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Pituitary gonadotropins perform essential functions in mammalian reproduction by stimulating gametogenesis and steroidogenesis in the ovaries and testicles. EZH2 is a histone methyltransferase that inhibits proliferation and aggravates apoptosis in stem cells subjected to pathological stimuli. However, the expression and molecular mechanisms of EZH2 in pituitary cells in vitro have not been extensively studied. In this study, the relative abundances of EZH2 mRNA (p < 0.01) and protein (p < 0.05) expression were larger in the pituitary cells of Hu sheep with relatively greater fecundity (GF) compared to those with lesser fecundity (LF). Loss-of-function examinations demonstrated that EZH2 gene knockdown led to an earlier induction of apoptosis in sheep pituitary cells (PCs). The relative abundance of CASP3, CASP9, and BAX was increased (p < 0.01), while BCL2's abundance was less decreased (p < 0.01) in PCs where there was EZH2 gene knockdown. Additionally, cell proliferation (p < 0.01) and viability (p < 0.01) were decreased in EZH2-knockdown sheep PCs, and the cell cycle was blocked compared to a negative control (NC). Notably, EZH2 gene knockdown led to reduced abundances of gonadotropin subunit gene transcripts (FSHβ, p < 0.05) and reduced FSH release (p < 0.01) from PCs. EZH2 gene knockdown led to reduced phosphorylation of AKT, ERK, and mTOR (p < 0.01). The results suggest that EZH2 regulates pituitary cell proliferation, apoptosis, and FSH secretion through modulation of the AKT/ERK signaling pathway, providing a foundation for further study of pituitary cell functions. [ABSTRACT FROM AUTHOR]

Graphical diagram illustrating the function and mechanism of Nrf2 in Pb-induced kidney injury. [Display omitted] • Lead (Pb)-induced persistent Nrf2 activation contributes to kidney injury. • Persistent Nrf2 activation promotes apoptosis and autophagic blockage. • Nrf2 is persistently activated in a p62-dependent non-canonical manner. Lead (Pb) is an environmental toxicant that poses severe health risks to humans and animals, especially renal disorders. Pb-induced nephrotoxicity has been attributed to oxidative stress, in which apoptosis and autophagy are core events. Nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a major contributor to counteract oxidative damage, while hyperactivation or depletion of Nrf2 pathway can cause the redox imbalance to induce tissue injury. This study was performed to clarify the function and mechanism of Nrf2 in Pb-triggered kidney injury. First, data showed that Pb exposure activates Nrf2 pathway in primary rat proximal tubular cells. Next, Pb-induced Nrf2 activation was effectively regulated by pharmacological modulation or siRNA-mediated knockdown in vitro and in vivo assays. Notably, Pb-triggered cytotoxicity, renal injury and concomitant apoptosis were improved by Nrf2 downregulation, confirming that Pb-induced persistent Nrf2 activation contributes to nephrotoxicity. Additionally, Pb-triggered autophagy blockage was relieved by Nrf2 downregulation. Mechanistically, we found that Pb-induced persistent Nrf2 activation is attributed to reduced Nrf2 ubiquitination and nuclear-cytoplasmic loss of Keap1 in a p62-dependent manner. In conclusion, these findings highlight the dark side of persistent Nrf2 activation and potential crosstalk among Pb-induced persistent Nrf2 activation, apoptosis and autophagy blockage in Pb-triggered nephrotoxicity. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 (H3K27) methyltransferase that plays vital roles in mouse spermatogenesis. However, the expression pattern and role of EZH2 in goat spermatogonial stem cells (SSCs) is unknown. In the present study, we investigated EZH2 expression in the testis of postpubertal goats and its effect on the biological characteristics of goat SSCs. We found that EZH2 mRNA (P < 0.01) and protein (P < 0.05) expression was increased in the testes of postpubertal goats compared to that of prepubertal goats. Moreover, EZH2 was more highly expressed in goat SSCs than in Leydig cells (P < 0.01) and Sertoli cells (P < 0.01) as determined by qPCR, Western blot, and immunofluorescence. Compared to a negative control (NC), cell proliferation (P < 0.01) and viability (P < 0.01) were decreased in SSCs in which EZH2 was knocked down, and the G2/M phase of the cell cycle was blocked (P < 0.01), as determined by Edu staining, CCK-8 assay, and flow cytometry analysis. Additionally, the expression of CASP3 , CASP9 , and BAX was significantly increased (P < 0.01) while BCL2 expression was decreased (P < 0.01) in EZH2 knockdown SSCs. Notably, the expression of GDNF , a SSCs marker gene, and DAZL , a spermatogenesis-related gene, were significantly decreased (P < 0.01) while GFRA1 expression was significantly up-regulated (P < 0.01) in EZH2 knockdown SSCs. Our data suggest that EZH2 plays a pivotal role in the self-renewal of goat SSCs, and knockdown of EZH2 might impair spermatogenesis in goats. • Increased expression of EZH2 in the testis of postpuberal goats and goat SSCs. • Knockdown of EZH2 compromised proliferation, and blocked G2/M phase in goat SSCs. • Knockdown of EZH2 elevated cell apoptosis of goat SSCs. • Knockdown of EZH2 impaired self-renewal of goat SSCs. • EZH2 serves an important role in the spermatogenesis of goat. [ABSTRACT FROM AUTHOR]

