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Medication-related osteonecrosis of the jaw (MRONJ) represents a rare yet serious adverse reaction associated with the prolonged use of anti-bone resorptive or anti-angiogenic agents. This study aimed to investigate the impact and underlying mechanisms of adipose-derived stem cells (ADSCs) in preventing MRONJ in a mouse model. Following tooth extraction in MRONJ mice, ADSCs or PBS were administered via the tail vein. The healing progress of gingival epithelium and the extraction socket was assessed using a stereoscopic microscope and histological analysis. Immunofluorescence was employed to examine markers associated with autophagy (LC3 and SQSTM1) and apoptosis (Cleaved-CASP 3). Statistical analysis involved unpaired Student's t-test and ANOVA on ABI Prism 7500, with P-values below 0.05 deemed statistically significant. ADSCs enhanced gingival epithelium migration and facilitated new bone formation. In the MRONJ group, the expressions of autophagy-related protein LC3 and SQSTM1 in gingival epithelium were concurrently elevated, which indicated autophagic flux was impaired. Conversely, when treated with ADSCs, the expression of LC3 and SQSTM1 were downregulated, similarly to the Control group. Mechanically, zoledronate induced a deficiency of autophagosome–lysosome fusion in epithelial cells, while ADSCs supernatant could promote the autolysosomes formation. Furthermore, ADSCs rescued the number of autophagy-related apoptotic cells in the gingival epithelium of MRONJ. ADSCs could effectively prevent the occurrence of MRONJ, likely through the activation of autophagic flux and the inhibition of autophagy-related apoptosis in gingival epithelium. These findings enhanced the understanding of MRONJ pathogenesis and propose a potential therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics. It has made significant progress in breaking the limitations of monotherapy and effectively eradicating tumors, especially when combined with traditional therapy, such as radiotherapy. According to their different biological characteristics, bacteria and their derivatives can not only improve the sensitivity of tumor radiotherapy but also protect normal tissues. Moreover, genetically engineered bacteria and bacteria-based biomaterials have further expanded the scope of their applications in radiotherapy. In this review, we have summarized relevant researches on the application of bacteria and its derivatives in radiotherapy in recent years, expounding that the bacteria, bacterial derivatives and bacteria-based biomaterials can not only directly enhance radiotherapy but also improve the anti-tumor effect by improving the tumor microenvironment (TME) and immune effects. Furthermore, some probiotics can also protect normal tissues and organs such as intestines from radiation via anti-inflammatory, anti-oxidation and apoptosis inhibition. In conclusion, the prospect of bacteria in radiotherapy will be very extensive, but its biological safety and mechanism need to be further evaluated and studied. Combined with radiotherapy, cancer therapy based on bacteria, bacteria metabolites and bacteria-based biomaterials can enhance the killing effect of tumor and the protective effect of normal tissue through various mechanisms. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Cukurova Medical Journal / Çukurova Üniversitesi Tip Fakültesi Dergisi is the property of Cukurova University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Peste des petits ruminants (PPR), caused by the PPR virus (PPRV), is an acute and fatal contagious disease that mainly infects goats, sheep, and other artiodactyls. Peripheral blood mononuclear cells (PBMCs) are considered the primary innate immune cells. Objectives: PBMCs derived from goats were infected with PPRV and analyzed to detect the relationship between PPRV replication and apoptosis or the inflammatory response. Methods: Quantitative real-time polymerase chain reaction was used to identify PPRV replication and cytokines expression. Flow cytometry was conducted to detect apoptosis and the differentiation of CD4+ and CD8+ T cells after PPRV infection. Results: PPRV stimulated the differentiation of CD4+ and CD8+ T cells. In addition, PPRV induced apoptosis in goat PBMCs. Furthermore, apoptosis and the inflammatory response induced by PPRV could be suppressed by Z-VAD-FMK and Z-YVAD-FMK, respectively. Moreover, the virus titer of PPRV was attenuated by inhibiting caspase-1-dependent apoptosis and inflammation. Conclusions: This study showed that apoptosis and the inflammatory response play an essential role in PPR viral replication in vitro, providing a new mechanism related to the cell host response. [ABSTRACT FROM AUTHOR]

Myocardial ischemia-reperfusion injury (MI/RI) seriously restricts the therapeutic effect of reperfusion. It is demonstrated that ferroptosis and apoptosis of cardiomyocytes are widely involved in MI/RI. Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Besides, transferrin receptor 1 (TfR1) is highly expressed in ischemic myocardium, and apoferritin (ApoFn) is a ligand of the transferrin receptor. In this study, CsA@ApoFn was prepared by wrapping cyclosporin A (CsA) with ApoFn and actively accumulated in ischemic cardiomyocytes through TfR1 mediated endoctosis in MI/RI mice. After entering cardiomyocytes, ApoFn in CsA@ApoFn inhibited ferroptosis of ischemic cardiomyocytes by increasing the protein expression of GPX4 and reducing the content of labile iron pool and lipid peroxides. At the same time, CsA in CsA@ApoFn attenuated the apoptosis of ischemic cardiomyocytes through recovering mitochondrial membrane potential and reducing the level of reactive oxygen species, which played a synergistic role with ApoFn in the treatment of MI/RI. In conclusion, CsA@ApoFn restored cardiac function of MI/RI mice by simultaneously blocking ferroptosis and apoptosis of cardiomyocytes. ApoFn itself not only served as a safe carrier to specifically deliver CsA to ischemic cardiomyocytes but also played a therapeutic role on MI/RI. CsA@ApoFn is proved as an effective drug delivery platform for the treatment of MI/RI. Recent studies have shown that ferroptosis is an important mechanism of myocardial ischemia-reperfusion injury (MI/RI). Therefore, simultaneous inhibition of ferroptosis and apoptosis of cardiomyocytes can be a promising strategy to treat MI/RI. Apoferritin, as a delivery carrier, can actively target to ischemic myocardium through binding with highly expressed transferrin receptor on ischemic cardiomyocytes. At the same time, apoferritin plays a protective role on ischemic cardiomyocytes by inhibiting ferroptosis. This strategy of killing two birds with one stone significantly improves the therapeutic effect on MI/RI while does not need more pharmaceutical excipients, which has the prospect of clinical transformation. [Display omitted] [ABSTRACT FROM AUTHOR]

Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are poor‐prognosis cancers that lack effective targeted therapies and harbor embryonic stem gene expression signatures. Recently, our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 (a cell‐permeable small molecule that directly binds to unphosphorylated FOXO1 protein to block transcriptional regulation) on BBC and GBM cell viability. We treated a set of BBC and GBM cancer cell lines with increasing concentrations of AS1842856 and found reduced colony formation. Treatment of BBC and GBM cancer cells with AS1842856 led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide. Treatment with another FOXO1 inhibitor AS1708727 or FOXO1 RNAi also led to FAS induction. This work is the first to show that targeting BBC and GBM with FOXO1 inhibition leads to apoptosis. These novel findings may ultimately expand the repertoire of therapies for poor‐prognosis cancers. [ABSTRACT FROM AUTHOR]

Medicinal plants are rich in nutrients and phytochemicals which prevent and treat a wide range of ailments. Accumulating experimental studies exhibit that some bioactive ingredients extracted from medicinal plants have suitable therapeutic effects on hepatic and renal injuries. This review focuses on the hepatoand reno-protective effects of thymoquinone, crocin, and carvacrol. The relevant literature was retrieved from PubMed, Scopus, Web of Science, and Google Scholar databases from the beginning of 2015 until the end of November 2021. According to the scientific evidence, the considered phytochemicals in this review have been applied with useful therapeutic effects on hepatic and renal damage. These therapeutic effects were mainly mediated through the amelioration of oxidative stress, suppression of inflammatory responses, and inhibition of apoptosis. Intracellular signaling pathways linked to nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase, c-jun N-terminal kinase, and extracellular signal-regulated kinase 1/2 and Toll-like receptors are the most important pathways targeted by these phytochemicals. Up-regulation of transcription factor Nrf2 and down-regulation of transforming growth factor-beta 1 by these natural compounds also contribute to the alleviation of hepatic and renal injuries. [ABSTRACT FROM AUTHOR]

