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Triple‐negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by the absence of estrogen and progesterone receptors and minimal HER2 expression, restricting the available treatment options. Actinobacteria have emerged as promising sources of anticancer compounds because of their remarkable ability to produce beneficial compounds. This study aimed to evaluate the antitumor effects of the halophilic Streptomyces violaceorubidus M4 extract on TNBC both in vitro and in vivo. The extracted compounds were analyzed by LC‐MS. MTT and annexin‐PI assays were used to assess the apoptosis‐inducing effects of the compounds on MDA‐MB‐231 and MCF‐10A cells. The expression of apoptosis‐related BAX, BCL2, P53, CASPASE‐8, and CASPASE‐9 genes was analyzed using Real‐time PCR. A TNBC mouse model was established using 4T1 cell transplantation, and the animals received the extract intravenously for 21 days. S. violaceorubidus M4 contained bioactive compounds, including amino acids, carboxylic acids, coumarins, isoflavones, phosphatidylcholine, tetrahydroxyanthraquinone, and flavonoids. The extract demonstrated selective cytotoxicity against MDA‐MB‐231 cells, with an IC50 of 48.04 μg/mL after 48 h, while the IC50 for MCF‐10A cells was 132 μg/mL. The reduction in Cas‐9 expression alongside the elevation of Cas‐8 and P53 expression suggests the participation of the extrinsic pathway in the process of apoptosis. Histopathological evaluation of tumor tissues from mouse models showed that the extract injection reduced the number of mitotic cells, nuclear pleomorphism, and angiogenesis in tumor tissue. This study suggests that S. violaceorubidus M4 has a pronounced anticancer effect on TNBC and can be considered for the production of anticancer substances. The antitumor effects of the halophilic Streptomyces violaceorubidus M4 extract on triple‐negative breast cancer, highlighting its selective cytotoxicity and apoptosis‐inducing properties. Key findings include the identification of bioactive compounds and their impact on apoptosis‐related gene expression, as well as significant reductions in tumor cell proliferation in a mouse model.

Abstract Caspases play a vital role during apoptosis. In addition to apoptosis, caspases play a role in cytokine gene induction and work to inhibit apoptosis. In order for individuals to thrive with useful tissue growth, the rate of cell growth and division must surpass the rate of cell division. It is well established that excessive cell death of embryonic cells is a vital process occurring before structural abnormalities, regardless of their nature. Here we describe a 13-month-old male patient with a 4.7Mb interstitial duplication of chromosome 2q33.1. This duplication was identified by chromosomal microarray (CMA) which is the first-tier clinical diagnostic test to identify copy number variants (CNVs) for patients with unexplained developmental delay or intellectual disability. This patient presents with global developmental delay, especially in speech, language, hypotonia, and bilateral simian creases. The duplicated region contains several disease-causing genes. We believe that the phenotype in this patient’s case was likely related to the gain of caspase 8 and 10 genes.

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo . Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves. Caspases and neurotoxicity Brain inflammation is a typical feature of neurodegenerative diseases and acute forms of brain injury. Microglia are thought to play a part in the pathogenesis of such disorders by secreting neurotoxic cytokines. Experiments in cell and animal models of inflammation show that microglia activation requires the orderly activation of caspase-8 and caspase-3/7 — well known as agents of cell death. Inhibition of the caspase cascade prevents activation of microglia and protects against neurotoxicity. Caspase activation also occurs in microglia in the brains of patients with Parkinson's disease and Alzheimer's disease, raising the prospect that caspase inhibitors may have therapeutic potential.

