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Aims: SERCA2, one of the P-type pumps encoded by gene ATP2A2, is the only calcium reflux channel of the endoplasmic reticulum (ER) and participates in maintaining calcium homeostasis. The present study was designed to explore SERCA2 expression pattern in auditory hair cells and the possible mechanism underlying the effects of SERCA2 on cisplatin-induced ototoxicity., Main Methods: The SERCA2 expression pattern in cochlea hair cells and HEI-OC1 cells was measured by Western blot (WB) and immunofluorescence staining. The apoptosis and its related factors were detected by TUNEL assay and WB. The expression levels of ER stress-related factors, ATF6, PERK, IRE1α, and GRP78, were measured via WB. As for the determination of SERCA2 overexpression and knockdown, plasmids and lentiviral vectors were constructed, respectively., Key Findings: We found that SERCA2 was highly expressed in cochlea hair cells and HEI-OC1 cells. Of note, the level of SERCA2 expression in neonatal mice was remarkably higher than that in adult mice. Under the exposure of 30 μM cisplatin, SERCA2 was down-regulated significantly compared with the control group. In addition, cisplatin administration triggered the occurrence of ER stress and apoptosis. Those events were reversed by overexpressing SERCA2. On the contrary, SERCA2 knockdown could aggravate the above processes., Significance: The findings from the present study disclose, for the first time, that SERCA2 is abundantly expressed in cochlea hair cells, and the suppression of SERCA2 caused by cisplatin could trigger ER homeostasis disruption, thereby implying that SERCA2 might be a promising target to prevent cisplatin-induced cytotoxicity of hair cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Although accumulated evidence supports the notion that calpain contributes to eye disease, the mechanisms by which calpain promotes RPE injury are not defined. The present study is aimed at investigating whether the effect of NaIO 3 -exos (exosomes derived from RPE cells under NaIO 3 stimulation) on the dysfunction of the autophagy-lysosomal pathway (ALP) and apoptosis is based on its regulation of calpain activation in ARPE-19 cells and rats. The results showed that calpain-2 activation, ALP dysfunction, and apoptosis were induced by NaIO 3 -exos in ARPE-19 cells. NaIO 3 -exo significantly increased autophagic substrates by activating lysosomal dysfunction. ALP dysfunction and apoptosis in vitro could be eliminated by knocking down calpain-2 (si-C2) or the inhibitor calpain-2-IN-1. Further studies indicated that NaIO 3 -exo enhanced calpain-2 expression, ALP dysfunction, apoptosis, and retinal damage in rats. In summary, these results demonstrate for the first time that calpain-2 is one of the key players in the NaIO 3 -exo-mediated ALP dysfunction, apoptosis, and retinal damage and identify calpain-2 as a promising target for therapies aimed at age-related macular degeneration (AMD)., Competing Interests: The authors declare no competing financial interest., (Copyright © 2023 Shuaishuai Zhang et al.)

Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation., (© 2022. The Author(s).)

Escherichia coli is one of the most important pathogens that cause clinical mastitis in dairy cattle worldwide and lead to severe economic losses. Antibiotics are often used to treat this inflammatory disease; however, antimicrobial resistance and environmental pollution cannot be ignored. Probiotic is the best alternative; however, its mechanisms of action to prevent mastitis remain unclear. Moreover, the role of probiotics in regulating mitophagy, a selective autophagy that maintains mitochondrial quality, needs to be explored. E. coli infection induced NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, Caspase-1 activation, and apoptosis in MAC-T cells. Infection also resulted in mitochondrial damage and subsequent increase in reactive oxygen species (ROS) production. Moreover, inhibition of ROS release by scavenger N-acetyl-L-cysteine (NAC) abrogated the importance of ROS in NLRP3 assembly and apoptosis in MAC-T cells. Pretreatment with Lactobacillus rhamnosus GR-1 (LGR-1), a probiotic, alleviated E. coli -induced NLRP3 inflammasome activation and apoptosis via ROS inhibition. Besides, E. coli infection inhibited mitophagy while LGR-1 pretreatment augmented PINK1/Parkin-mediated mitophagy activation, which further blocked ROS generation. To explore the effect of LGR-1 in vivo , a mouse mastitis model was established. The results showed that LGR-1 pretreatment had preventive and protective effects on E. coli induced mastitis, and could reduce cytokines levels such as IL-1β and TNF-α. In accordance with the results in vitro , E. coli can inhibit mitophagy and activate NLRP3 inflammasome and apoptosis, while LGR-1 can weaken the effect of E. coli . Taken together, our data indicated that LGR-1 pretreatment induced PINK1/Parkin-mediated mitophagy that eliminated damaged mitochondria and reduced ROS production and NLRP3 inflammasome activation, which subsequently decreased E. coli -induced apoptosis. To conclude, our study suggests that therapeutic strategies aiming at the upregulation of mitophagy under E. coli -induced mastitis may preserve mitochondrial function and provide theoretical support for the application of probiotics in bovine mastitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhu, Chu, Liu, Chen and Wang.)