Copyright of Cukurova Medical Journal / Çukurova Üniversitesi Tip Fakültesi Dergisi is the property of Cukurova University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family which are implicated in development of cancer through the inhibition of apoptosis process. This case-control study was intended to investigate livin/BIRC7 gene expression in endometrial hyperplasia and carcinoma and its correlation to some oxidative stress markers in addition to its possible diagnostic performance. Methods: This study included 90 participants [30 endometrial hyperplasia patients, 30 endometrial carcinoma patients, and 30 healthy controls]. Livin/BIRC7 gene expression was analyzed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Serum catalase activity was assessed by enzyme-linked immunosorbent assay (ELISA) and malondialdehyde level was measured by the colorimetric method. Results: Livin/BIRC7 gene expression was significantly (p < 0.001) higher in endometrial carcinoma from patients with endometrial hyperplasia when compared to controls. A positive correlation was found between livin/BIRC7 expression and serum catalase activity and malondialdehyde level in endometrial hyperplasia and carcinoma. The detection of livin/BIRC7 in endometrial carcinoma has excellent sensitivity and specificity. Conclusions: Livin/BIRC7 was overexpressed in endometrial carcinoma with excellent power to differentiate endometrial carcinoma from endometrial hyperplasia or healthy subjects, suggesting that it might be a useful molecular marker for endometrial carcinoma diagnosis. [ABSTRACT FROM AUTHOR]

Lead (Pb) is a heavy metal that has been recognized as a neurotoxin, meaning it can cause harmful effects on the nervous system. However, the neurotoxicology of Pb to birds still needs further study. In this study, we examined the neurotoxic effects of Pb exposure on avian cerebellum by using an animal model-Japanese quail (Coturnix japonica). The one-week old male chicks were exposed to 50, 200 and 500 mg/kg Pb of environmental relevance in the feed for five weeks. The results showed Pb caused cerebellar microstructural damages charactered by deformation of neuroglia cells, granule cells and Purkinje cells with Nissl body changes. Moreover, cerebellar neurotransmission was disturbed by Pb with increasing acetylcholine (ACh) and decreasing acetylcholinesterase (AChE), dopamine (DA), γ-Aminobutyric Acid (GABA) and Na+/K+ ATPase. Meanwhile, cerebellar oxidative stress was caused by Pb exposure represented by increasing reactive oxygen species (ROS) and malondialdehyde (MDA) as well as decreasing catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH) and superoxide dismutase (SOD). Moreover, RNA-Seq analysis showed that molecular signaling pathways in the cerebellum were disrupted by Pb exposure. In particular, the disruption of nuclear factor erythroid-2-related factor 2 (Nfr2)/kelch-like ECH-associated protein 1 (Keap1) pathway and glutathione metabolism pathway indicated increasing cell apoptosis and functional disorder in the cerebellum. The present study revealed that Pb induced cerebellar toxicology through structural injury, oxidative stress, neurotransmission interference and abnormal apoptosis. [Display omitted] • Pb exposure induced microstructural injury in the cerebellum of Japanese quails. • Pb exposure interfered with cerebellar neurotransmission. • Pb caused neurotoxicology through oxidative stress to the cerebellum. • Pb led to cerebellar apoptosis via Nrf2-regulated glutathione metabolism disruption. [ABSTRACT FROM AUTHOR]

To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells. Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1). High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients. The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor. [ABSTRACT FROM AUTHOR]

During the early phase of tumorigenesis, primary malignant cells survive within a low nutrition environment caused by a poorly organized vascular system. Here, we sought to determine the functional significance of CD133 in the survival of cancer cells under nutrient‐poor conditions. Knockdown and overexpression experiments demonstrated that CD133 suppresses colon cancer cell death induced by serum deprivation through activation of Akt‐mediated anti‐apoptosis and protein synthesis pathways. Furthermore, serum deprivation increased the amount of endogenous CD133 protein, which was regulated at least in part by phosphoinositide 3‐kinase. Thus, it is highly likely that CD133 contributes to the acquisition/maintenance of the resistance to stress arising from nutrient deficiency in early avascular tumor tissues. [ABSTRACT FROM AUTHOR]

Acquired and intrinsic radioresistance remains a major challenge during the treatment of patients with colorectal cancer (CRC). Aberrant cholesterol metabolism precipitates the development of multiple cancers. Here, we report that exogenous or endogenous cholesterol enhances the radioresistance of CRC cells. The addition of cholesterol protects CRC cells against irradiation both in vitro and in vivo. Sterol response element‐binding protein 1/fatty acid synthase (SREBP1/FASN) signaling is rapidly increased in response to radiation stimuli, resulting in cholesterol accumulation, cell proliferation and inhibition of apoptosis. Blocking the SREBP1/FASN pathway impedes cholesterol synthesis and accelerates radiation‐induced CRC cell death. Our findings provide novel insights into the role of the SREBP1/FASN/cholesterol axis in radiotherapy and suggest that it may be a potential target for CRC treatment. Clinically, our results suggest that CRC patients undergoing radiotherapy may benefit from a lowered cholesterol intake. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a regressive joint disease that mainly affects the cartilage and surrounding tissues. Mounting studies have confirmed that the paracrine effect is related to the potential mechanism of mesenchymal stem cell (MSC) transplantation and that small extracellular vesicles (sEVs) play an imperative role in this paracrine signaling. In fact, hypoxia can significantly improve the effectiveness of MSC transplantation in various disease models. However, it remains unknown whether MSCs in the state of a hypoxic environment can enhance OA cartilage repair and whether this enhancement is mediated by sEV signaling. The primary aim of the present study was to determine whether sEVs from MSCs in the state of hypoxia (Hypo-sEVs) have a superior effect on OA cartilage repair relative to sEVs from MSCs in the normoxia (Nor-sEVs) state. By using an OA model and performing in vitro studies, we verified that Hypo-sEV treatment facilitated the proliferation, migration, and apoptosis suppression of chondrocytes to a greater extent than Nor-sEV treatment. Furthermore, we verified the functional role of sEV miR-216a-5p in the OA cartilage repair process. We also identified JAK2 as the target gene of sEV miR-216a-5p through a series of experiments. Our findings indicated that HIF-1α induces hypoxic BMSCs to release sEVs, which promote the proliferation, migration, and apoptosis inhibition of chondrocytes through the miR-216a-5p/JAK2/STAT3 signaling pathway. Therefore, hypoxic pretreatment is a prospective and effective method to maximize the therapeutic effect of MSC-derived sEVs on OA. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is an age‐related, chronic degenerative disease. With the increasing median age of the population, this disease has become an important public health problem. New, disease‐modifying therapies are needed. A potential novel molecular target is phospholipase Cγ1 (PLCγ1), a critical enzyme with important functions including calcium signaling regulation and cell proliferation. In rat chondrocytes treated with IL‐1β (20 ng·mL−1 for 36 h), inhibition of PLCγ1 with U73122 (2 μm for 12 h) increased levels and expression of the cartilage matrix components Collagen2 and Aggrecan. This beneficial effect of PLCγ1 inhibition was counteracted by increased chondrocyte apoptosis and necroptosis, increased cell death, and increase levels of ROS, all potentially negative for OA. Combined treatment of IL‐1β + U73122‐treated chondrocytes with inhibitors of apoptosis (Z‐VAD, 10 μm) and necroptosis (Nec‐1, 30 μm) enhanced the increases in levels and expression of Collagen2 and Aggrecan, and prevented the increases in cell death and ROS levels. These results suggest that PLCγ1 inhibition may be a viable approach for an OA therapy, if combined with targeted inhibition of chondrocyte apoptosis and necroptosis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common hematologic malignancy of immunoglobulin‐secreting plasma cells. Recent modern combination therapies have improved survival rates, but many patients develop resistance to novel drugs, leading to relapse. Trifluoperazine (TFP), a typical antipsychotic drug, has been reported to exert antitumor effects by targeting various pathways. Thus far, the role of TFP in MM has not been elucidated. In the current study, we demonstrated that TFP inhibited cell growth and autophagy activity but induced apoptosis of U266 and RPMI 8226 MM cells. Furthermore, cotreatment of these cell lines with TFP and rapamycin, a potent autophagy inducer, reduced cell apoptosis compared with TFP treatment alone. We also found that TFP inhibited nuclear protein 1 (NUPR1) expression. In the presence of TFP, cells stably overexpressing NUPR1 showed a higher viability than cells treated with the nonspecific control. Autophagy suppression and apoptosis induction caused by TFP were also reversed in MM cells upon NUPR1 overexpression. Overall, our results indicate that in the context of MM, TFP targets NUPR1, inhibiting cell growth and inducing apoptosis by autophagy inhibition. Our results could contribute toward efforts for the development of more effective therapies for MM to be tested in future clinical trials. [ABSTRACT FROM AUTHOR]