Objective Bleomycin (BLM) has been found safe and highly effective in the treatment of the mucoceles by intralesional injection in our previous study. The present research was designed to investigate whether epithelial-to-mesenchymal transition (EMT) contributes to the therapeutic effects of BLM for mucoceles of the salivary glands. Material and methods The cell proliferation and apoptosis of human submandibular gland cells (HSG cells) were examined by Cell Counting Kit-8 assay and Annexin V binding assay respectively. Epithelial and mesenchymal markers of HSG cells were measured by real-time quantitative PCR and Western blot analysis. Acinar differentiation and cell migration assays were performed to evaluate HSG cells function. Results High-dose BLM (≥0.5 μg/mL) significantly inhibited the cell proliferation and induced the cell apoptosis, while the treatment with low-dose BLM (0.05 and 0.1 μg/mL) for 48 h induced EMT in HSG cells. Furthermore, Akt/mTOR pathway, rather than MAPK pathway, was activated through treated with 0.05 and 0.1 μg/mL BLM, as well as activation of the transcription factor Slug and Zeb 1. The migration of HSG cells was also enhanced through 0.05 and 0.1 μg/mL BLM, but the ability of acinar differentiation was diminished. Conclusion Our results indicated that an EMT process was involved in the BLM-induced therapeutic effects on the HSG cells through the Akt/mTOR pathway. Importantly, the results indicated the potential role of this process in the BLM sclerotherapy of mucoceles of the salivary glands. [ABSTRACT FROM AUTHOR]

A great deal of experimental evidence has accumulated in the past several decades, suggesting that polysaccharides have wide bioactivities. Cladonia furcata polysaccharide, CFP-2, a water-soluble lichenin with a mean Mr 7.6×104, was first obtained by 0.25 M NaOH solution extraction, ethanol precipitation, DEAE-cellulose, and Sephadex G-200 column chromatography. Gas chromatography of acid hydrolyzate of CFP-2 suggested that it was composed of d-glucose, d-galactose, and d-mannose in the molar ratios of 8:1:1. Periodate oxidation, Smith degradation, IR, and NMR spectroscopy analysis revealed that CFP-2 had a backbone consisting of α-(1→3) and α-(1→4)-linked d-glucopyranosyl residues substituted at O-6 with β-(1→6)-linked d-galactopyranosyl residue and α-(1→6)-linked d-mannopyranosyl residue. CFP-2 was able to reduce viability of cultured HL-60 and K562 cells. The antiproliferative properties of CFP-2 appeared to be attributable to its induction of apoptotic cell death as determined by ultrastructural change, internucleosomal DNA fragmentation, and increased proportion of the subdiploid cell population. To elucidate molecular events in the apoptosis, protein expressions of Bcl-2, Bax, Fas, and FasL were measured by Western blotting using specific antibodies in HL-60 cells. The level of Bcl-2 remained largely unchanged, but the Bax, Fas, and FasL expression showed up-regulation. Moreover, the telomerase activity analyzed by TRAP-ELISA assay in HL-60 cells treated with CFP-2 decreased as compared with the untreated control cells. These results suggest that CFP-2 could have a possible cancer therapeutic potential. [Copyright &y& Elsevier]