Heat stress-induced decline in milk production and mammary glands dysfunction are economically important challenges facing the dairy industry, especially in summer. Choline is an organic water-soluble compound that can regulate a series of vital biological process, including cellular structural integrity and oxidative stress. However, it is unclear whether choline plays an anti-apoptosis and antioxidant effect in heat stress-induced mammary epithelial cells. This study aimed to determine the antioxidant effect of choline on heat stress-induced apoptosis and oxidative stress and its underlying molecular mechanism in bovine mammary epithelial cells (MAC-T cells). The MAC-T cells were divided into four treatment groups: control (37℃), choline (37℃), heat stress (HS, 42℃), and HS + choline. The results showed that heat stress up-regulated the HSP70 and HSP90 expression both in mRNA and protein, enhanced ROS accumulation, increased malondialdehyde (MDA) content, reduced the superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, significantly increased the expression of caspase-3 and upregulated the ratio of Bax/Bcl-2 and ultimately lead to oxidative stress and apoptosis in MAC-T cells. However, choline pretreatment reversed the above phenomenon compared with the HS group. The HS + choline group inhibited heat stress-induced phosphorylation of PERK, nuclear translocation of Nrf-2 and the protein expression of GRP78. In addition, the ratio of Bax/Bcl-2 and the expression of caspase-3 were significantly reduced in HS + choline group, thereby reduced the HS-induced oxidative stress and apoptosis in MAC-T cells. In conclusion, choline attenuates heat stress-induced oxidative stress and apoptosis of MAC-T cells by modulating PERK/Nrf-2 pathway., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The mixture of GX (guttiferone E and xanthochymol), an inseparable polycyclic polyprenylated acylphloroglucinol (PPAP), showed moderate cytotoxic activities. The chemical transformation of GX yielded three different types of PPAPs (1, 2, and 3/4). A series of analogs were prepared, and the structures of the 40 newly synthesized compounds were elucidated by 1D and 2D NMR and HR-ESI-MS. The derivatives were screened in vitro for antiproliferative activity against five human cancer cell lines: human leukemic cell lines (HEL and K562), cervical cancer cell line (Hela), human breast adenocarcinoma cell line (MCF-7), and human non-small cell lung cancer cell line (A549), using the MTT assay, and most of the derivatives showed good cytotoxic activities. Noticeably, compound 2, a novel tautomer with a hemiketal, exhibited selective cytotoxic activities against HEL (IC 50  = 4.79 ± 0.23 μM) and K562 (IC 50  = 7.69 ± 0.34 μM) leukemia cells. The mechanism studies indicated that compound 2 induced apoptosis and arrested the cell cycle at the G0/G1 phase in the HEL cell line. Furthermore, compound 2 activated the intrinsic pathway by reducing the expression of anti-apoptotic protein Bcl-2 and cell cycle-specific cyclin D1 and by enhancing the pro-apoptotic protein Bax. Moreover, the caspase-3 and PPRP1 levels were also upregulated. Our present results suggest that compound 2 is a potential candidate for developing novel anti-leukemia agents in the future., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Our previous study showed that during in vitro experiments changes in calcium concentration were associated with apoptosis. We presumed that the calcium ion might play a role as intermediate messenger for apoptosis-related genes. No such evidence has been reported in the literature. Here, we investigate the effect of calcium ionophore A23187 on the apoptosis of rat hepatic stellate cells (HSCs) stimulated by transforming growth factor-β 1 (TGF-β 1 ) to explore the mechanism of apoptosis through the endoplasmic reticulum stress pathway., Methods: The apoptotic rate was determined using flow cytometry. The changes in Ca 2+ level in HSCs were examined with laser confocal microscopy. The expressions of caspase-12 GRP78 and caspase-9 were assayed via western blot., Results: The respective apoptosis rates for the blank group, the TGF-β 1 group and the TGF-β 1  + low, medium and high dose calcium ionophore A23187 groups were 3.40 ± 0.10%, 1.76 ± 0.12%, 5.86 ± 0.31%, 11.20 ± 0.48% and 15.08 ± 0.75%, with significant differences between the groups ( p  < 0.05). The concentration of Ca 2+ and the expression of the GRP78, caspase-9 and caspase-12 proteins significantly increased with increasing calcium ionophore A23187 doses ( p  < 0.05)., Conclusion: Calcium ionophore A23187 increased intracellular Ca 2+ and activated endoplasmic reticulum stress, which promoted HSC apoptosis., Competing Interests: This study was approved by North China University of Science and Technology.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Mycoplasma Ovipneumoniae (M. ovipneumoniae) is a primary etiological agent of enzootic pneumonia in sheep and goats. It can enter and colonize ovine respiratory epithelial cells to establish an infection, which leads a serious cell death of epithelial cells. However, the nature of the interaction between pathogen of M. ovipneumoniae and host cells in the cell injury is currently not well understood. In this study, we investigated the epithelial cell apoptosis caused by an infection of M. ovipneumoniae in sheep primary air-liquid interface (ALI) epithelial cultures. The results showed that M. ovipneumoniae could specifically bind to ciliated cells at early stage of infection. Flow cytometric analysis demonstrated that an infection of M. ovipneumoniae induced a time-dependent cell apoptotic cell death, accompanied with an increased production of extracellular nitric oxide (NO), intracellular reactive oxygen species (ROS) production and activation of caspase-3 signaling in sheep bronchial epithelial cells. The induced cell apoptosis was further confirmed by a transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay. Interestingly, the M. ovipneumoniae-induced apoptosis and activation of caspase-3 were correlated with the production of ROS but not NO. Mechanistically, M. ovipneumoniae-induced cell apoptosis was mediated by a mechanism by increasing the expression of phosphorylation of p38 and pro-apoptotic proteins, and activating caspase-3, caspase-8 and poly ADP-ribose polymerase (PARP) cleavage. These results suggest a ROS-dependent and caspase-3-mediated cell apoptosis in sheep bronchial epithelial cells in response to M. ovipneumoniae infections., (Copyright © 2017. Published by Elsevier B.V.)

In an attempt to better understand the pathogen-host interaction between invading Mycoplasma ovipneumoniae ( M. ovipneumoniae ) and sheep airway epithelial cells, biological effects and possible molecular mechanism of capsular polysaccharide of M. ovipneumoniae (CPS) in the induction of cell apoptosis were explored using sheep bronchial epithelial cells cultured in air-liquid interface (ALI). The CPS of M. ovipneumoniae was first isolated and purified. Results showed that CPS had a cytotoxic effect by disrupting the integrity of mitochondrial membrane, accompanied with an increase of reactive oxygen species and decrease of mitochondrial membrane potential (ΔΨ m ). Of importance, the CPS exhibited an ability to induce caspase-dependent cell apoptosis via both intrinsic and extrinsic apoptotic pathways. Mechanistically, the CPS induced extrinsic cell apoptosis by upregulating FAS/FASL signaling proteins and cleaved-caspase-8 and promoted a ROS-dependent intrinsic cell apoptosis by activating a JNK and p38 signaling but not ERK1/2 signaling of mitogen-activated protein kinases (MAPK) pathways. These findings provide the first evidence that CPS of M. ovipneumoniae induces a caspase-dependent apoptosis via both intrinsic and extrinsic apoptotic pathways in sheep bronchial epithelial cells, which may be mainly attributed by a ROS-dependent JNK and p38 MAPK signaling pathways., Competing Interests: The authors declare that they have no conflict of interests.

We previously reported that a soluble form of the TNF-family receptor death receptor-3 (DR3) is expressed in osteoblasts. DR3 regulates death or differentiation in other tissues, and DR3 ligands occur in bone, but the function of DR3 in the osteoblast was unknown. We studied the expression of DR3 and the effects crosslinking antibodies to DR3 or of natural DR3 ligands in human osteoblasts. Western analysis showed that nontransformed osteoblasts and the MG63 osteosarcoma cell line produce both soluble decoy receptor and transmembrane isoforms of DR3. Cell surface labeling showed that low and high DR3-expressing osteoblast populations occur. Verification of by cloning showed a point mutation in DR3 from MG63 cells. Activation of DR3 by antibody crosslinking or with DR3 ligands caused apoptosis in osteoblasts and in MG63 cells, but only in low-density cell cultures. In dense cultures apoptosis did not occur, but nuclear factor-kappaB nuclear translocation was observed under some conditions. Crosslinking of DR3 in high-density MG63 cultures blocked expression of bone matrix elements. DR3 activation in high-density nontransformed osteoblasts had only minor effects on cell maturation. We conclude that DR3 activation can mediate apoptosis in osteoblasts. Its activity is, however, highly restricted by its soluble ligand-binding isoform and possibly also by alternate survival signals. In the presence of survival signals, DR3 may affect cell maturation although effects on differentiation were clearly seen only in the MG63 transformed cell line., ((c) 2006 Wiley-Liss, Inc.)