Nickel (Ni), an environmental health hazard, is nephrotoxic to humans, but the exact mechanism is unknown. This study aims to identify whether nephrotoxicity is associated with autophagy. Here, nickel chloride (NiCl 2) increased autophagy in TCMK-1 cells. NiCl 2 induces autophagy through Akt and AMPK/mTOR pathways. Next, oxidative stress was investigated in NiCl 2 -induced autophagy. The findings demonstrated that the antioxidant (NAC) or mitochondrial targeted antioxidant (Mito-TEMPO) attenuated NiCl 2 -induced autophagy, reversed the influence on AMPK-mTOR and Akt pathways. Additionally, our study examined the role of autophagy in NiCl 2 -induced nephrotoxicity. Autophagy inhibition with 3-MA could inhibit cell viability and increase apoptosis in the TCMK-1 cells, however, autophagy promotion with rapamycin relieved cytotoxicity and decreased apoptosis. Additionally, co-treatment with Z-VAD-FMK reduced cytotoxicity, but did not affect autophagy. Besides, NiCl 2 can increase the level of mitophagy in vivo and vitro. Mitophagy inhibition could inhibit cell viability and increase apoptosis in the TCMK-1 cells, whereas, promotion of mitophagy could increase cell viability and decrease apoptosis. In summary, above-mentioned results showed that NiCl 2 induces autophagy in TCMK-1 cells through oxidative stress-dependent AMPK/AKT-mTOR pathway, autophagy plays a role in reducing NiCl 2 -induced renal toxicity, and a major mechanism in autophagy's inhibitory effect on NiCl 2 -induced apoptosis may be mitophagy. [Display omitted] • Ni exposure induces autophagy through oxidative stress-dependent AMPK/AKT-mTOR pathway in TCMK-1 cells. • Autophagy plays a protective role in NiCl 2 -induced renal toxicity. • High Ni exposure could induce renal mitophagy in vivo and in vitro. • Mitophagy is one of the important mechanisms in the inhibition of apoptosis induced by NiCl 2. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS) is recognized as an environmental endocrine disruptor with widespread use in industrial manufacturing and daily life, contributing to various public health concerns. However, the precise impacts of PFOS on the ovary and its regulatory mechanisms remain unclear. This study aims to delineate the ovarian toxicity of PFOS and scrutinize its effects on apoptosis and autophagy through modulation of the PI3K/AKT/mTOR pathway in the human granulosa cell line (KGN). Cell viability, assessed via the Cell Counting Kit-8 (CCK8), revealed a dose-dependent reduction in cell viability upon PFOS exposure. Flow cytometry analysis demonstrated an elevated proportion of apoptotic cells following PFOS treatment. Western blot analyses unveiled increased expression of Bax, Cyt c , cleaved caspase-9, and LC3-II/I, coupled with decreased expression of Bcl-2 and p62. Transmission electron microscopy (TEM) observations illustrated a heightened number of autophagosomes induced by PFOS. Molecular docking investigations, in conjunction with Western blot experiments, substantiated PFOS's significant inhibition of the PI3K/AKT/mTOR signaling pathway. These findings collectively underscore that PFOS induces apoptosis and autophagy in KGN cells through modulation of the PI3K/AKT/mTOR pathway, providing experimental evidence for PFOS-induced ovarian toxicity and elucidating the underlying regulatory mechanisms in KGN cells. [Display omitted] • To investigate toxic effects and regulatory mechanism of PFOS to KGN cells. • PFOS decreased the viability of KGN cells and thus induced ovarian toxicity. • PFOS-activated apoptosis and autophagy accompany mitochondria structure disorder. • Apoptosis and autophagy induced by PFOS may mediated by the PI3K/AKT/mTOR pathway. [ABSTRACT FROM AUTHOR]

Waterborne exposure to arsenic trioxide (As 2 O 3) is inevitable due to its widespread industrial and agricultural applications. Oxidative stress and cascaded programmed cell death is now hypothesized to be the dominant mechanisms of arseniasis evidenced in vivo and in vitro. This study aimed to explore the interaction of divalent zinc ion (Zn2+), an efficient reactive oxygen species (ROS) scavenger with arsenite in the heart of common carp, and extensively investigated the exact signaling molecules involved. Significant induction of cardiotoxicity including oxidative stress, apoptosis and autophagy was evident in heart tissues following arsenite exposure (P < 0.05). The dissipation of antioxidant enzymes (SOD and CAT) was induced by ROS burst, leading to oxidative damage and lipid peroxidation (MDA). Arsenite induced classic apoptotic hallmarks, characterized by chromatin degradation and subsequent formation of clumps adjacent, and elevated expression of Bax/Bcl-2 and Caspase family, and also increased autophagic flux evidenced by accelerated formation (LC3) and degradation (p62) of autophagosomes. PI3K/Akt/mTOR pathway was phosphorylated inhibited, while MAPK signaling (p38, ERK and JNK) displayed elevated phosphorylation levels in arsenite-exposed heart tissues. In contrast, above phenomena were effectively inhibited by Zn2+, which supplement attenuated arsenite-induced myocardial toxicity through inhibition of apoptosis and autophagy via PI3K/Akt/mTOR pathway, as well as suppressing intracellular ROS cluster via activating antioxidative system via MAPK pathway. Our results provided experimental explanation and evidences for cardiotoxicity of arsenite. Furthermore, our findings hint that the application of zinc preparations may provide a candidate for the prevention and treatment for arsenic poisoning. Image 1 • Arsenic cardiac accumulation induces ROS burst and collapse of antioxidant system. • Apoptosis and autophagy are induced under arsenic stress. • Zinc antagonizes cardiotoxicity of arsenic via MAPK and PI3K/Akt/mTOR pathways. [ABSTRACT FROM AUTHOR]

• Apoptosis and oxidative stress are the main mechanisms of hepatic IR injury. • CoQ 10 exhibited a potent anti-apoptotic activity. • CoQ 10 regulates Bax/Bcl-2/PUMA, PI3K/Akt/mTOR and GSK-3β/β-catenin signaling pathways. • CoQ 10 suppressed NF-κB-p65 and JAK1/STAT-3 expressions. • CoQ 10 up-regulated Nrf-2, Sirt-1 and FOXO-3 expressions. Coenzyme Q 10 (CoQ 10) is a component of the mitochondrial electron transport chain and regarded as a strong anti-oxidant agent. In this study, we focused on the mechanistic insights involved in the hepato-protective effects of CoQ 10 against hepatic ischemia reperfusion (IR) injury. Our results revealed that CoQ 10 significantly improved hepatic dysfunctions and oxidative stress caused by IR injury. Interestingly, as compared to IR subjected rat, CoQ 10 inhibited apoptosis by marked down-regulation of both Bax and PUMA genes while the level of Bcl-2 gene was significantly increased. Moreover, CoQ 10 up-regulated PI3K, Akt and mTOR protein expressions while it inhibited the expression of both GSK-3β and β-catenin. Additionally, CoQ 10 restored oxidant/antioxidant balance via marked activated Nrf-2 protein as well as up-regulation of both Sirt-1 and FOXO-3 genes. Moreover, CoQ 10 strongly inhibited inflammatory response through down-regulation of NF-κB-p65 and decrease both JAK1 and STAT-3 protein expressions with a subsequent modulating circulating inflammatory cytokines. Furthermore, histopathological analysis showed that CoQ 10 remarkably ameliorated the histopathological damage induced by IR injury. Taken together, our results suggested and proved that CoQ 10 provided a hepato-protection against hepatic IR injury via inhibition of apoptosis, oxidative stress, inflammation and their closed related pathways. [ABSTRACT FROM AUTHOR]