Obesity is characterized by the deposition of excessive body fat, and is caused by energy imbalance, especially when consuming fat-rich diets. High fat diet (HFD)-associated obesity is greatly common in patients with non-alcoholic fatty liver disease (NAFLD) that is emerging as one of the most universal causes of liver disease worldwide, especially in Western countries. In spite of its high prevalence, only a small proportion of affected individuals will become inflamed, followed by fibrosis and chronic liver diseases, and most patients only show simple steatosis. In this case, the full comprehension of the mechanisms underlying the progression of NAFLD is of extreme significance; in spite of progress in this field, awareness on the development of NAFLD is still incomplete. Traditionally, liver steatosis is commonly connected with HFD, obesity, and insulin resistance (IR). Recently, various possible mechanisms have been put forward for liver damage, including endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, gut microbiota imbalance, dysregulation of microRNAs, and genetic/epigenetic risk factors, as well as an increase in inflammatory responses, among many others. Collectively, these proposed mechanisms allow for a variety of hits acting together on subjects to mediated NAFLD and will offer a more accurate explanation for progression of NAFLD. Therefore, this review summarizes the present information concerning NAFLD after HFD exposure, as well as discusses possible mechanisms through which it may arise. • High fat diet (HFD) is a crucial contributory factor affecting NAFLD progression. • HFD-triggered possible mechanisms are posited to explain NAFLD pathogenesis. • Currently, effective therapeutic options for NAFLD remain lifestyle interventions. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a prevalent chronic diseases characterized by formation of osteophytes and degradation of articular cartilage. Previous evidence has identified the regulatory effects of microRNAs (miRNAs) in OA. The goal of this study is to clearly explore the biological function of miR‐1207‐5p in OA. Methods: MiR‐1207‐5p and C‐X3‐C motif chemokine receptor 1 (CX3CR1) expression in OA cartilages were revealed by accessing to Gene Expression Omnibus database. In vitro OA model was established by lipopolysaccharide (LPS) stimulation. Western blot and quantitative real‐time polymerase chain reaction were conducted to detect the expression level of genes. Cell counting kit‐8 (CCK‐8) and flow cytometric experiments were performed to investigate the proliferation and apoptosis capacities of CHON‐001 cells. Bioinformatics analysis was applied to predict the binding site of miR‐1207‐5p and CX3CR1, the connections of which were ascertained using luciferase reporter assay. Results: MiR‐1207‐5p expression was decreased while CX3CR1 was increased in OA cartilages. Up‐regulation of miR‐1207‐5p alleviated the LPS‐induced damage in the view of cell proliferation, apoptosis and extracellular matrix (ECM) degradation. A target of miR‐1207‐5p CX3CR1, its down‐regulation intensified the impacts of miR‐1207‐5p mimic, promoted proliferation and mitigated apoptosis. LPS exposure increased the protein expression of the phosphorylated IκBα and P65, and this phenomena was reversed due to miR‐1207‐5p up‐regulation and CX3CR1 knockdown. The treatment of Betulinic acid (BA; an activator of nuclear factor‐κB pathway) reversed the miR‐1207‐5p mimic‐induced inhibitory effect on apoptosis in LPS‐treated CHON‐001. Conclusion: Our results highlight that miR‐1207‐5p can prevent CHON‐001 from LPS‐stimulated injury, providing a novel biomarker for OA progression and further advancing treatment of OA. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug. [ABSTRACT FROM AUTHOR]