Coronavirus disease 2019 (COVID-19) has been wreaking havoc for 3 years. PANoptosis, a distinct and physiologically relevant inflammatory programmed cell death, perpetuates cytokine storm and multi-organ injuries in COVID-19. Although PANoptosis performs indispensable roles in host defense, further investigation is needed to elucidate the exact processes through which PANoptosis modulates immunological responses and prognosis in COVID-19. This study conducted a bioinformatics analysis of online single-cell RNA sequence (scRNA-seq) and bulk RNA-seq datasets to explore the potential of PANoptosis as an indicator of COVID-19 severity. The degree of PANoptosis in bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) indicated the severity of COVID-19. Single-cell transcriptomics identified pro-inflammatory monocytes as one of the primary sites of PANoptosis in COVID-19. The study subsequently demonstrated the immune and metabolic characteristics of this group of pro-inflammatory monocytes. In addition, the analysis illustrated that dexamethasone was likely to alleviate inflammation in COVID-19 by mitigating PANoptosis. Finally, the study showed that the PANoptosis-related genes could predict the intensive care unit admission (ICU) and outcomes of COVID-19 patients who are hospitalized. [ABSTRACT FROM AUTHOR]

Background: Sodium formononetin-3ʹ-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia‐reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis. Results: The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1β and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke. Conclusions: Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke. [ABSTRACT FROM AUTHOR]

Bovine mastitis seriously affects bovine health and dairy product quality. Escherichia coli is the most important pathogen in the environment and dairy products. Enteropathogenic Escherichia coli (EPEC) is a zoonotic pathogen, which seriously threatens the health of people and dairy cows. We recently reported that E. coli can induce endogenous apoptosis in bovine mammary epithelial cells. However, the mechanism of EPEC-damaged mitochondria and -induced bovine mastitis is unclear. In this study, we found that EPEC can induce DRP-1-dependent mitochondrial fission and apoptosis. This was verified by the application of Mdivi, a DRP-1 inhibitor. Meanwhile, in order to verify the role of the Map virulence factor in EPEC-induced bovine mastitis, we constructed a map mutant, complementary strain, and recombinant plasmid MapHis. In the present study, we find that Map induced DRP-1-mediated mitochondrial fission, resulting in mitochondrial dysfunction and apoptosis. These inferences were further verified in vivo by establishing a mouse mastitis model. After the map gene was knocked out, breast inflammation and apoptosis in mice were significantly alleviated. All results show that EPEC targets mitochondria by secreting the Map virulence factor to induce DRP-1-mediated mitochondrial fission, mitochondrial dysfunction, and endogenous apoptosis in bovine mastitis. [ABSTRACT FROM AUTHOR]

Intravascular hemolysis is a fundamental feature of hemorrhagic venereal infection or tissue and releases the endogenous damage-associated molecular pattern hemoglobin (Hb) into the plasma or tissues, which results in systemic inflammation, vasomotor dysfunction, thrombophilia, and proliferative vasculopathy. However, how the cytotoxic Hb affects the tissues of grass carp remains unclear. Here, we established a hemolysis model in grass carp by injecting phenylhydrazine (PHZ). The data revealed that the PHZ-induced hemolysis increased the content of Hb and activated the antioxidant system in plasma. The histopathology analysis data showed that the PHZ-induced hemolysis increased the accumulation of Hb and iron both in the head and middle kidney. The results of quantitative real-time PCR (qRT-PCR) detection suggested that the hemolysis upregulated the expressions of iron metabolism-related genes. In addition, the immunofluorescence and immunohistochemistry data revealed that the hemolysis caused an obvious deposition of collagen fiber, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) accumulation and increased the content of oxidative-related enzymes such as β-galactosidase (β-GAL), lipid peroxide (LPO), and MDA in both the head and middle kidney. Furthermore, the PHZ-induced hemolysis significantly increased the production of reactive oxygen species (ROS), which resulted in apoptosis and modulated the expressions of cytokine-related genes. Taken together, excess of Hb released from hemolysis caused tissue oxidative damage, which may be associated with ROS and inflammation generation. [ABSTRACT FROM AUTHOR]

A tumor redox-activatable micellar nanoplatform based on the naturally occurring biomacromolecule hyaluronic acid (HA) was developed for complementary photodynamic/chemotherapy against CD44-positive tumors. Here HA was first conjugated with L -carnitine (Lc)-modified zinc phthalocyanine (ZnPc) via disulfide linkage and then co-assembled with tirapazamine (TPZ) to afford the physiologically stable micellar nanostructure. The mitochondria-targeted photodynamic activity of ZnPc-Lc could efficiently activate the mitochondrial apoptosis cascade and deplete the oxygen in the tumor intracellular environment to amplify the hypoxia-dependent cytotoxic effect of TPZ. [ABSTRACT FROM AUTHOR]

In this paper, electron beam irradiated rice protein hydrolysates (ERPHs) were assessed for their ability to prevent hydrogen peroxide-induced oxidative stress in human HepG-2 cells. The related mechanism was also studied by analyzing the structural changes. Cytotoxicity experiments showed that rice protein hydrolysates pretreated with electron beam irradiation (EBI) were not toxic to cells if appropriate concentrations were applied. Cell viability markedly increased when the cells were treated with ERPHs before H2O2 induction. Furthermore, the ERPHs effectively suppressed H2O2-induced ROS production and lipid peroxidation and increased the protein expression levels of the intracellular antioxidant enzymes SOD, GSH-Px and CAT in H2O2-stressed HepG-2 cells. Consequently, the loss of mitochondrial membrane potential and cell apoptosis was alleviated. Circular dichroism analysis showed that pretreatment of rice protein with EBI significantly changed the secondary structure (the conversion of α-helices to random coils), which is beneficial to the improvement of its antioxidative activity. ERPHs exhibited stronger antioxidative effects than those without irradiation, possibly because of the difference in molecular weight distribution and amino acid composition. These findings indicate an efficient way to produce peptides with better antioxidant activity. [ABSTRACT FROM AUTHOR]

Difenoconazole (DFZ) is a classical triazole fungicide that causes immunosuppression in non-target organisms. Ferulic acid (FA) is a polyphenolic molecule found in nature that has antioxidant and anti-inflammatory activities. The purpose of this investigation was to see if FA could prevent DFZ-induced immunosuppression and to identify the potential mechanisms. Carp were exposed to 1/10 LC 50 of DFZ as well as fed normal feed or feed containing dietary additive FA for 30 d. It was found that DFZ-induced immunosuppression could be improved by FA, as evidenced by upregulation of Hb, C3 and IgM and downregulation of LDH. It was then investigated that FA could ameliorate DFZ-induced splenic injury through p53-mediated apoptosis. At the same time, enhancing the levels of CAT, GSH and T-AOC in spleen and transcription levels Nrf2 signaling pathway related genes indicated that FA reduced oxidative damage caused by DFZ by blocking the Nrf2 signaling pathway. In addition, FA inhibited the inflammatory response triggered by TRAF/TAK1/NF-κB signaling pathway, downregulated the transcript levels of pro-inflammatory factors (il-1β , tnf-α , il-6) and the level of NLRP3 inflammasome (NRLP3, ASC, Caspase 1), and upregulated the transcript levels of anti-inflammatory factors (tgf-β1 , il-10). In conclusion, the above results suggested that FA mediated TRAF/TAK1/NF-κB, Nrf2, and p53 pathways to attenuate DFZ-induced inflammation, oxidative stress, and apoptosis thereby enhancing the immune capacity of carp. ● FA alleviated DFZ -induced immunosuppression in carp. ● FA inhibited DFZ-induced apoptosis in carp spleen via p53. ● FA activation of Nrf2 attenuated DFZ-induced oxidative stress in the spleen. ● FA ameliorated DFZ-induced inflammation via TRAF/TAK1/NF-κB pathway in the spleen. [ABSTRACT FROM AUTHOR]