Neuronal apoptosis is the main pathological feature of spinal cord injury (SCI), while autophagy contributes to ameliorating neuronal damage via inhibition of apoptosis. Here, we investigated the role of tectonic family member 2 (TCTN2) long non‐coding RNA on apoptosis and autophagy in SCI. TCTN2 was down‐regulated in the spinal cord tissues of a rat model of SCI and in oxygen–glucose deprivation‐induced hypoxic SY‐SH‐5Y cells, while microRNA‐216b (miR‐216b) was up‐regulated. Overexpression of TCTN2 reduced neuron apoptosis by inducing autophagy, and TCTN2 was observed to negatively regulate miR‐216b. Furthermore, TCTN2 promoted autophagy to repress apoptosis through the miR‐216b–Beclin‐1 pathway, and overexpression of TCTN2 improved neurological function in the SCI rat model. In summary, our data suggest that TCTN2 enhances autophagy by targeting the miR‐216b–Beclin‐1 pathway, thereby ameliorating neuronal apoptosis and relieving spinal cord injury. [ABSTRACT FROM AUTHOR]

Recent evidence has suggested that cadmium (Cd) ions-induced neurotoxicity is associated with increased oxidative stress and mitochondrial-dependent and endoplasmic reticulum (ER) stress-induced apoptosis. This study aimed to investigate if rutin hydrate (RH), a well-reported neuroprotective and an antioxidant flavonoid, can ameliorate cadmium chloride (CdCl2)-induced neurotoxicity by inhibiting the resultant ER stress. Rats were divided into 4 groups (n = 16/group) of control, control + RH (100 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RH. All treatments were administered orally for 30 days, on daily basis. Brain homogenates from CdCl2-treated rats showed increased oxidative stress and induced activation of ER stress characterized by increasing mRNA and protein levels of GRP78, ATF-6, CHOP and Xbp-1 and protein levels of p-elF2α, p-JNK1/2 and cleaved caspase-12. Also, CdCl2 significantly reduced Bcl-2, enhanced Bax translocation to the mitochondrial membrane, increased cytoplasmic levels of cytochrome-C and caspase-3, and reduced mitochondrial membrane potential (Δψm) (increased Vmax and reduced time to Vmax). In contrast, RH significantly enhanced levels GSH and activities of SOD, GSH-Px, decreased levels of MDA and inhibited mitochondrial permeability transition pore (mtPTP) in the brains of both control and CdCl2-treated rats. Interestingly, in brain homogenates of CdCl2-treated rats only, RH reduced all markers of ER stress, increased Bcl-2, reduced mitochondrial Bax translocation and improved mitochondrial coupling. It also reduced cytosolic levels of cytochrome-C, cleaved caspase-3, and cleaved caspase-12. Overall, these findings support the efficiency of RH to inhibit ER stress in brains CdCl2-treated rats which is added to its existing mechanisms of neuroprotection. Abbreviations: ATF-6: activating transcription factor-6; Bax: Bcl-associated x; BBB: blood-brain barrier; Bcl-2: B-cell lymphoma 2; BiP: immunoglobulin heavy-chain-binding protein; [Ca2+]i: intracellular free Ca2+ concentration; Cd: cadmium; CdCl2: cadmium chloride; CHOP: CCAAT/enhancer-binding protein-homologous protein; CMC: carboxymethyl cellulose; Δψm: mitochondrial membrane potential; elF2α: phospho-eukaryotic translation initiation factor 2-alpha; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERK1/2: extracellular signal-regulated kinases 1 and 2; GADD 153: growth arrest and DNA damage-inducible protein 153; GRP78, 78 kDa glucose-regulated protein; GSH: reduced glutathione; GSH: reduced glutathione; GSH-Px: glutathione peroxidase; GSSG: glutathione disulfide (oxidized glutathione); IRE-1: inositol-requiring enzyme-1; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; mTOR: Akt/mammalian target of rapamycin; mtPTP: mitochondrial permeability transition pore; ONOO−: peroxynitrite; PCR: polymerase chain reaction; PERK: protein kinase RNA-like ER kinase; p-JNK: phospho-JNK; qPCR: quantitative PCR; RCR: respiratory control ratio; RH: rutin hydrate; RHoGDI: Rho-GDP-dissociation inhibitor; ROS: reactive oxygen species; SOD: superoxide dismutase; UPR: unfolded protein response; VDAC: voltage-dependent anion channel; Vmax: maximal rate of pore opening; Xbp-1: X-box binding protein 1. [ABSTRACT FROM AUTHOR]

Ibaraki virus (IBAV) is an arbovirus that is transmitted by biting midges and causes Ibaraki disease in cattle. IBAV induces apoptosis in several mammalian cell lines, and apoptosis in turn facilitates IBAV replication. In addition, virus-induced apoptosis may contribute to mammalian-specific pathogenicity considering that some arboviruses induce apoptosis in mammalian cells but not in insect cells. In this study, we found that when hamster lung cells (HmLu-1) are used as a virus host, IBAV causes severe cytopathic effects with little induction of apoptosis. Furthermore, pharmacological inhibition of apoptosis did not affect IBAV-induced cytotoxicity. These results indicate the existence of an apoptosis-independent pathway in which IBAV replicates and exerts cytotoxicity in mammalian cells. [ABSTRACT FROM AUTHOR]

Abstract Objective Our aim was to explore whether heat stress protein (HSP) 9 preferentially expresses under heat stress and affects the expression of other heat stress proteins as well as to explore the effect of HSPB9 overexpression and knockdown on apoptosis in DF-1. Methods We used gene cloning to construct an overexpression vector of the target gene, and synthesized the target gene interference fragment to transfect the chicken fibroblast cell line. Gene and protein expression, as well as apoptosis, were detected by RT-qPCR, Western blot, and flow cytometry. Results Chicken DF-1 cells showed an early state of apoptosis in the early stages of HSPB9 overexpression. In the later stages, as HSPB9 expression increased, the cells showed inhibition of apoptosis. When the cells were under heat stress, HSPB9 expression was much higher and earlier than the expression of HSPB1 and HSPA2. In addition, high expression of HSPB9 had a negative effect on HSPB1 and HSPA2 expression. This negative feedback decreased the percentage of early stages of apoptotic cells and promoted cell survival. Conclusion HSPB9 expression, although rapid, is detrimental to cell survival early during its overexpression. In heat stress, HSPB9 overexpression, while inhibiting the expression of HSPA2 and HSPB1, is beneficial to cell survival. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is the most important environmental pollution in the world. Ni has been confirmed to have multi-organ toxicology and carcinogenicity. Recently, Ni also can impair the male reproductive system, however, its precious mechanism still has not been clarified. The current work found that nickel chloride (NiCl 2) induced histopathological lesions in testis. And, the Johnsen's score, seminiferous tubule diameter, and spermatogenic epithelium thickness were decreased in NiCl 2 -treated mice. The number of spermatogonium, primary spermatocyte, and round spermatid also were significantly reduced after Ni treatment. Next the potential molecular mechanism was measured. NiCl 2 treatment elevated ROS production in the testis. Additionally, NiCl 2 was found to induce apoptosis with features including up-regulation of Bax, cleaved-caspase-3, cleaved-caspase-8, caspase-9, and caspase-12, while down-regulation of Bcl-2 expression. In the meantime, the marker protein of DNA damage γ-H2AX was significantly increased in NiCl 2 -primed mice testis. To clarify effects of reactive oxygen species (ROS) in apoptosis and DNA damage induced by NiCl 2 , NiCl 2 was used to co-treat antioxidant NAC (N-Acetyl-L-cysteine). NAC weakened ROS production induced by NiCl 2 , and played an inhibition role in apoptosis and DNA damage. Moreover, co-treatment using NiCl 2 and NAC group also eliminated spermatogenesis disorders. In summary, research results reveal the relations of spermatogenesis disorder induced by NiCl 2 with apoptosis and DNA damage mediated by ROS and apoptosis in the testis. [Display omitted] • NiCl 2 impairs histological structure in testis and epididymis. • NiCl 2 increases ROS, DNA damage and apoptosis in the testis. • ROS is an important primary inducer in Ni-induced sperm parameters disorder • NiCl 2 -induced spermatogenesis disorder is related to ROS-mediated apoptosis and DNA damage. [ABSTRACT FROM AUTHOR]