Polycystic ovarian syndrome (PCOS) is related to pro‐apoptotic and pro‐inflammatory conditions generated by Endoplasmic reticulum (ER) stress. This study aimed to determine the effect of Astaxanthin (ASX), as carotenoid with potent antioxidant and anti‐inflammatory properties, on serum inflammatory markers, apoptotic factors and ER stress‐apoptotic genes in peripheral blood mononuclear cells (PBMCs) of women with PCOS. This randomized, double‐blind clinical trial included 56 PCOS patients aged 18–40. For 8 weeks, subjects were randomly assigned to one of two groups: either 12 mg ASX (n = 28) or placebo (n = 28). Real‐time PCR was used to quantify gene expression associated with ER stress‐apoptosis in PCOS women's PBMCs. The levels of TNF‐α, IL18, IL6 and CRP were determined by obtaining blood samples from all patients before and after the intervention using Enzyme‐linked immunosorbent assay (ELISA). Also, the levels of active caspase‐3 and caspase‐8 were detected in the PBMC by ELISA kit. Furthermore, we evaluated the efficacy of ASX on disease symptoms. Following the 8‐week intervention, ASX supplementation was able to reduce the expression of GRP78 (p = 0.051), CHOP (p = 0.008), XBP1 (p = 0.002), ATF4 (0.038), ATF6 (0.157) and DR5 (0.016) when compared to the placebo. However, this decrease was not statistically significant for ATF6 (p = 0.067) and marginally significant for GRP78 (p = 0.051). The levels of TNF‐α (p = 0.009), IL‐18 (p = 0.003), IL‐6 (p = 0.013) and active caspase‐3 (p = 0.012) were also statistically significant lower in the therapy group. However, there was no significant difference in CRP (p = 0.177) and caspase‐8 (p = 0.491) levels between the treatment and control groups. In our study, ASX had no significant positive effect on BMI, hirsutism, hair loss and regularity of the menstrual cycle. It appears that ASX may benefit PCOS by changing the ER stress‐apoptotic pathway and reducing serum inflammatory markers; however, additional research is required to determine this compound's potential relevance.

Legionella pneumophila is a Gram-negative, flagellated bacterium that survives in phagocytes and causes Legionnaires' disease. Upon infection of mammalian macrophages, cytosolic flagellin triggers the activation of Naip/NLRC4 inflammasome, which culminates in pyroptosis and restriction of bacterial replication. Although NLRC4 and caspase-1 participate in the same inflammasome, Nlrc4-/- mice and their macrophages are more permissive to L. pneumophila replication compared with Casp1/11-/-. This feature supports the existence of a pathway that is NLRC4-dependent and caspase-1/11-independent. Here, we demonstrate that caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in response to flagellin-positive bacteria. Accordingly, caspase-8 is activated in Casp1/11-/- macrophages in a process dependent on flagellin, Naip5, NLRC4 and ASC. Silencing caspase-8 in Casp1/11-/- cells culminated in macrophages that were as susceptible as Nlrc4-/- for the restriction of L. pneumophila replication. Accordingly, macrophages and mice deficient in Asc/Casp1/11-/- were more susceptible than Casp1/11-/- and as susceptible as Nlrc4-/- for the restriction of infection. Mechanistically, we found that caspase-8 activation triggers gasdermin-D-independent pore formation and cell death. Interestingly, caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in wild-type macrophages, but it is only activated when caspase-1 or gasdermin-D is inhibited. Our data suggest that caspase-8 activation in the Naip5/NLRC4/ASC inflammasome enable induction of cell death when caspase-1 or gasdermin-D is suppressed.

Over the recent few years rutin has gained wider attention in exhibiting inhibitory potential against several oncotargets for inducing apoptotic and antiproliferative activity in several human cancer cells. Several deregulated signaling pathways are implicated in cancer pathogenesis. Therefore we have inclined our research towards exploring the anticancerous efficacy of a very potent phytocompound for modulating the incontinent expression of these two crucial E6 and E7 oncogenes. Further, inhibitory efficacy of rutin against human papillomavirus (HPV)-E6 and E7 oncoproteins in cervical cancer has not been elucidated yet. This research addresses the growth inhibitory efficacy of rutin against E6 and E7 oncoproteins in HeLa cells, which is known to inactivate several tumor suppressor proteins such as p53 and pRB. Rutin treatment exhibited reduced cell viability with increased cell accumulation in G0/G1 phase of cell cycle in HeLa cell lines. Additionally, rutin treatment has also led to down-regulation of E6 and E7 expression associated with an increased expression of p53 and pRB levels. This has further resulted in enhanced Bax expression and decreased Bcl-2 expression releasing cytochrome c into cytosol followed by caspase cascade activation with cleavage of caspase-3, caspase-8 and caspase-9. Further, in silico studies have also supported our in vitro findings by exhibiting significant binding energy against selected target oncoproteins. Therefore, our research findings might recommend rutin as one of the potent drug candidate in cervical cancer management via targeting two crucial oncoproteins associated with viral progression.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