Abnormal apoptosis can lead to uncontrolled cell growth, aberrant homeostasis or the accumulation of mutations. Therapeutic agents that re-establish the normal functions of apoptotic signaling pathways offer an attractive strategy for the treatment of breast cancer. Baicalin (BA) is one of the natural compounds with anti-proliferation and pro-apoptosis activities against numerous tumor cells. However, low bioavailability restricts the clinical application of BA. In order to improve its therapeutic efficacy and study the mechanism of actions, active targeting delivery systems were developed for targeting tumor environment and selective cell killing effects. It emphasized on the construction of folate-conjugated albumin nanoparticles loaded with baicalin (FA-BSANPs/BA) and mechanisms of which on the promotion of breast cancer apoptosis. The physicochemical properties and structural characteristics of FA-BSANPs/BA were investigated. Cell experiments were carried out to study the targeted anti-breast cancer effects of FA-BSANPs/BA and its mechanism. The results showed that FA-BSANPs/BA was successfully constructed with stable structural characteristics and sustained release effects. Cellular uptake and MTT showed that it increased targeted uptake efficiency and cytotoxicity. Flow cytometry and western blot confirmed that it promoted apoptosis by increasing the expression of caspase-8 and ROS, and decreasing the level of Bid. It is suggested that the pro-apoptotic mechanism of FA-BSANPs/BA is related to regulation of key proteins in extrinsic apoptotic pathway. In conclusion, FA-BSANPs/BA is a good delivery carrier and significantly inhibits the breast cancer growth compared with free BA. The mechanism of FA-BSANPs/BA promoting apoptosis of breast cancer may be due to its action on the caspase-8/Bid/ROS pathway. [ABSTRACT FROM AUTHOR]

Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds ( 5h and 5j ) that can be used for further optimization studies as well as mechanism of action investigations. [ABSTRACT FROM AUTHOR]

Abstract: Ginger is one of the most widely used spices and has been used in traditional oriental medicines for long time. Its extract and major pungent principles have been shown to exhibit a variety of biological activities. In order to find more active constituents and evaluate their structure–activity relationship (SAR) we isolated from the rhizomes of Chinese ginger (Zingiber officinale Roscoe) five new diarylheptanoids along with 20 known diarylheptanoids and gingerol-related compounds and studied their cytotoxic and apoptotic activities against human promyelocytic leukemia (HL-60) cells. It was found that compounds 1a, 2a, 5, 6a, 6b and 7 possess significant cytotoxicity against HL-60 cells (IC50 <50μM) and that the cytotoxic activity is associated with the cell apoptosis. SAR analysis demonstrates that the following structural determinants contribute critically to the enhancement of the activity: (i) acetoxyl groups at 3- and/or 5-positions of the side chain; (ii) the appropriate longer alkyl side-chain length; (iii) the ortho-diphenoxyl functionality on the aromatic ring; (iv) the α,β-unsaturated ketone moiety in the side chain. These provide useful information for potential chemopreventive drug design. [Copyright &y& Elsevier]

HT-2 toxin is widely found in moldy crops and is the major metabolite of T-2 toxin, which has been shown to exert various toxic effects in farm animals. However, little is known about the effects of HT-2 toxin on male reproduction, particularly spermatogenesis. This study aims to investigate the toxic effects of HT-2 toxin on goat spermatogonial stem cells (SSCs) and related autophagy-regulated mechanisms. Our results showed that HT-2 toxin exposure resulted in decreased cell viability and proliferation, disrupted SSCs self-renewal, and reduced germ cell-related gene expression. HT-2 toxin exposure also induced oxidative stress and cell apoptosis, as shown by ROS accumulation, increased antioxidant enzyme activity levels, decreased the mitochondrial membrane potential, and increased caspase-9 mRNA and Bcl/bax protein levels. Additionally, HT-2 toxin exposure increased the expression of the autophagy-inducing genes Atg5 , Atg7 and Beclin1 and the number of autophagosomes, which indicated that HT-2 toxin induced autophagy in the goat SSCs. Moreover, we also examined a possible mechanism by which HT-2 toxin exposure induced higher expression of AMPK, mTOR and ULK at both the mRNA and protein levels. our results indicated that HT-2 toxin caused apoptosis and autophagy by activating AMPK-mTOR-ULK1 pathway, which further affected SSCs viability. • HT-2 toxin exposure affects cell viability and renewal of goat SSCs. • HT-2 toxin exposure induces cell apoptosis and autophagy. • HT-2 toxin exposure activates AMPK-mTOR-ULK1 pathway in goat SSCs. [ABSTRACT FROM AUTHOR]