Abstract Crotonaldehyde is a common environmental contaminant. Autophagy, apoptosis, and necrosis, were all respectively reported to be induced by crotonaldehyde. However, the relationships between programmed cell deaths, especially between autophagy and apoptosis, have not been elucidated. In the present study, alterations of autophagy, apoptosis and necrosis were investigated in human bronchial epithelial cells (BEAS-2B) exposed to crotonaldehyde, and effects of autophagy on apoptosis and necrosis were detected. We found that a high concentration (160 μmol/L, μM) of crotonaldehyde did not induce apoptosis, while a low concentration (80 μM) of crotonaldehyde induced autophagy, apoptosis and necrosis. In 80 μM crotonaldehyde-exposed BEAS-2B cells, autophagy and apoptosis exhibited a trend of increasing prior to decreasing with the increase of time, while the time point inducing the highest level of autophagy was 2 h, and that of apoptosis was 4 h. With the pretreatment of bafilomycin A 1 , the apoptosis was inhibited and the necrosis was enhanced significantly in cells exposed to 80 μM crotonaldehyde. Autophagy mediated the induction of apoptosis via the intrinsic apoptotic pathway. The results indicate that autophagy mediates the initiation of apoptosis and plays a role in protecting from necrosis in low concentrations of crotonaldehyde-exposed BEAS-2B cells. Graphical abstract fx1 Highlights • High concentration (160 μM) of crotonaldehyde does not induce apoptosis in BEAS-2B. • Low concentration (80 μM) of crotonaldehyde induces apoptosis in BEAS-2B. • Crotonaldehyde (80 μM)-induced autophagy promotes apoptosis and inhibits necrosis. • Autophagy induces apoptosis via the intrinsic apoptotic pathway. [ABSTRACT FROM AUTHOR]

Abstract Objective To determine the mitigating effects of sodium 4-phenylbutyrate (4-PBA) on high-fat diet (HFD)-induced spermatogenesis dysfunction. Methods Male rats (n = 30) were randomly divided into three groups: control, HFD, and 4-PBA (HFD+4-PBA). After 13 weeks, rats were euthanized. Testes and epididymis were harvested for further analysis. Sex hormones were detected, and hematoxylin and eosin staining was performed to examine the histological changes in the testes. Semen samples were collected to evaluate sperm quality. Spermatogenic cell apoptosis was detected by TUNEL assay. Results Compared with the control group, the final body weight and body weight gain were significantly higher in HFD-fed rats, while the testicle/body weight ratios were lower (P < 0.05). In HFD-fed rats, obvious pathological changes in the testicular tissue were observed. Treatment with 4-PBA attenuated HFD-induced histological damage, ameliorated the HFD-induced decrease in serum testosterone (T), and reduced the rate of testicular cell apoptosis (P < 0.05) in obese male rats. Finally, 4-PBA significantly improved semen parameters in HFD rats (P < 0.05). Conclusion HFD exposure induced detrimental effects on spermatogenesis, semen quality, serum T level, and testicular cell apoptosis in rats. Treatment with 4-PBA ameliorated HFD-induced impaired spermatogenesis via inhibition of apoptosis in rats. 4-PBA may have therapeutic value in the treatment of obesity-related impairment of spermatogenesis. [ABSTRACT FROM AUTHOR]

Background: Sinonasal inverted (schneiderian) papilloma (IP) is histologically benign but shows a propensity for malignant transformation. Survivin, a member of the inhibitor of the apoptosis family of proteins that controls cell division, apoptosis, metastasis, and, probably, also neoangiogenesis, is overexpressed in essentially all human cancers. Overexpression of the multidomain protein cortactin has also been associated with increased cell migration, invasion, and metastatic potential in several malignancies. Objective: The aim of the present study was to preliminarily investigate survivin and cortactin expression in a consecutive series of sinonasal IPs, and IP-associated squamous cell carcinomas (SCC). Methods: Immunohistochemical expression of nuclear survivin and cortactin was measured in 19 consecutive sinonasal IPs and 3 IP-associated SCCs. Results: The mean ± standard deviation nuclear survivin expression was 9.4 ± 9.2% and 31.7% ± 15.4% in sinonasal IPs and SCCs, respectively (p < 0.0001). Results of cortactin immunostaining was strongly positive in the cytoplasm of both sinonasal IPs and SCCs: no significant difference emerged between the IP and SCC epithelial components. Conclusion: Nuclear survivin expression was significantly higher in SCCs than in IPs. Prospective, multi-institutional prognostic studies, preferably on an international scale (given the few cases treated at single institutions), are needed to confirm the role of survivin in IP malignant transformation. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA), bioactive ion and nitric oxide (NO) are beneficial to myocardial repair after myocardial infarction (MI); however, to achieve efficient intervention of circRNA and delivery of NO and ion throughout myocardium still remains difficult. Injectable hydrogels have been frequently used to release angiogenic factors; however, due to the limited drug diffusion distance, angiogenic factors are difficult to reach the epicardium – a viable target for angiogenesis. Herein, a combined strategy based on coadministration of lipo/pcircRNA and strontium ions-containing nanoparticles-encapsulated injectable hydrogel and NO-bearing liposome-loaded pericardial adhesive hydrogel patch is proposed to realize intramyocardial gene/ion delivery and epicardial NO delivery to inhibit cardiomyocyte apoptosis and inflammatory response, and circumvent insufficient angiogenesis problem. The hydrogel prepared via Schiff-reaction of hydrazide-hyaluronic acid and aldehydated-laminarin with self-immunoregulation function is injected into the myocardium to deliver lipo/pcircRNA nanoparticles and strontium ions to inhibit cardiomyocyte apoptosis and partially promote angiogenesis. To further boost angiogenesis, an adhesive hyaluronic acid-based hydrogel is bonded to the myocardial surface by pre-anchored sponge that can remove hydration layer, to achieve the release of NO nanodrug in epicardium. This combination therapy contributes to a significant inhibition of cardiomyocyte apoptosis and inflammatory response and maximum angiogenesis, thus improving cardiac function. [Display omitted] • A ROS-responsive liposome is prepared to mediate circFndc3b overexpression in cardiomyocyte for the first time. • Lipo/pcircRNA and SiSr NPs-loaded HL hydrogel realizes intrinsic immunoregulation and inhibition of cardiomyocyte apoptosis. • A wet pericardial adhesive hydrogel loaded with lipo/NO achieves epicardial NO delivery to maximize angiogenesis. • The combined therapy strategy efficiently restores cardiac function after MI. [ABSTRACT FROM AUTHOR]

Treatment of pulmonary fibrosis caused by paraquat (PQ) poisoning remains problematic. Amitriptyline (AMT) has multiple pharmacological effects. Here we investigated the anti-fibrotic effect of AMT on PQ-induced pulmonary fibrosis and its possible mechanism. C57BL/6 mice were randomly divided into control, PQ, PQ + AMT and AMT groups. Histopathology of the lungs, blood gas analysis, and levels of hydroxyproline (HYP), transforming growth factor β1 (TGF-β1) and interleukin 17 (IL-17) were measured. The siRNA transfection inhibited caveolin-1 in A549 cells, which induced epithelial-mesenchymal transition (EMT) by PQ and followed intervention with AMT. E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA) and caveolin-1 were studied by immunohistochemistry and western blot analysis. The apoptosis rate was measured by flow cytometry. Compared with the PQ group, the PQ + AMT group displayed mild pathological changes in pulmonary fibrosis, lower HYP, IL-17 and TGF- β1 levels in lung, but high TGF- β1 in serum. Levels of N-cadherin and α-SMA in the lungs were significantly decreased, but caveolin-1 was increased, while SaO 2 and PaO 2 levels were higher. Compared with the PQ group, the apoptosis rate, N-cadherin and α-SMA levels in A549 cells were significantly decreased after PQ treatment and high dose AMT intervention (p < 0.01). The expressions of E-cadherin, N-cadherin and α-SMA in the PQ-induced cells transfected with caveolin-1 siRNA or siControl RNA were significantly different (p < 0.01), but the apoptosis rate was unaltered. AMT inhibited PQ-induced EMT in A549 cells and improved lung histopathology and oxygenation in mice by up-regulating caveolin-1. • Amitriptyline is anti-fibrotic for paraquat-induced pulmonary fibrosis. • Anti-fibrotic effect was confirmed by histopathological and proteomic methods. • Amitriptyline inhibits epithelial-mesenchymal transition by upregulating caveolin-1. • Amitriptyline down-regulated the apoptosis rate, which was not related to Caveolin-1. • Conventional drug in new use for amitriptyline is worth expecting. [ABSTRACT FROM AUTHOR]

