 h/d. The high temperature (HT) and high temperature with resveratrol (HT+Res) groups received basal diet without and with 400 mg/kg resveratrol, respectively, and treated at 37℃ ± 2℃ for 8 h/d and 24°C ± 2°C for the rest of the time for 12 d. The results revealed the heat-stress responses impaired the villous structure of the jejunum, causing a rough and uneven surface of the jejunal villus, and local intestinal villi were even more prone to rupture. However, resveratrol significantly improved the morphology and structure of jejunal mucosa under heat stress. Heat stress increased the mRNA levels of toll-like receptor 4 (TLR4), c-Jun, c-fos, caspase-3, and p38 (P < 0.05), reduced mRNA level of Bcl-2, and reduced the expression of tight junction proteins Occludin, ZO-1, and Claudin1 (P < 0.05) in the jejunal mucosa. However, resveratrol inhibited the TLR4/ mitogen-activated protein kinase (MAPK) signaling pathway via downregulating TLR4, c-Jun, p38, and caspase-3 (P < 0.05); upregulating Bcl-2 (P < 0.05); decreasing the protein levels of MKK3, p53, and myeloid differentiation factor 88 (MYD88); and increasing the protein levels of Occludin, ZO-1, and Claudin1. In addition, it reduced the levels of JNK and p38 proteins (P < 0.05) and inflammatory factors like tumor necrosis factor-α (TNF-α) in the jejunal mucosa of black-boned chickens under heat stress. In conclusion, resveratrol may play a regulatory role in heat-stress-induced damage and inflammatory response in the intestinal mucosa of black-boned chickens under heat stress.
Effects of elevated temperature on 8-OHdG expression in the American oyster (Crassostrea virginica): Induction of oxidative stress biomarkers, cellular apoptosis, DNA damage and γH2AX signaling pathways
2023, Fish and Shellfish Immunology ReportsGlobal temperature is increasing due to anthropogenic activities and the effects of elevated temperature on DNA lesions are not well documented in marine organisms. The American oyster (Crassostrea virginica, an edible and commercially important marine mollusk) is an ideal shellfish species to study oxidative DNA lesions during heat stress. In this study, we examined the effects of elevated temperatures (24, 28, and 32 °C for one-week exposure) on heat shock protein-70 (HSP70, a biomarker of heat stress), 8‑hydroxy-2′-deoxyguanosine (8-OHdG, a biomarker of pro-mutagenic DNA lesion), double-stranded DNA (dsDNA), γ-histone family member X (γH2AX, a molecular biomarker of DNA damage), caspase-3 (CAS-3, a key enzyme of apoptotic pathway) and Bcl-2-associated X (BAX, an apoptosis regulator) protein and/or mRNA expressions in the gills of American oysters. Immunohistochemical and qRT-PCR results showed that HSP70, 8-OHdG, dsDNA, and γH2AX expressions in gills were significantly increased at high temperatures (28 and 32 °C) compared with control (24°C). In situ TUNEL analysis showed that the apoptotic cells in gill tissues were increased in heat-exposed oysters. Interestingly, the enhanced apoptotic cells were associated with increased CAS-3 and BAX mRNA and/or protein expressions, along with 8-OHdG levels in gills after heat exposure. Moreover, the extrapallial (EP) fluid (i.e., extracellular body fluid) protein concentrations were lower; however, the EP glucose levels were higher in heat-exposed oysters. Taken together, these results suggest that heat shock-driven oxidative stress alters extracellular body fluid conditions and induces cellular apoptosis and DNA damage, which may lead to increased 8-OHdG levels in cells/tissues in oysters.
Cell-cycle arrest and mitochondria-dependent apoptosis induction in T-47D cells by the capsular polysaccharide from the marine bacterium Kangiella japonica KMM 3897
2023, Carbohydrate PolymersIn this study, we reported the in vitro mechanisms of antiproliferative activity of capsular polysaccharide derived from marine Gram-negative bacteria Kangiella japonica KMM 3897 in human breast сarcinoma T-47D cells. Flow cytometric and Western blot analysis revealed that capsular polysaccharide effectively suppressed T-47D cell proliferation by inducing G0/G1 phase arrest and mitochondrial-dependent apoptosis. Moreover, polysaccharide influenced the ERK1/2 and p38 signaling pathways. The results of this study would enrich our understanding of the molecular mechanism of the anti-cancer activity of sulfated polysaccharides from marine Gram-negative bacteria.
Bioactive compounds and mechanism of Xianglian pill in the treatment of gastric cancer: Network pharmacology analysis and experimental validation
2023, Journal of EthnopharmacologyGastric cancer (GC) affects people's quality of life because of its high incidence rate and mortality. The Xianglian Pill (XLP) is a traditional Chinese medicine (TCM) prescription used to treat gastrointestinal (GI) diseases. Its anti-tumor effect has been found in recent years, but it's bioactive compounds and mechanism of action in treating GC are remain unknown.