Highlights • Effects of anesthetics on fetal rats. • Midazolam can reduce ROS in PC12 cells. • The harmful effects of ketamine can be ameliorated by midazolam. Abstract Every year between 0.75% and 2% of pregnant women require surgery that is related to either the pregnancy or other medical problems in USA. Therefore, the neurodegeneration following anesthesia in a variety of animal models has attracted our attention. Neurotoxic effects of ketamine cannot be ignored. In contrast, some anesthetics, including midazolam, protect neurons and increase dendritic spine density. However, the mechanism of neuroprotection by midazolam is not clear, and whether midazolam can relieve the damage caused by ketamine is unknown. Therefore, in this study, we explored the effects of midazolam on ketamine anesthesia. We measured protein levels of cleaved-caspase-3 (c-caspase-3), beclin-1, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), autophagy-related gene 4 (ATG4), ATG5, p62 (SQSTM1), and the autophagy marker light chain 3 (LC3) in hippocampus by Western analysis. We also measured total antioxidant capacity (T-AOC), and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in hippocampus and PC12 cells. Results showed that ketamine induced apoptosis through activation of the mitochondrial pathway by increasing the expression of c-caspase-3 and Bax, and decreasing the expression of Bcl-2 at the protein level. Ketamine also increased the expression of LC3II and ATG5, proteins, decreased the expression of ATG4 and P62, and finally induced autophagy. Ketamine promoted the production of ROS and MDA, and reduced total antioxidant capacity (T-AOC); these effects were attenuated by midazolam. In conclusion, ketamine induces toxicity in human neurons through ROS-mediated activation of mitochondrial apoptotic pathway and autophagy. The harmful effects of ketamine can be ameliorated by midazolam. [ABSTRACT FROM AUTHOR]

Drug abuse during pregnancy is a serious problem. Like alcohol, anticonvulsants, sedatives, and anesthetics, such as ketamine, can pass through the placental barrier and affect the growing fetus. However, the mechanism by which ketamine causes damage to fetal rats is not well understood. Therefore, in this study, we anesthetized pregnant rats with ketamine and evaluated the Total Antioxidant Capacity (T-AOC), Reactive Oxygen Species (ROS), and Malondialdehyde (MDA). Moreover, we determined changes in the levels of Cleaved-Caspase-3 (C-Caspase-3), Beclin-1, B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X Protein (Bax), Autophagy-related gene 4 (Atg4), Atg5, p62 (SQSTM1), and marker of autophagy Light Chain 3 (LC3). In addition, we cultured PC12 cells in vitro to determine the relationship between ROS, autophagy, and apoptosis following ketamine treatment. The results showed that ketamine induced changes in autophagy- and apoptosis-related proteins, reduced T-AOC, and generated excessive levels of ROS and MDA. In vitro experiments showed similar results, indicating that apoptosis levels can be inhibited by 3-MA. We also found that autophagy and apoptosis can be inhibited by N-acetyl-L-cysteine (Nac). Thus, anesthesia with ketamine in pregnant rats may increase the rate of autophagy and apoptosis in the fetal hippocampus and the mechanism may be through inhibition of antioxidant activity and ROS accumulation. [ABSTRACT FROM AUTHOR]

Antibiotics are used to treat illnesses in animals and humans worldwide. Yet, many antibiotics and other secondary metabolites can contaminate the water supply, creating a substantial risk to human health. A comprehensive investigation is currently focusing on the systematic effects of dietary antibiotics on fish liver, particularly on their impacts on oxidative stress, transcriptome profiles, toxicity, and apoptosis. In the present study, healthy grass carp were treated orally with 10 mg/kg enrofloxacin or florfenicol for 14 days. The enzyme activity outcomes reflected that the administration of enrofloxacin or florfenicol could significantly induce oxidative stress by decreasing CAT, SOD and GPx and increasing MDA. In addition, KEGG analysis showed that both antibiotics activated the PPAR signal pathway. The expression levels of the six genes, namely FABP6, APOA1, CYP27A1, ACSL1, CPT1A, and ANGPTL4, in the PPAR signal pathway were determined to further clarify the transcriptomic data. Enrofloxacin induced apoptosis in grass carp liver tissue, while hepatocytes from grass carp treated with enrofloxacin and florfenicol activated cytotoxicity and apoptosis. The present study suggests that antibiotics can induce antioxidant stress, impair the immune system, and attenuate the PPAR signal pathway in the grass carp liver, thus being harmful to grass carp as a dietary supplement, mainly within the aquaculture industry. [Display omitted] • 14-day antibiotic treatments have impact on immune system in grass carp liver. • Dietary enrofloxacin and florfenicol treatments activated the PPAR signal pathway. • Compared with florfenicol, enrofloxacin relatively induced apoptosis in grass carp liver tissue. • Hepatocytes from grass carp treated with enrofloxacin and florfenicol activated cytotoxicity and apoptosis. [ABSTRACT FROM AUTHOR]

• In the study of AR, many researchers focus on mast cells, dendritic cells, T cells, innate lymphocytes, eosinophils, basophils and other immune cells and their complex interactions while ignoring the important role and function of epithelial cells in this process. • Our conclusions indicate that apoptosis, pyroptosis, and autophagy in AR epithelial cells also play an important role in the development of AR, but the specific mechanism is still not fully understood. • Investigation of these types of programmed cell death may be a new direction for future AR research. In AR, the epithelial barrier composed of Nasal epithelial cells is the first line of defense, which is crucial to protect the host immune system from harmful stimuli. Moreover, irreversible structural changes in Nasal epithelial cells can occur in response to different allergens, but the mechanism leading to such abnormal changes has not been determined. Programmed cell death is regulated by genes and interacts with multiple cell signaling pathways. To explore the regulatory mechanism and signal pathway of programmed cell death in epithelial cells of allergic rhinitis, is helpful to clarify the pathogenesis of AR and put forward treatment strategies. In this paper, the regulation mechanisms of programmed cell death such as apoptosis, pyroptosis, and autophagy occurring in epithelial cells in AR, are retrospectively summarized to better understand the pathogenesis of AR. [ABSTRACT FROM AUTHOR]