We investigated the potential effects and mechanisms of vascular endothelial growth factor (VEGF)-nanofiber membranes (NFMs) treatment in a rat model of chronic cerebral hypoperfusion (CCH). VEGF-NFMs treatment promoted angiogenesis in surgical temporal cortex and hippocampus, alleviating decreased CBF in these two cerebral regions. VEGF-NFMs application improved reduced NAA/Cr ratio, preventing neuronal loss. VEGF-NFMs sticking decreased the number of TUNEL-positive cells in surgical temporal cortex, ameliorated impaired synaptic plasticity, and inhibited the release of pro-inflammatory cytokines and the activation of microglia and astrocytes in surgical temporal cortex and hippocampus. Furthermore, BDNF-TrkB/PI3K/AKT, BDNF-TrkB/ERK and HIF-1a/VEGF/ERK pathways were involved in the treatment of VEGF-NFMs against CCH-induced neuronal injury. These results showed the neuroprotective effects of VEGF-NFMs sticking may initiate from neurovascular repairing followed by inhibition of neuronal apoptosis and neuronal and synaptic damage, eventually leading to the suppression of cognitive dysfunction, which provided theoretical foundation for further clinical transformation of VEGF-NFMs. VEGF-NFMs treatment could promote cerebral revascularisation and neurorestoration composed of increasing appropriate cerebral perfusion volume by angiogenesis induction, altering neurometabolites NAA/Cr ratio, improving synaptic plasticity, inhibiting neuroinflammation, neuronal apoptosis and neuronal loss, leading to the alleviation of CCH-induced cognitive impairment. These changes may be partially mediated by BDNF-TrkB/PI3K/AKT, BDNF-TrkB/ERK and HIF-1a/VEGF/ERK pathways. [Display omitted] [ABSTRACT FROM AUTHOR]

Apoptosis inhibitor of macrophage (AIM) is initially reported to protect macrophages from apoptosis. In this study, we determined the effect of AIM on the macrophage-derived tumor, histiocytic sarcoma cell lines (HS) of dogs. Five HS and five other tumor cell lines were used. When recombinant canine AIM was applied to non-serum culture media, cell numbers of all the HS and two of other tumor cell lines decreased dose-dependently. The DNA fragmentation, TUNEL staining and flow cytometry tests revealed that AIM induced both of apoptosis and cell cycle arrest in the HS. Although AIM is known as an apoptosis inhibitor, these results suggest that a high dose of AIM could have an opposite function in HS and some tumor cell lines. [ABSTRACT FROM AUTHOR]

Remote ischemic preconditioning (RIPC) is a novel strategy of protection against ischemia-reperfusion (IR) injury in the heart (and/or other organs) by brief episodes of non-lethal IR in a distant organ/tissue. Importantly, RIPC can be induced noninvasively by limitation of blood flow in the extremity implying the applicability of this method in clinical situations. RIPC (and its delayed phase) is a form of relatively short-term adaptation to ischemia, similar to ischemic PC, and likely they both share triggering mechanisms, whereas mediators and end-effectors may differ. It is hypothesized that communication between the signals triggered in the remote organs and protection in the target organ may be mediated through substances released from the preconditioned organ and transported via the circulation (humoral pathways), by neural pathways and/or via systemic anti-inflammatory and antiapoptotic response to short ischemic bouts. Identification of molecules involved in RIPC cascades may have therapeutic and diagnostic implications in the management of myocardial ischemia. Elucidation of the mechanisms of endogenous cardioprotection triggered in the remote organ could lead to the development of diverse pharmacological RIPC mimetics. In the present article, the authors provide a short overview of RIPC-induced protection, proposed underlying mechanisms and factors modulating RIPC as a promising cardioprotective strategy. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a heavy metal pollutant in the environment, and the kidney is one of the target organs after Cd exposure. Previous studies have shown that apoptosis and autophagy disorders are the main mechanisms of Cd-induced nephrotoxicity in rats. As a transcription factor that balances cell survival and death, nuclear factor-kappaB (NF-κB) protein plays dual regulatory effects on apoptosis and autophagy in multiple renal diseases. However, the regulatory mechanisms of NF-κB in Cd-induced kidney injury remain unclear. Therefore, the normal rat kidney cell line (NRK-52E cells) was applied to investigate the above questions in this study. Here, we found that Cd promotes the nuclear translocation and activation of NF-κB in a concentration-dependent manner, and activated NF-κB mediates NRK-52E cells survival after Cd exposure. Next, our study elaborated the mechanisms of NF-κB in antagonizing Cd-induced renal cytotoxicity. Inhibition of NF-κB by inhibitor BAY 11-7082 (BAY) and NF-κB p65 siRNA (siNF-κB p65) exacerbate Cd-induced apoptosis and autophagy inhibition, and then aggravate Cd-induced NRK-52E cells injury. Activation of NF-κB by activator phorbol-12-myristate-13-acetate (PMA) alleviates Cd-induced apoptosis and autophagy inhibition, and then attenuates Cd-induced NRK-52E cells injury. In conclusion, Cd exposure promotes the activation of NF-κB, and activated NF-κB mediates the survival of NRK-52E cells after Cd exposure via promoting autophagy and inhibiting apoptosis. Cadmium (Cd) exposure induces the phosphorylations levels of IκB and NF-κB p65 to promotes the nuclear translocation and activation of NF-κB, then activated NF-κB mediates the survival of rat kidney cells after Cd exposure via promoting authophagy and inhibiting apoptosis. [Display omitted] • Cd promotes the nuclear translocation and activation of NF-κB in NRK-52E cells. • Activated NF-κB mediates the survival of NRK-52E cells after Cd exposure. • NF-κB regulates the autophagy and apoptosis in Cd-exposed NRK-52E cells. [ABSTRACT FROM AUTHOR]

The obligatory intracellular bacterium Chlamydia pneumoniae ( C. pneumoniae ) can survive and multiply in neutrophil granulocytes. Since neutrophils are short living cells, inhibition of neutrophil apoptosis appears to play a major role in the productive infection of neutrophils by C. pneumoniae . In the present study, we have investigated which survival pathways and which events of the apoptotic process are modulated in C. pneumoniae -infected neutrophils. All infection experiments were carried out using primary human neutrophils in vitro. We show that infection with C. pneumoniae activates PI3K/Akt as well as the ERK1/2 and p38 MAP kinases and present evidence that activation of the PI3K/Akt and ERK1/2 pathways are essential to initiate the apoptosis delay in C. pneumoniae -infected neutrophils. Both the PI3K/Akt and ERK1/2 pathways are involved in the maintained expression of the anti-apoptotic protein Mcl-1. In addition, we also showed that the PI3K/Akt pathway leads to the activation of NF-κB-dependent release of IL-8 by infected neutrophils. Infection with C. pneumoniae activates the PI3K/Akt and ERK1/2 MAPK survival pathways in neutrophils, induces the NF-κB dependent release of IL-8 and leads to the maintenance of Mcl-1 expression in neutrophils. [ABSTRACT FROM AUTHOR]