This study reveals the bioactive compounds and mechanisms of XLP in the treatment of GC through network pharmacology analysis and experimental verification.
The main compounds in XLP were searched and the active compounds with anti-GC activity were selected. Compounds targets and GC- related targets were predicted, and common targets were obtained. Subsequently, a protein-protein interaction (PPI) network of common targets is constructed, while GO and KEGG enrichment analyses were performed on common targets. Finally, the anti-GC effects of active compounds in XLP were verified in GC cell lines MGC-803 and HGC-27 by wound healing assay, cell cycle assay, cell apoptosis assay and western blotting (WB) assay.
A total of 33 active compounds of XLP were obtained. MTT assay showed that dehydrocostus lactone (DHL) and berberrubine (BRB) had lower IC50 value in GC cells HGC-27 and MGC-803, and has a less inhibitory effect on normal gastric epithelial cells. Further, 73 common targets were obtained after the total target of DHL and BRB intersected with GC. Among them, CASP3, AKT1, SRC, STAT3,and CASP9 were the most associated genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vitro experiment revealed that DHL and BRB inhibited GC cell viability via inducing cell cycle arrest at G2/M phase, and promoting cell apoptosis by up-regulating the caspase3 expression and down-regulating the expression of Bcl2/Bax.
DHL and BRB are the two main anti-GC active compounds in XLP, and their mechanism is mainly to inhibit cell cycle and promote cell apoptosis.
Molecular mechanism of kidney damage caused by abamectin in carp: Oxidative stress, inflammation, mitochondrial damage, and apoptosis
2023, ToxicologyIndiscriminate use of pesticides not only leads to environmental pollution problems, but also causes poisoning of non-target organisms. Abamectin (ABM), a widely used insecticide worldwide, is of wide concern due to its persistence in the environment and its high toxicity to fish. The kidney, as a key organ for detoxification, is more susceptible to the effects of ABM. Unfortunately, few studies investigated the mechanisms behind this connection. In this study, carp was used as an indicator organism for toxicological studies to investigate renal damage caused by ABM residues in carp. In this work, carp were exposed to ABM (0, 3.005, and 12.02 μg/L) for 4 d and the nephrotoxicity was assessed. Histopathological findings revealed that ABM exposure induced kidney damage in carp, as well as an increase Creatinine and BUN levels. Meanwhile, ABM as a reactive oxygen species (ROS) stimulator, boosted ROS bursts and lowered antioxidant enzyme activity while activating the body's antioxidant system, the Nrf2-Keap1 signaling pathway. The accumulation of ROS can also lead to the imbalance of the body's oxidation system, leading to oxidative stress. At the same time, NF-κB signaling pathway associated with inflammation was activated, which regulated expression levels of inflammatory cytokines (TNF-α, IL-6, IL-1β, and iNOS increased, while IL-10 and TGF-β1 decreased). In addition, ABM exposure caused structural damage to kidney mitochondria of carp, resulting in decreased mitochondrial membrane potential and ATP production capacity, and mediated apoptosis through endogenous pathways Bax/Bcl-2/Caspase-9/Caspase-3. In conclusion, ABM caused kidney damage in carp by inducing oxidative stress, inflammation, and apoptosis through mitochondrial pathway. These findings will be useful for future research into molecular mechanisms of ABM-induced nephrotoxicity in aquatic organisms.
p53 upregulated by HIF-1α promotes gastric mucosal epithelial cells apoptosis in portal hypertensive gastropathy
2023, Digestive and Liver DiseasePortal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of gastrointestinal bleeding. Mucosal apoptosis is an essential pathological feature of PHG. However, whether HIF-1α and p53 are involved in mucosal apoptosis and whether HIF-1α induces PHG by mediating p53 remains unclear.
Gastric mucosal injury and apoptosis were examined in PHG patients and animal models. The mechanisms of HIF-1α- and p53-mediated apoptosis were analyzed. The GES-1 cell line was used to elucidate the underlying mechanisms using siRNA knockdown of HIF-1α and p53 in a hypoxic environment in vitro.
Epithelial apoptosis, HIF-1α, and p53 were markedly induced in the gastric mucosa of PHG. Apoptosis was attenuated in mice with HIF-1α- and p53-specific inhibitors. Apoptotic signaling factors were markedly induced in the gastric mucosa of PHG. Inhibition of p53 demonstrably attenuated the mucosal apoptosis; however, it did not affect HIF-1α expression. Conversely, targeted deletion of HIF-1α significantly inhibited p53 expression and attenuated the injury and p53-mediated apoptosis. Bax and Bcl-2 expression can be upregulated and downregulated by p53, respectively, to increasecleaved caspase-3 expression, which can be regulated by HIF-1α.
These results indicate that HIF-1α regulates the p53-induced mucosal epithelial apoptotic signaling pathway and that HIF-1α and p53 are potential therapeutic targets for PHG.