Piperine (PIP) exerts numerous pharmacological effects and its involvement in endoplasmic reticulum (ER) stress (ERS)-led apoptosis has garnered attention. The present study focused on whether PIP played protective effects on hypoxia/reoxygenation (H/R)-induced cardiomyocytes by repressing ERS-led apoptosis. The potential molecular mechanisms in association with the PI3K/AKT signaling pathway were investigated. Primary neonatal rat cardiomyocytes (NRCMs) were isolated and randomized into four groups: Control + vehicle group, control + PIP group, H/R + vehicle group and H/R + PIP group. The H/R injury model was constructed by 4 h of hypoxia induction followed by 6 h of reoxygenation. A total of 10 µM PI3K/AKT inhibitor LY294002 was supplemented to the cells during the experiments. Cell viability and myocardial enzymes were detected to evaluate myocardial damage. A flow cytometry assay was performed to assess apoptotic response. Western blot analysis was performed to detect the expression of related proteins including PI3K, AKT, CHOP, GRP78 and cleaved caspase-12. The results showed that H/R markedly promoted myocardial damage as shown by the increased release of lactate dehydrogenase and creatine kinase levels, but a reduction in cell viability. In addition, ERS-induced apoptosis was markedly promoted by H/R in NRCMs, as shown by the increased apoptotic rates and expression of C/EBP-homologous protein, endoplasmic reticulum chaperone BiP and caspase-12. PIP administration reversed cell injury and ERS-induced apoptosis in H/R. Mechanistic studies concluded that the apoptosis-inhibitory contributions and cardio-favorable effects of PIP were caused partly by the activation of the PI3K/AKT signaling pathway, which was verified by LY294002 administration. To conclude, PIP can reduce ERS-induced apoptosis by activating the PI3K/AKT signaling pathway during the process of H/R injury, which could be a potential therapeutic target for the treatment of myocardial ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells.Methods: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection.Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models.Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) have anti‐viral and anti‐tumour effects. Type III interferon, as a member of the recently discovered interferon family, has been proved to inhibit tumour proliferation and promote the apoptosis of various tumour cells. However, whether type III IFN could inhibit the proliferation of lung cancer was not clear. In this study, we found that interferon λ (IFN λ) could inhibit the proliferation of A549 cells and induce autophagy and apoptosis of A549 cells. IFN λ could promote the expression of autophagy gene Beclin1 and interfere the expression of autophagy gene Beclin1 with small interfering RNA, thus inhibiting the effect of type III interferon on anti‐proliferation and promoting apoptosis of lung cancer cell. These results suggested that IFN λ could inhibit the proliferation of A549 cells by activating autophagy pathway, and IFN λ might be one of the potential therapeutic drugs for lung cancer. [ABSTRACT FROM AUTHOR]

Xuefu Zhuyu Decoction (XFZYD), the classical recipe for promoting blood circulation by removing blood stasis, has been used in China for a long history clinically. XFZYD has been found to improve cardiac function through reducing inflammation. However, the effect of XFZYD on myocardial apoptosis remains unclear. Herein, we investigated the mechanism of XFZYD preconditioning on myocardial injury in sepsis rats. The rats were treated with XFZYD one week, followed with intraperitoneal injection of lipopolysaccharide (LPS: 10 mg/kg) to induce sepsis. Pretreatment with XFZYD could reverse the effects of LPS-induced decreased mean arterial pressure (MAP) and increased heart rate (HR). XFZYD decreased the levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in serum or in heart. TUNEL staining revealed that the apoptotic index of XFZYD was significantly lower compared with the LPS group (P<0.05). Western blot results showed that the high doses of pretreatment XFZYD group can reduce the Bax expression of myocardial tissue in rats (P<0.05, P<0.01). The expression of Bcl-2 in XFZYD group was significantly higher than that in the LPS group (P<0.01), while the expression of caspase-3 in treatment group was significantly lower than that in the LPS group only after 12 h modeling (P<0.01). In addition, caspase-3 activity in rat cardiomyocytes of XFZYD-treated animals was significantly decreased. These findings suggest that pretreatment with XFZYD exerts a protective effect in the myocardium of septic rats by inhibiting myocardial cell apoptosis and antioxidation. [ABSTRACT FROM AUTHOR]