Copyright of Arquivos Brasileiros de Oftalmologia is the property of Arquivos Brasileiros de Oftalmologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Arquivos Brasileiros de Oftalmologia is the property of Arquivos Brasileiros de Oftalmologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Demyelination disease as diabetes mellitus (DM) complication is characterized by apoptosis of Schwann cells (SCs) and several reports have demonstrated that high glucose content can induce an inflammation response and lead to the apoptosis of SCs. For NF-κB plays a pivotal role in the inflammatory response, hence we hypothesized that high glucose content can induce inflammation though the NF-κB pathway. First we verified that 150 mM high glucose can increase the expression of cleaved caspase 3, interleukin (IL)− 1β, Cyto-C and NF-κB with time through Western blot and increase the apoptosis of RSC96s through Flow Cytometry. Then we found that high glucose can increase the nuclear translocation NF-κB through confocal system which can promote the expression of inflammation genes such as IL-1β. Curcumin has been reported to possess anti-inflammation activities to protect cells. In this study, we found that application with 25 μM curcumin could alleviate the inflammation response and protect the cells from apoptosis. We revealed that the expression of NF-κB and p-NF-κB was decreased and the translocation was also inhibited after curcumin application. Accordingly, the secretion of IL-1β and the apoptosis of RSC96s induce by high glucose was suppressed. Our cumulative findings suggest that curcumin can protect SCs from apoptosis through the inhibition of the inflammatory response though the NF-κB pathway. • Curcumin can protect the RSCs form hyperglycemia. • Curcumin can inhibit the NF-κB pathway to suppress inflammation. • The inflammation response induced by hyperglycemia can result in apoptosis of RSCs. [ABSTRACT FROM AUTHOR]

An in-house enzyme-linked immunosorbent assay (ELISA) was developed in this study to detect circulating IgG antibodies to peptide antigens derived from baculoviral IAP repeat-containing protein 5 isoform 2 (BIRC5) and myc proto-oncogene protein (MYC) in non-small cell lung cancer (NSCLC). Student’s t -test revealed that circulating anti-MYC IgG levels were significantly increased in patients with NSCLC compared with control subjects in the discovery sample ( t = 3.96, P = 0.0001) but not in the validation sample ( t = 1.24, P = 0.217), generating a combined P -value of 0.0003. Neither the discovery sample nor the validation sample showed a significant change in anti-BIRC5 IgG levels in NSCLC. Further analysis was performed to investigate whether circulating IgG antibodies to these two tumor-associated antigens (TAAs) significantly changed with early (stages I + II) and late (stages III + IV) NSCLC stages. The results showed that neither anti-MYC IgG nor anti-BIRC5 IgG levels significantly changed in patients with early stage NSCLC, while patients with late stage NSCLC had higher levels of circulating anti-MYC IgG than control subjects in the discovery sample ( t = 4.74, P < 0.0001) but not in the validation sample ( t = 0.80, P = 0.423), generating a combined P -value of 0.00003 ( X 2 = 26.13, df = 4). In conclusion, circulating IgG antibodies to MYC and BIRC5 do not appear to serve as biomarkers for early diagnosis of lung cancer but anti-MYC IgG might have a prognostic value. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is the most important air-borne pathogenic fungus of humans. Upon inhalation of conidia, the fungus makes close contact with lung epithelial cells, which only possess low phagocytic activity. These cells are in particular interesting to address the question whether there is some form of persistence of conidia of A. fumigatus in the human host. Therefore, by also using uracil-auxotrophic mutant strains, we were able to investigate the interaction of A549 lung epithelial cells and A. fumigatus conidia in detail for long periods. Interestingly, unlike professional phagocytes, our study showed that the presence of conidial dihydroxynaphthalene (DHN) melanin enhanced the uptake of A. fumigatus conidia by epithelial cells when compared with non-pigmented pksP mutant conidia. Furthermore, conidia of A. fumigatus were able to survive within epithelial cells. This was due to the presence of DHN melanin in the cell wall of conidia, because melanised wild-type conidia showed a higher survival rate inside epithelial cells and led to inhibition of acidification of phagolysosomes. Both effects were not observed for white (non-melanised) conidia of the pksP mutant strain. Moreover, in contrast to pksP mutant conidia, melanised wild-type conidia were able to inhibit the extrinsic apoptotic pathway in A549 lung epithelial cells even for longer periods. The anti-apoptotic effect was not restricted to conidia, because both conidia-derived melanin ghosts (cell-free DHN melanin) and a different type of melanin, dihydroxyphenylalanine (DOPA) melanin, acted anti-apoptotically. Taken together, these data indicate the possibility of melanin-dependent persistence of conidia in lung epithelial cells. [ABSTRACT FROM AUTHOR]

Background: Numerous molecular markers of sinonasal inverted papillomas (IP) were investigated in the past; however, significance of angiogenesis and inhibition of apoptosis were not well documented. This study was designed to determine expression of angiogenic marker CD34 antigen, antiapoptotic marker Bcl-2 oncoprotein, and proliferative marker Ki-67 antigen in the group of patients with IP. We matched up these findings to the group of patients with sinonasal carcinoma (SNC) and used chronic rhinosinusitis (CRS) patients as control group. In addition, we compared expression of the markers among IP patients who displayed distinctly different patterns of clinical behavior. Methods: Tissue samples were obtained from 46 surgically treated patients; 18 of them had a diagnosis of IP, 9 had documented SNC, and the remaining 19 patients had CRS. All specimens were stained using immunohistochemistry techniques for CD34 (mean vessel density [MVD]), Bcl-2, and Ki-67 antigens. Morphometry was evaluated by computer image analysis system. Results: We noted statistically significant differences in expression of CD34 antigen, Bcl-2 protein, and Ki-67 antigen (for all groups, ANOVA p < 0.001) among the investigated groups. The mean value of CD34 antigen was significantly higher in the IP group than in the CRS group, but it was below the levels of the SNC group. Compared with the cases not complicated by recurrence, the patients with recurrent IP exhibited higher MVD levels, while levels of bcl-2 and Ki67 protein expression did not differ in a significant way between recurrent and nonrecurrent cases. The significant positive correlations were observed between Bcl-2 protein and Ki-67 antigen in IP and SNC groups and between Bcl-2 protein and CD34 antigen in the CRS group. Conclusion: Our findings underscore importance of angiogenesis in the development and prognosis of IP and support further investigation of this aspect of IP tumor growth. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this work was to investigate the anti-proliferation, apoptotic and antioxidant effects of unfractionated polyphenols of green tea (GRTP) and ginger (GNRP), compared to cisplatin and ascorbic acid in human hepatocellular carcinoma. The cells’ growth rate and survival (MMT assay) were investigated in cells treated with different doses of polyphenols. The apoptotic fraction of treated cells was measured by flow cytometry, whereas the antioxidant effect of polyphenols was investigated in the presence or absence of thioacetamide (TAA), and compared to that of ascorbic acid. The results indicated that GRTP and GNRP, inhibited the growth rate of cells. GRTP was more cytotoxic, where cell viability of GRTP-treated cells was lower than cells treated with GNRP. The IC50 values were 39.3μg/ml and 64.9μg/ml, respectively. GRTP induced more apoptosis than GNRP or cisplatin. Moreover, the oxidative stress induced by TAA was challenged by GRTP, where reduced glutatione (GSH) in cells dually treated with GRTP/TAA was higher than untreated, GNRP/TAA and TAA/ascorbic acid treated cells. The data revealed the antihepatocarcinogenic effect of these polyphenols, where they triggered apoptosis and showed antioxidant effect in TAA treated cells. Green tea polyphenol was more antineoplasitic, apoptotic, compared to ginger polyphenols, and more antioxidant than ascorbic acid. [Copyright &y& Elsevier]

Objective: We first reported that electroacupuncture (EA) pretreatment at the Baihui acupoint (GV20) induces ischemic tolerance. Our recent study demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) expression was up-regulated following transient focal cerebral ischemia. Therefore, we investigated whether NDRG2 was involved in the ischemic tolerance induced by EA pretreatment in rats. Methods: Twenty-four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 120 minutes in male Sprague-Dawley rats. The neurobehavioral score, infarction volume, and extent of neuronal apoptosis were evaluated at 24 hours after reperfusion. The expression of NDRG2 in the brain was evaluated by reverse transcriptasepolymerase chain reaction (RT-PCR), western blotting, and immunofluorescent staining. Results: Electroacupuncture pretreatment decreased infarction volume and improved neurologic scores at 24 hours after reperfusion. Double immunofluorescence revealed that NDRG2 expression in astrocytes was suppressed in the EA group at 24 hours after reperfusion, and that NDRG2 protein expression was weak in the nucleus and strong in the cytoplasm of the EA group, but strong in the nucleus of the MCAO group. Triple immunofluorescent staining for terminal deoxynucleotidyl transferase nick-end labeling (TUNEL), NDRG2, and 4',6-diamidino-2-phenylindole (DAPI) showed that NDRG2 co-localised with apoptotic cells. Moreover, the number of apoptotic cells decreased with the attenuation of NDRG2 expression in the EA group compared to the MCAO group. Conclusion: Our results indicated that NDRG2 is involved in anti-apoptosis induced by EA pretreatment after focal cerebral ischemia in rats. N-Myc downstream-regulated gene 2 was involved in EA pretreatmentinduced cerebral ischemic tolerance. These findings may be important for our understanding of the cellular signaling pathways induced by EA pretreatment. [ABSTRACT FROM AUTHOR]