Map, not EspF, is vital virulence factor of E. coli -induced apoptosis though ERK/DRP-1 signaling pathway. E. coli (EPEC) secretes effector protein-Map and -EspF through the type III secretion system. Map, not EspF, to activate the ERK signaling pathway, which decreases the levels of MFN-1, MFN-2 and p-DRP-1 (ser637) and increases the level of DRP-1. Map and EspF promotes mitochondrial fission (mitochondrial fragmentation), the continuous opening of mPTP and a decrease in MMP. Then it causes the release of pro-apoptotic factor Cyt-C and Ca2+, and increased the caspase 3 activation. Eventually this causes cell apoptosis. The black arrows indicate promotion. The red arrow represents the level increase or decrease. Red X represents no. [Display omitted] • Map and EspF could destroy tight junction. • Map and EspF are vital effectors in E. coli -induce apoptosis in bovine mastitis. • Map, not EspF, could activate ERK signaling pathway The incidence of bovine mastitis induced by enteropathogenic Escherichia coli (EPEC) in the environment has increased, but the mechanism of effector-Map and -EspF secreted by EPEC in breast epithelial cells is not clear. Therefore, this study focused on Map and EspF to explore the role of these two virulence factors in EPEC-induced bovine mastitis. We established Δmap and/or ΔEspF mutant strains to explore their role in EPEC-induced bovine mastitis. It was found that both Map and EspF could affect the mitochondrial membrane potential, apoptosis, and tight junctions in MAC-T cells. In addition, we also found that Map could affect the ERK signaling pathway. In order to further verify the effect of Map on the ERK signaling pathway, we introduced an ERK inhibitor (PD98059) and pc DNA3.1 plasmid with the map gene. It was found that DRP-1 and apoptosis were no longer affected by Map. In summary, the study implies that E. coli can promote breast epithelial cell apoptosis and destroy tight junctions through Map and EspF. However, Map, but not EspF, induces breast epithelial cell apoptosis through the ERK-DRP-1 pathway. [ABSTRACT FROM AUTHOR]

Background: Calcineurin (CaN) having a high expression in hippocampal neurons is closely related to apoptosis. Pretreatment with nimodipine can lower the apoptosis rate of hippocampal neuron to reduce the incidence of postoperative cognitive dysfunction (POCD). However, the relationship between cerebral protective effect of pretreatment with nimodipine and CaN is controversial in the literature. The aim of this study is to evaluate the relationship between neuroprotective effect of nimodipine and CaN on POCD in aged rats. Methods: Ninety-six 18-month-old male Sprague-Dawley rats were randomly assigned into 4 groups (n = 24 each): control group (Group C), nimodipine group (Group N), surgery group (Group S) and nimodipine + surgery group (Group N + S). In Group N and Group N + S, nimodipine 1 mg/kg was intraperitoneally injected, while the equal volume of normal saline was given instead in Group S. 30 min later, Group N and Group C inhaled pure oxygen for 2 h, and Group S and N + S inhaled 3% sevoflurane for 2 h when exploratory laparotomy was performed. Morris water maze test was performed on 1 day before operation and 1, 3 and 7 days after operation. After the end of Morris water maze test at 1 day before operation and 1 and 7 days after operation, 8 rats were sacrificed, brains were removed and hippocampal tissues were obtained for detection of apoptosis in hippocampal neurons, cytoplasmic calcium ([Ca2+]i), and hippocampal CaN and caspase-3 expression. Results: Compared with the 1st day before operation, the escape latency, apoptosis rate, [Ca2+]i, expression of CaN and caspase-3 increased significantly, but the frequency of crossing the original platform decreased dramatically in Group S and N + S(P<0.05). In addition, the escape latency, apoptosis rate, [Ca2+]i, and expression of CaN and caspase-3 decreased markedly, but the frequency of crossing the original platform increased significantly in Group N + S as compared with Group S (P<0.05). Conclusions: Pretreatment with nimodipine reduces the incidence of POCD by decreasing CaN mediated hippocampal neuroapoptosis in aged rats. [ABSTRACT FROM AUTHOR]

The Qi-Qin-Hu-Chang Formula (QQHCF) is a traditional Chinese medicine prescription that is clinically used at the Affiliated Hospital of Nanjing University of Chinese Medicine for the treatment of colitis-associated colorectal cancer (CAC). To evaluate the potential therapeutic effects of QQHCF on a CAC mouse model and investigate its underlying mechanisms using network pharmacology and experimental validation. The active components and potential targets of QQHCF were obtained from Traditional Chinese Medicine Systems Pharmacology (TCMSP) and herb-ingredient-targets gene network were constructed by Cytoscape 3.9.2. Target genes of CAC were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank database. The drug disease target protein-protein interaction (PPI) network was constructed and the core targets were visualized and identified using Cytoscape. The Metascape database was used for GO and KEGG enrichment analysis. UHPLC-MS/MS was used to further identify the active compounds in QQHCF. Subsequently, the therapeutic effects and potential mechanism of QQHCF against CAC were investigated in AOM/DSS-induced CAC mouse in vivo , and HT-29 and HCT116 cells in vitro. Finally, interactions between JNK, p38, and active ingredients were assessed by molecular docking. A total of 176 active compounds, 273 potential therapeutic targets, and 2460 CAC-related target genes were obtained. The number of common targets between QQHCF and CAC were 165. KEGG pathway analysis indicated that the MAPK signaling pathway was closely associated with CAC, which may be the potential mechanism of QQHCF against CAC. Network pharmacology and UHPLC-MS/MS analyses showed that the active compounds of QQHCF included quercetin, kaempferol, luteolin, wogonin, oxymatrine , lupanine, and baicalin. Animal experiments demonstrated that QQHCF reduced tumor load, number, and size in AOM/DSS-treated mice, and induced apoptosis in colon tissue. In vitro experiments further showed that QQHCF induced apoptosis and inhibited cell viability, migration, and invasion in HCT116 and HT-29 cells. Notably, QQHCF activated the JNK/p38 MAPK signaling pathway both in vivo and in vitro. Molecular docking analysis revealed an ability for the main components of QQHCF and JNK/p38 to bind. The present study demonstrated that QQHCF could ameliorate AOM/DSS-induced CAC in mice by activating the JNK/p38 MAPK signaling pathway. These results have important implications for the development of effective treatment strategies for CAC. [Display omitted] • We firstly conducted bioinformatic methods and animal experiments to illuminate the anti-CAC mechanism of QQHCF. • QQHCF can ameliorate AOM/DSS-induced CAC mice. • QQHCF can promote apoptosis in HT29 and HCT116 cells. • QQHCF can inhibit the migration and invasion of HT29 cells. • QQHCF can activate the JNK/p38 MAPK signaling pathway in vitro and vivo. • Our study provides a novel approach and mechanism for the treatment of CAC. [ABSTRACT FROM AUTHOR]