[Display omitted] • TGF-β1-pretreated MSCs have significant protective effects on intrahepatic biliary EpiCs. • TGF-β1-pretreatment enhanced MSCs-EXO production and its tissue repair ability. • MSCs-EXO exhibited therapeutic significance to biliary IRI. • EXO derived from TGF-β1-pretreated MSCs obviously alleviated biliary IRI. • EXO derived from TGF-β1-pretreated MSCs had apparent protective effects on biliary IRI through Jagged1/Notch/SOX9 pathway. This study aimed to evaluate the efficacy of exosomes (EXO) derived from TGF-β1-pretreated mesenchymal stem cells (MSCs) on biliary ischemia reperfusion injury (IRI) and further reveal the possible mechanisms. Bone marrow-derived MSCs were treated with exogenous TGF-β1, Jagged1/Notch1/SOX9 pathway inhibitor LY450139, or their combination. Then, EXO were isolated from the culture supernatants and further characterized. After establishing IRI model of biliary epithelial cells (EpiCs), EXO derived from differently-treated MSCs were applied to detect their protective effects on EpiCs, and LY450139 was applied in EpiCs to detect the possible mechanisms after treatment with MSCs-EXO. EXO derived from differently-treated MSCs were further injected into the hepatic artery immediately after establishment of intrahepatic biliary IRI for animal studies. Pretreatment with TGF-β1 significantly enhanced MSCs-EXO production and elevated the levels of massive miRNAs associated with anti-apoptosis and tissue repair, which were evidently decreased after TGF-β1 plus LY450139 cotreatment. Notable improvement was observed in EpiCs after MSCs-EXO treatment, evidenced by reduced cellular apoptosis, increased cellular proliferation and declined oxidative stress, which were more evident in EpiCs that were treated with EXO derived from TGF-β1-pretreated MSCs. However, application of EXO derived from TGF-β1 plus LY450139-cotreated MSCs reversely enhanced cellular apoptosis, decreased cellular proliferation and anti-oxidants production. Interestingly, LY450139 application in EpiCs after treatment with MSCs-EXO also reversed the declined cellular apoptosis and enhanced oxidative stress induced by TGF-β1 pretreatment. In animal studies, administration of EXO derived from TGF-β1-pretreated MSCs more effectively attenuated biliary IRI through reducing oxidative stress, apoptosis, inflammation and enhancing the expression levels of TGF-β1 and Jagged1/Notch1/SOX9 pathway-related markers, which were reversed after administration of EXO derived from TGF-β1 plus LY450139-cotreated MSCs. Our results provided a vital insight that TGF-β1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway. [ABSTRACT FROM AUTHOR]

Cancer is a significant public health problem worldwide. Complete identification of genes related to one type of cancer facilitates earlier diagnosis and effective treatments. In this study, two widely used algorithms, the random walk with restart algorithm and the shortest path algorithm, were adopted to construct two parameterized computational methods, namely, an RWR-based method and an SP-based method; based on these methods, an integrated method was constructed for identifying novel disease genes. To validate the utility of the integrated method, data for oral cancer were used, on which the RWR-based and SP-based methods were trained, thereby building two optimal methods. The integrated method combining these optimal methods was further adopted to identify the novel genes of oral cancer. As a result, 85 novel genes were inferred, among which eleven genes (e.g., MYD88, FGFR2, NF-κBIA) were identified by both the RWR-based and SP-based methods, 70 genes (e.g., BMP4, IFNG, KITLG) were discovered only by the RWR-based method and four genes (L1R1, MCM6, NOG and CXCR3) were predicted only by the SP-based method. Extensive analyses indicate that several novel genes have strong associations with cancers, indicating the effectiveness of the integrated method for identifying disease genes. [ABSTRACT FROM AUTHOR]