Gingival overgrowth is an adverse effect of several classes of drugs including anticonvulsants, calcium channel blockers and the immunosuppressant cyclosporine A (CsA). Current treatment options of drug-induced gingival hyperplasia include both nonsurgical and surgical interventions. Surgical interventions have a high rate of recurrence and are not the most appropriate treatment options in immunocompromised patients. The preferred nonsurgical interventions are symptomatic and do not resolve the condition, and as yet, there is no effective, nonsurgical option for its treatment. Gingival tissue is constantly involved in cycles of tissue resorption, remodeling and replacement by apoptotic pathways. Apoptosis and cell clearance are necessary for constant tissue remodeling, and a lack of these processes plays a critical role in gingival overgrowth. We hypothesized that CsA-induced gingival overgrowth can be controlled by the use of specific agents to induce apoptosis. An in vitro cell culture model of gingival cells was overproliferated using CsA to mimic gingival overgrowth, following which, the cells were exposed to either 100ng/ml or 500ng/ml of Cytochrome C to induce apoptosis at 3, 6 and 9 day time points. Cell densities were calculated both pre and post Cyt C treatment. Cells were also immunostained with DAPI to visualize the nuclei and laser scanning confocal microscopy was used to image and record the features of apoptotic nuclei. Statistical analyses were carried out. Our data indicate that following treatment with Cyt C, cell densities at 3, 6 and 9 day time points showed statistically significant decreases. This study is an important first step in determining if inducing apoptosis could be a viable, nonsurgical method of managing cellular proliferative disorders like drug-induced gingival overgrowth. [ABSTRACT FROM AUTHOR]

Abstract: Docosahexaenoic acid (DHA) is known as a major nutrient from marine origin. Considering its beneficial effect in vascular risk prevention, the effect of DHA on blood components, especially platelets, will be reviewed here. Investigating the dose-effect of DHA in humans shows that daily intake lower than one gram/day brings several benefits, such as inhibition of platelet aggregation, resistance of monocytes against apoptosis, and reinforced antioxidant status in platelets and low-density lipoproteins. However, higher daily intake may be less efficient on those parameters, especially by losing the antioxidant effect. On the other hand, a focus on the inhibition of platelet aggregation by lipoxygenase end-products of DHA is made. The easy conversion of DHA by lipoxygenases and the formation of a double lipoxygenation product named protectin DX, reveal an original way for DHA to contribute in platelet inhibition through both the cyclooxygenase inhibition and the antagonism of thromboxane A2 action. [Copyright &y& Elsevier]

Abstract: Benzo(a)pyrene (B(a)P), which is the most studied member of PAH family is released into the environment (air, water and soil) from natural and man-made sources including industrial and automobile exhaust fumes. Since B(a)P is an omnipresent environmental pollutant and is believed to be a risk factor for human chemical carcinogenesis, it is important to identify potent naturally occurring/synthetic agents that could modulate B(a)P-induced toxicity. The present study explores the effect of the flavonoid silymarin (2.4mg/ml) in counteracting the toxicity of B(a)P (1μM) in PBMC. Flourimetry and Confocal Laser Scanning Microscopy results showed that silymarin reduces the B(a)P induced ROS production and DNA damage. Atomic Absorption Spectroscopy analysis and fluorescent microscopic pictures proved that silymarin reduces the increased intracellular calcium and apoptosis induction during B(a)P treatment. Furthermore, silymarin did not show any inhibition for CYP1B1 activity at transcriptional level by semiquantitative RT PCR but it affects the catalytic activity of Phase I CYP1A1/CYP1B1 enzyme (EROD assay) during B(a)P treatment. The findings reveal that silymarin possesses substantial protective effect against B(a)P induced DNA damage and calcium mediated apoptosis by inhibiting the catalytic activity of CYP1B1 and maintaining the intracellular calcium dysregulation; hence, it could be considered as a potential protective agent for environmental contaminant induced immunotoxicity. [Copyright &y& Elsevier]

Background: IL-10–treated dendritic cells (DCs) have been shown to inhibit T-cell responses through induction of anergy and regulatory T cells in various model systems, including allergic inflammation, but the factors being involved in this inhibition are still unclear. Objective: This study set out to analyze such factors produced or induced by IL-10–treated DCs by using gene expression profiling and to explore their function. Methods: CD4+ T cells from allergic donors were stimulated with autologous monocyte-derived allergen-pulsed mature DCs or IL-10–treated DCs. After 24 hours, the transcriptional profile was analyzed by using Affymetrix technology. Results were validated by using quantitative real-time PCR, protein expression, and functional in vitro and in vivo studies. Results: In CD4+ T-cell/IL-10–treated DC cocultures the expression of several known genes, such as IL13, IL5 and OX40, was suppressed. Interestingly, there was only one factor that was strongly upregulated: the DC-derived chemokine CCL18. In vitro addition of CCL18 to cocultures of CD4+ T cells and allergen-pulsed DCs resulted in a similar inhibition of TH2 cytokine production as induced by allergen-pulsed IL-10–treated DCs without exogenous CCL18, whereas TH1 cytokine production, IL-10 production, and proliferation were not affected. Furthermore, in a humanized mouse model of allergy using PBMC-engrafted NOD-scid-γc−/− mice, CCL18, but not another TH2-associated chemokine, CCL17, inhibited airway reactivity and lung inflammation. Chemotaxis assays revealed that CCL18 preferentially attracted regulatory T cells and, less efficiently, TH2 cells. Conclusion: These data demonstrate that CCL18 might represent a molecule of significant importance in immunoregulation and might be a therapeutic target in patients with allergic airway diseases. [Copyright &y& Elsevier]

Abstract: Decreased β-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore β-cell mass and normoglycemia is to improve β-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein (Faim/TOSO), which regulates apoptosis upstream of caspase 8, blocked β-cell apoptosis and increased proliferation in human islets. TOSO was clearly expressed in pancreatic β-cells and down-regulated in T2DM. TOSO expression correlated with β-cell turnover; at conditions of improved survival, TOSO was induced. In contrast, TOSO downregulation induced β-cell apoptosis. Although TOSO overexpression resulted in a 3-fold induction of proliferation, proliferating β-cells showed a very limited capacity to undergo multiple rounds of replication. Our data suggest that TOSO is an important regulator of β-cell turnover and switches β-cell apoptosis into proliferation. [Copyright &y& Elsevier]

Abstract: Exposure of the skin to ultraviolet B (UVB) radiation leads to epidermal damage and the generation of reactive oxygen species (ROS) in skin cells, including keratinocytes. Therefore, the photo-protective effect of 3-bromo-4, 5-dihydroxybenzaldehyde (BDB) against UVB was assessed in human HaCaT keratinocytes exposed to UVB radiation in vitro. BDB restored cell viability, which decreased upon exposure to UVB radiation. BDB exhibited scavenging activity against 1, 1-diphenyl-2-picrylhydrazyl radicals, intracellular ROS induced by hydrogen peroxide (H2O2) or UVB radiation, the superoxide anion generated by the xanthine/xanthine oxidase system, and the hydroxyl radical generated by the Fenton reaction (FeSO4+H2O2). Moreover, BDB absorbed UVB and decreased injury resulting from UVB-induced oxidative stress to lipids, proteins and DNA. Finally, BDB reduced UVB-induced apoptosis, as exemplified by fewer apoptotic bodies and a reduction in DNA fragmentation. Taken together, these results suggest that BDB protects human keratinocytes against UVB-induced oxidative stress by scavenging ROS and absorbing UVB rays, thereby reducing injury to cellular components. [Copyright &y& Elsevier]