[Display omitted] • AR attenuates cisplatin-induced injury in auditory cells. • AR reduces cisplatin-induced mitochondrial apoptotic pathway activation and decreases mitochondrial ROS accumulation. • AR alleviates cisplatin-induced impairment of mitochondrial biogenesis by binding to AdipoR 1. AdipoRon (AR) can exert antidiabetic and anti-inflammatory effects by maintaining mitochondrial structure and function. The present study was designed to explore whether AR protects the auditory cells from cisplatin-induced damage and, if so, to probe the possible mechanisms underlying its action on this type of cells. Cell viability and apoptosis in House Ear Institute-Organization of Corti 1 (HEI-OC1 cells) and mouse cochlea hair cells (HCs) were detected by CCK8 and immunofluorescence. The expressions of apoptosis-related proteins (cleaved caspase-3 and Bcl-2), adiponectin receptor 1 (AdipoR 1) and the key factors relevant to mitochondrial biogenesis（SIRT1 and TFAM）were determined by Western blot and immunofluorescence. Changes in apoptotic rate and expression of SIRT1 and TFAM after silencing of AdipoR 1 (AdipoR 1-siRNA) in HEI-OC1 cells were measured by flow cytometry and Western blot. The levels of reactive oxygen species (ROS) were evaluated by MitoSox red staining. We found that 30 μM cisplatin exposure induced severe cellular damage, which resulted from activation of the mitochondrial apoptotic pathway. Cisplatin decreased the expression of AdipoR 1, SIRT1, and TFAM proteins, leading to impaired mitochondrial biogenesis and increased mitochondrial ROS production. 10 μM AR pre-treatment enhanced mitochondrial biogenesis, decreased mitochondrial ROS levels, alleviated imbalances in the mitochondrial apoptotic pathway, thus reducing cisplatin-induced apoptosis. Taken together, this work reveals that AR exerts anti-apoptotic effects, possibly via regulating mitochondrial biogenesis and function. Interestingly, AR might possess the promising potential to be a novel drug for the prevention and/ or treatment of cisplatin-induced ototoxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • The phytochemical study of Magnolia grandiflora led to the isolation of 39 sesquiterpenoids, including 15 new compounds. • A series of derivatives of 28 were designed, synthesized, and screened for their antitumor activities. • 17 Compounds were active with the IC 50 values ranging from 1.91 ± 0.39 μM to 12.29 ± 1.68 μM. • Compound 29 induced apoptosis through influencing the key apoptotic related proteins. Phytochemical study of Magnolia grandiflora led to the isolation of 39 sesquiterpenoids, including 15 new compounds (1 – 15). Compounds 1 and 2 are discovered to be the first 13-norgermacrane type sesquiterpenoids in natural products. Compound 15 is a rare 5,6-seco-guaiane type sesquiterpene and its possible biogenic precursor is presumed to be compound 20. Subsequent structural modification for compound 28 led to 21 derivatives, among which 15 derivatives were new compounds. All compounds were tested for the inhibitory effects on three tumor cell lines, and 17 compounds were active with the IC 50 values ranging from 1.91 ± 0.39 μM to 12.29 ± 1.68 μM. The structure–activity relationships implied that an α , β -unsaturated lactone group was an important active group for the cytotoxicity. Two most active compounds (19 and 29) with low toxicity on normal human liver cell line were selected for further mechanism study. Compound 29 could induce apoptosis on Colo320DM cells through influencing the key apoptotic related proteins, such as PARP, Cleaved PARP, cleaved Caspase-3, and pro-Caspase 3. In addition, compound 19 with the best cytotoxic activity on HEL cells also could induce the apoptosis in dose- and time-dependent manners. In summary, our investigation implied that compounds 19 and 29 are two new potential anti-cancer candidates for ongoing study in the future. [ABSTRACT FROM AUTHOR]

DJ-1, a multifunctional protein encoded by the Park7 gene, is tightly related to mitochondrial dysfunction, oxidative stress, protein aggregation, and autophagy regulation. The current study was designed to investigate whether DJ-1 is expressed in auditory cells and, if so, to explore the possible correlation between DJ-1 and cisplatin-induced ototoxicity in this type of cells. The location and dynamic expression of DJ-1 in mouse cochlea hair cells (HCs) and House Ear Institute-Organ of Corti 1 (HEI-OC1 cells) were detected by immunofluorescence, real-time PCR, and western blot. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. The levels of ROS were evaluated by MitoSox red staining. The expression of protein cleaved caspase-9, cleaved caspase-3, and LC3B was examined by immunofluorescence and western blot. The expressions of certain key factors relevant to apoptosis (Bcl-2 and Bax) and autophagy (Beclin1, p-JNK, and p-c-Jun) were determined by western blot. The dynamic alterations of those factors in response to DJ-1 knockdown in HEI-OC1 cells (DJ-1-KD) were measured by western blot and MitoSox red staining. The expression of DJ-1 was clearly shown in both HCs and HEI-OC1 cells and cisplatin led to the reduction of DJ-1 expression in a concentration and time-dependent manner. Meanwhile, cisplatin-induced apoptotic process was implemented by promoting reactive oxygen species (ROS) production and activating the mitochondrial pathway. Furthermore, DJ-1 explicitly participated in cisplatin-trigged cell damage by regulating autophagy. Findings from this work clearly reveal, for the first time, that DJ-1 is expressed in the cochlea. Of particular importance, DJ-1 exerts its protective action against cisplatin-elicited injury on auditory cells via regulating apoptosis and autophagy, which provides a new strategy for the prevention of cisplatin-induced ototoxicity. • Cisplatin induced a decrease in DJ-1 and activated apoptosis of auditory cells. • DJ-1 knockdown promoted cisplatin-induced increment of mitochondrial ROS and mitochondrial pathway relevant elements. • DJ-1 regulated autophagy in auditory cells under cisplatin exposure. [ABSTRACT FROM AUTHOR]

Stroke patients are often complicated by cerebral ischemia-reperfusion injury (CIRI) after the restoration of cerebral perfusion, and how to prevent CIRI at an early stage has received close attention. The imbalance of iron metabolism is one of the essential factors in the aggravation of CIRI, and NCOA4-mediated ferritinophagy, as a critical pathway to regulate iron metabolism, is expected to be an effective intervention target. We established a mouse model of cerebral ischemia-reperfusion (CIR) with NCOA4 silencing. We found that activation of NCOA4-mediated ferritinophagy atthe early stage of CIR mediated the onset of oxidative stress and contributed to autophagy and apoptosis, and eventually resulted in increased brain injury. This suggests that NCOA4-mediated ferritinophagy plays a vital role in early CIR and can be an effective target to prevent and treat CIRI. We next explored the upstream regulatory targets of NCOA4-mediated ferritinophagy. The previous evidence for the cGAS-STING pathway's importance during CIR and its strong relationship with autophagy attracted our attention. To investigate whether the cGAS-STING pathway regulates NCOA4-mediated ferritinophagy, we further administered a cGAS inhibitor to mice with CIR and overexpressed NCOA4. Along with the inhibition of the cGAS-STING pathway, ferritinophagy, oxidative stress, autophagy, and apoptosis were inhibited, and CIRI was ameliorated, which was attenuated by NCOA4 overexpression. In conclusion, our results suggest that activation of the cGAS-STING pathway exacerbates CIRI at the early stage of CIR, which may be achieved by mediating NCOA4-mediated ferritinophagy. [Display omitted] • Activation of NCOA4-mediated ferritinophagy occurs at the early stage of CIR. • NCOA4 silencing mitigate cerebral infarction, oxidative stress, excessive autophagy, and apoptosis at the early stage of CIR. • The cGAS-STING inhibitor RU.521 exerts neuroprotection against CIRI, which can be abrogated by NCOA4 overexpression. [ABSTRACT FROM AUTHOR]