Caspase-8 is the initiator caspase of extrinsic apoptosis 1 , 2 and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality 3 , which can be rescued by deletion of either Ripk3 or Mlkl 4 – 6 . Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8 −/− mice 3 , 7 , Casp8 C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8 C362S/C362S mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice 8 . Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1β. Both embryonic lethality and premature death were completely rescued in Casp8 C362S/C362S Mlkl −/− Asc −/− or Casp8 C362S/C362S Mlkl −/− Casp1 −/− mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood. The enzymatic activity of caspase-8 controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.

Caspase-8 is a protease with both pro-death and pro-survival functions: it mediates apoptosis induced by death receptors such as TNFR1 1 , and suppresses necroptosis mediated by the kinase RIPK3 and the pseudokinase MLKL 2 , 3 – 4 . Mice that lack caspase-8 display MLKL-dependent embryonic lethality 4 , as do mice that express catalytically inactive CASP8(C362A) 5 . Casp8 C362A/C362A Mlkl −/− mice die during the perinatal period 5 , whereas Casp8 −/− Mlkl −/− mice are viable 4 , which indicates that inactive caspase-8 also has a pro-death scaffolding function. Here we show that mutant CASP8(C362A) induces the formation of ASC (also known as PYCARD) specks, and caspase-1-dependent cleavage of GSDMD and caspases 3 and 7 in MLKL-deficient mouse intestines around embryonic day 18. Caspase-1 and its adaptor ASC contributed to the perinatal lethal phenotype because a number of Casp8 C362A/C362A Mlkl −/− Casp1 −/− and Casp8 C362A/C362A Mlkl −/− Asc −/− mice survived beyond weaning. Transfection studies suggest that inactive caspase-8 adopts a distinct conformation to active caspase-8, enabling its prodomain to engage ASC. Upregulation of the lipopolysaccharide sensor caspase-11 in the intestines of both Casp8 C362A/C362A Mlkl −/− and Casp8 C362A/C362A Mlkl −/− Casp1 −/− mice also contributed to lethality because Casp8 C362A/C362A Mlkl −/− Casp1 −/− Casp11 −/− ( Casp11 is also known as Casp4 ) neonates survived more often than Casp8 C362A/C362A Mlkl −/− Casp1 −/− neonates. Finally, Casp8 C362A/C362A Ripk3 −/− Casp1 −/− Casp11 −/− mice survived longer than Casp8 C362A/C362A Mlkl −/− Casp1 −/− Casp11 −/− mice, indicating that a necroptosis-independent function of RIPK3 also contributes to lethality. Thus, unanticipated plasticity in death pathways is revealed when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited. Alternative cell death pathways are revealed in the absence of caspase-8-dependent apoptosis and MLKL-dependent necroptosis.

The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells. The activation of caspase 3, the up-regulation of both Bim and cleaved poly (ADP-ribose) polymerase (PARP) 1, the down-regulation of Bcl-xL, as well as the release of cytochrome c from mitochondria were significantly induced upon IFN-α treatment, indicating that the intrinsic apoptotic pathway could be activated by IFN-α treatment. In addition, caspase 4—which is involved in the endoplasmic reticulum (ER) stress-induced apoptosis—was activated in response to IFN-α treatment. Knocking down caspase 4 by small interfering RNA (siRNA) markedly reduced the IFN-α-mediated cell apoptosis. However, no significant changes in the expressions of caspases 8 and 10 were observed upon IFN-α treatment, indicating that the apoptosis caused by IFN-α might be independent of the extrinsic apoptotic pathway. These findings suggest that IFN-α may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and caspase-4-related ER stress-induced pathway.