This current study tested expression and potential biological functions of Gab3 in human glioma. Gab3 mRNA and protein expression was significantly elevated in human glioma tissues and glioma cells. Its level was however low in normal brain tissues and primary human astrocytes. In both established (U251MG cell line) and primary human glioma cells, Gab3 knockdown by shRNA/siRNA significantly inhibited Akt activation and cell proliferation. Reversely, forced Gab3 overexpression in U251MG cells promoted Akt activation and cell proliferation. In vivo, the growth of U251MG tumors in nude mice was inhibited following expressing Gab3 shRNA. Akt activation in cancer tissues was also suppressed by Gab3 shRNA. Together, we conclude that Gab3 overexpression in human glioma mediates Akt activation and cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Identification of disease genes is a hot topic in biomedicine and genomics. However, it is a challenging problem because of the complexity of diseases. Inflammatory bowel disease (IBD) is an idiopathic disease caused by a dysregulated immune response to host intestinal microflora. It has been proven to be associated with the development of intestinal malignancies. Although the specific pathological characteristics and genetic background of IBD have been partially revealed, it is still an overdetermined disease and the blueprint of all genetic variants still needs to be improved. In this study, a novel computational method was built to identify genes related to IBD. Samples from two subtypes of IBD (ulcerative colitis and Crohn’s disease) and normal samples were employed. By analyzing the gene expression profiles of these samples using minimum redundancy maximum relevance and incremental feature selection, 21 genes were obtained that could effectively distinguish samples from the two subtypes of IBD and the normal samples. Then, the shortest-path approach was used to search for an additional 20 genes in a large network constructed using protein-protein interactions based on the above-mentioned 21 genes. Analyses of the 41 genes obtained indicate that they are closely associated with this disease. [ABSTRACT FROM AUTHOR]

Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2- H -tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid’s ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and activating JNK signaling pathways in human cervical cancer cells, which supplied a potential therapy for the application of carnosic acid in clinical treatment. [ABSTRACT FROM AUTHOR]

Apoptosis is the process of programmed cell death (PCD) that occurs in multicellular organisms. This process of normal cell death is required to maintain the balance of homeostasis. In addition, some diseases, such as obesity, cancer, and neurodegenerative diseases, can be cured through apoptosis, which produces few side effects. An effective comprehension of the mechanisms underlying apoptosis will be helpful to prevent and treat some diseases. The identification of genes related to apoptosis is essential to uncover its underlying mechanisms. In this study, a computational method was proposed to identify novel candidate genes related to apoptosis. First, protein-protein interaction information was used to construct a weighted graph. Second, a shortest path algorithm was applied to the graph to search for new candidate genes. Finally, the obtained genes were filtered by a permutation test. As a result, 26 genes were obtained, and we discuss their likelihood of being novel apoptosis-related genes by collecting evidence from published literature. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI), characterized by a rapid decline in renal function, is triggered by an acute inflammatory response that leads to kidney damage. An effective treatment for AKI is lacking. Using in vitro and in vivo AKI models, our laboratory has identified a series of anti-inflammatory molecules and their derivatives. In the current study, we identified the protective role of rutaecarpine (Ru) on renal tubules. We obtained a series of 3-aromatic sulphonamide-substituted Ru derivatives exhibiting enhanced renoprotective and anti-inflammatory function. We identified Compound-6c(Cpd-6c) as having the best activity and examined its protective effect against cisplatin nephropathy both in vivo and in vitro in cisplatin-stimulated tubular epithelial cells (TECs). Our results showed that Cpd-6c restored renal function more effectively than Ru, as evidenced by reduced blood urea nitrogen and serum creatinine levels in mice. Cpd-6c alleviated tubular injury, as shown by PAS staining and molecular analysis of kidney injury molecule-1 (KIM-1), with both prevention and treatment protocols in cisplatin-treated mice. Moreover, Cpd-6c decreased kidney inflammation, oxidative stress and programmed cell death. These results have also been confirmed in cisplatin-treated TECs. Using web-prediction algorithms, molecular docking, and cellular thermal shift assay (CETSA), we identified phosphodiesterase 4B (PDE4B) as a Cpd-6c target. In addition, we firstly found that PDE4B was up-regulated significantly in the serum of AKI patients. After identifying the function of PDE4B in cisplatin-treated tubular epithelial cells by siRNA transfection or PDE4 inhibitor rolipram, we showed that Cpd-6c treatment did not protect against cisplatin-induced injury in PDE4B knockdown TECs, thus indicating that Cpd-6c exerts its renoprotective and anti-oxidative effects via the PDE4B-dependent pathway. Collectively, Cpd-6c might serve as a potential therapeutic agent for AKI and PDE4B may be highly involved in the initiation and progression of AKI. [ABSTRACT FROM AUTHOR]