Hemorrhagic venereal infection or tissue injury usually results in the hemolysis of red blood cells (RBCs) and releases the endogenous damage-associated molecular pattern hemoglobin (Hb) into the plasma or tissues. The redox-reactive Hb induces oxidative stress and inflammation, disrupting the redox balance and impairing the immune response of immune cells. However, how the cytotoxic Hb affects the head-kidney macrophages in grass carp remains unclear. Here, we showed that the head-kidney macrophages in grass carp were capable of engulfing large amounts of Hb. The incubation with Hb increased the level of intracellular reactive oxygen species (ROS) in head-kidney macrophages through the Fenton reaction of Hb. The results of quantitative real-time PCR and RNA-seq analyses indicated that the high oxidation activity of Hb up-regulated the expression of proinflammation cytokines in head-kidney macrophages. Apoptosis detection suggested that the incubation of Hb induced the apoptosis of macrophages and up-regulated the transcription of apoptosis-related genes, which was likely mediated through the ROS released by Hb. Overall, these data demonstrate that Hb can stimulate inflammation and induce apoptosis in head-kidney macrophages. • Head-kidney macrophages in grass carp were capable of engulfing of Hb. • Hb increased the level of intracellular ROS in head-kidney macrophages. • Hb up-regulated the expression of proinflammation cytokines in macrophages. • Hb induced the apoptosis in head-kidney macrophages. [ABSTRACT FROM AUTHOR]

Fas-associated protein with Death Domain (FADD) is closely associated with cell death and plays a key role in hematopoiesis, cell cycle regulation, embryogenesis, and particularly, innate immune signaling. However, the mechanisms underlying the apoptotic and immune responses against bacterial infection associated with FADD in teleost fish have yet to be elucidated. In this study, we attempted to identify these mechanisms by cloning and characterizing the FADD gene in Ctenopharyngodon idellus (grass carp) (GcFADD). The ORF (open reading frame) of GcFADD was 579 bp and encoded a 22.169 kDa putative protein consisting of 192 amino acids. Phylogenetically, the identity of the deduced amino acid sequence was similar to that of other teleost and contained both DEATH and DED domains. In healthy grass carp, the mRNA transcripts of GcFADD were detectable in a range of tissues, in the following order of expression (high to low): liver > middle kidney > head-kidney > heart > gills > spleen > intestines > muscle > brain. In addition, the mRNA transcription and protein expression of GcFADD following infection by Aeromonas hydrophila and Staphylococcus aureus were predominantly up-regulated in the head-kidney, spleen, and liver tissues. Moreover, when a C. idellus kidney (CIK) cell line was incubated with LPS and LTA, the expression of GcFADD transcripts was also considerably up-regulated. In addition, the overexpression of GcFADD in CIK cells activated the significant expression of apoptosis-related genes, including p53 , CytoC , caspase-3 , caspase-8 , and caspase-9. Herein, we demonstrated that GcFADD plays a significant role in innate immunity. Our findings indicate the potential framework by which teleost acquire antibacterial immunity. • FADD cDNA was isolated and successfully cloned from grass carp (GcFADD). • GcFADD was expressed in all the tissues examined in healthy grass carp. • The transcripts and protein levels of GcFADD were significantly up-regulated after S. aureus and A. hydrophila infection. • In CIK cells, overexpression of GcFADD in CIK cells could activate apoptosis-related genes. • GcFADD has a significant role in the apoptosis pathway of grass carp innate immunity. [ABSTRACT FROM AUTHOR]

The fruit of Lycium ruthenicum Murr is used as traditional medicine and functional food. Previously we reported that one RG-I pectin from this fruit might inhibit pancreatic cancer cells growth. We further hypothesized that there might be other type of polysaccharides in this fruit also have anti-tumor effect. Here, we showed novel structure of a homogeneous polysaccharide named LRP1-S2 from this fruit and its anti-pancreatic cancer effect. Structure analyses suggested that LRP1-S2 was a novel arabinogalactan with the molecular weight (Mw) of 17.0 kDa. Bioactivity test showed that LRP1-S2 might attenuate the proliferation of pancreatic cancer cells in vitro and in vivo without significant cytotoxicity to normal pancreatic HPDE6-C7 cells and LO2 liver cells. Mechanism study indicated that it might induce apoptosis of BxPC-3 by inactivating P38 MAPK/NF-κB and GSK-3β/β-Catenin signaling pathways. These results suggested that LRP1-S2 could be a potential anti-tumor leading compound for functional food and new drug development. arabinogalactan, pectin, galactan, arabinan, RN-1, HH1-1, LRP1-S2, LRP3-S1. [Display omitted] • A novel polysaccharide named LRP1-S2 is characterized from Lycium ruthenicum. • LRP1-S2 is an novel arabinogalactan mainly contained galactose and arabinose. • LRP1-S2 impedes the proliferation of pancreatic cancer cells. • LRP1-S2 induces apoptosis of BxPC-3 via MAPK/NF-κB and GSK-3β/β-Catenin signaling. [ABSTRACT FROM AUTHOR]

[Display omitted] • Bioactivity-guided isolation for Aglaia abbreviata , which led to isolation of 19 compounds (16 steroids). • Nine steroids exhibited good selective anti-leukemic activity. • All active compounds showed lower toxicity on human normal liver cell line. • Compound 14 induced apoptosis through influencing the key apoptotic related proteins. The strategy of bioactivity-guided isolation is widely used to obtain active compounds as quickly as possible. Thus, the inhibitory effects on human erythroleukemia cells (HEL) were applied to guide the isolation of the anti-leukemic compounds from Aglaia abbreviata. As a result, 19 compounds (16 steroids, two phenol derivatives, and a rare C12 chain nor-sesquiterpenoid), including 13 new compounds, were isolated and identified based on spectroscopic data analysis, single-crystal X-ray diffraction data, and electronic circular dichroism (ECD) calculations. Among them, 9 steroids exhibited good selective anti-leukemic activity against HEL and K562 (human chronic myeloid leukemia cells) cells with IC 50 values between 2.29 ± 0.18 μM and 19.58 ± 0.13 μM. Notably, all the active compounds had relatively lower toxicity on the normal human liver cell line (HL-7702). Furthermore, five compounds (1 , 4 , 8 , 10 , and 19) displayed good anti-inflammatory effects, with IC 50 values between 7.15 ± 0.16 and 27.1 ± 0.37 μM. An α,β-unsaturated ketone or a 5,6Δ double bond was crucial for improving anti-leukemic effect from the structure–activity relationship analysis. The compound with the most potential, 14 was selected for the preliminary mechanistic study. Compound 14 can induce apoptosis and cause cell cycle arrest. The expression of the marker proteins, such as PARP and caspase 3, were notably effected by this compound, thus inducing apoptosis. In conclusion, our investigation implied that compound 14 may serve as a potential anti-leukemia agent. [ABSTRACT FROM AUTHOR]

Zukamu Granules (ZKMG) is one of the representative Uygur patent drugs widely used in China, which is included in the National Essential Drugs List (2018 edition). As the first choice for common cold treatment in Uygur medicine theory, it has unique anti-inflammatory and antitussive efficacy. According to the recent inflammatory hypothesis, the abnormal proliferation, autophagy and apoptosis process of lung cells especially alveolar macrophages (AMs) may play an important role in the progress of idiopathic pulmonary fibrosis (IPF). Therefore, we came up with a novel treatment approach for IPF by regulating the balance of AMs "autophagy - apoptosis", and took ZKMG as the sample drug for our research. Network pharmacology approach was conducted to predict the active components and intersected targets between ZKMG and inflammation. PPI network, GO and KEGG enrichment analysis were screened and analyzed to predict the anti-inflammatory mechanism of ZKMG. Biological experiment adopted from 128 rats, and hematoxylin-eosin staining, flow cytometry and RT-PCR were performed to examine the pathological morphology, HYP contents in lung tissue, AMs counting, AMs apoptosis, AMs phagocytosis rate, mRNA relative quantity determination of 3 key factors associated with AMs "autophagy - apoptosis" and mRNA relative quantity determination of AMs surface receptor signaling pathway. The predicted results showed that the mechanism of ZKMG in anti-inflammatory was related to the response and elimination of inflammatory stimuli, the intervention of apoptosis and surface receptor signaling pathways of cells. The verification experiments showed that excessive apoptosis and insufficient autophagy of AMs always existed in the progression of IPF. ZKMG could inhibit AMs proliferation, significantly reduce AMs apoptosis rate, intervene the binding of the Bcl-2 to Beclin 1, inhibit the Caspase 3 activation, stimulate the enhancement of AMs phagocytosis, and inhibit the high expression of TLR4/MyD88/NF-κB surface receptor signaling pathway, which may partly retard the fibrosis process. By inhibiting proliferation, enhancing phagocytosis, inhibiting the formation of Bcl-2 complex, and inhibiting the high expression of MYD88-dependent TLR4 signaling pathway, ZKMG can regulate the balance of AMs "autophagy - apoptosis" in the alveolitis stage to retard the fibrosis process partly. With a comprehensive strategy of "target prediction - experimental verification", we have demonstrated that inhibiting the apoptosis and promoting autophagy activity of AMs may suggest a new perspective for IPF treatment, which would provide reference for the subsequent development. [Display omitted] • Excessive apoptosis and insufficient autophagy exist in idiopathic pulmonary fibrosis. • Zukamu Granules retarded bleomycin induced idiopathic pulmonary fibrosis process. • Network pharmacology analysis revealed Zukamu Granules regulating apoptosis. • Zukamu Granules inhibited apoptosis and promoted autophagy of alveolar macrophages. • Zukamu Granules inhibited the TLR4/MyD88/NF-κB pathway of alveolar macrophages. [ABSTRACT FROM AUTHOR]

Fish blood contains RBCs (Red blood cells) as the major cells. Unlike the absence of nucleus in mammalian RBC, fish RBC contains a nucleus. Previous researches have indicated that fish RBCs have a significant function in immune responses. However, the mechanism underlying the immune responses against bacterial infection of teleost RBCs remains enigmatic. To decipher the mechanisms, after the infection of Aeromonas hydrophila , transcriptomic profiling of grass carp RBCs was analyzed. Outcomes demonstrated that there were 2144 altogether DEGs (Differently Expressed Genes) between the A. hydrophila -infected and non-infected groups, which includes 817 up-regulated and 1327 down-regulated DEGs. Differently Expressed Genes were allocated to 45 GO terms, including 20 natural procedure terms, 14 cell related element, and 11 terms related to molecular functions. In addition, to validate our transcriptomic data, the expression levels of cytokines by Quantitative Reverse Transcription Polymerase Chain Reaction showed that they (e.g. CCL4 , CCL11 , CCL20 , IL-4 , IL-12 , and IFNα) were significantly increased after A. hydrophila infection, which was identical to the expression patterns of transcriptomic data. The infection could cause the apoptosis of RBCs which was confirmed by annexin V/PI assay. To further elucidate the apoptosis pathway, the expression levels of genes by mRNA included in cellular apoptosis were monitored. The outcomes indicated that the expressions of mRNA of p53 , Fas , Leucine-rich repeats, death domain-containing (LRDD) and caspase 8 were all significantly increased, respectively. Our results support the notion that A. hydrophila infection could activate Fas-related death receptor apoptosis pathway in grass carp RBCs, which will reveal another insight on the mechanisms underlying the antibacterial immunity of teleost fish RBCs. • A. hydrophila infection induced 2144 DEGs in grass carp RBCs. • The expression levels of cytokines were significantly increased after A. hydrophila infection. • Death receptor apoptosis pathway was activated in A. hydrophila -infected grass carp RBCs. • Teleost fish erythrocyte has an important role in antibacterial innate immune response. [ABSTRACT FROM AUTHOR]

In cancers, apoptosis evasion through dysregulation of pro-apoptotic and anti-apoptotic intracellular signals is a recurring event. Accordingly, selective inhibition of specific proteins represents an exciting therapeutic opportunity. Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic protein of the BCL-2 family, which is overexpressed in many cancers. Here, we demonstrate that MCL1 can be modified by the small ubiquitin-like modifier (SUMO) at K234 and K238 sites. The SUMOylation of MCL1 can improve its stability by inhibiting the MCL1 ubiquitin-proteasome pathway mediated by the Tripartite motif-containing 11 (TRIM11, a novel MCL1 ubiquitin E3 ligase that we identify in this study). Moreover, SUMOylation of MCL1 increases the proliferation of cancer cells by inhibiting apoptosis. These results suggest that the SUMOylation of MCL1 may play a significant role in the regulation of its function. • MCL1 can be modified by SUMOs • MCL1 SUMOylation upregulatesits stability • TRIM11 is a novelubiquitin E3 ligase of MCL1 • SUMOylation of MCL1 inhibits TRIM11-mediated MCL1 ubiquitination • SUMOylation of MCL1 promotes theproliferation ofcancer cells [ABSTRACT FROM AUTHOR]