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Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease, with few effective treatments besides alcohol abstinence. Angelicae Gigantis Radix (AG), Glycyrrhizae Radix et Rhizoma (GR), Paeoniae Radix (PR), and Zizyphi Fructus (ZF) are traditional herbs used to treat various ailments, including liver diseases. While several studies have reported the beneficial effects of GR on ALD, the effects of AG, PR, and ZF remain underexplored. Therefore, their efficacy and mechanisms against ALD were investigated using an alcohol-related liver injury model. The model was induced by ethanol gavage in C57BL/6J mice for 14 days, followed by oral administration of AG, GR, PR, and ZF one hour post-induction. The administration of these herbs reduced liver weight, and improved serum biomarkers of liver injury (ALT, AST, albumin). The herbs enhanced hepatic antioxidant capacity (GSH, SOD, catalase) and suppressed the production of proinflammatory cytokines (TNF-α, IL-1β) and apoptotic changes (caspase-3). The mechanisms of action involved lipid-lowering gene modulation through regulation of the cytochrome P450 2E1/Sirtuin 1/Nrf2 pathways. Histopathological and immunohistochemical analyses revealed that these herbs attenuated hepatocyte damage and steatosis via antioxidant, anti-inflammatory, and antiapoptotic effects. These findings suggest that traditional herbs, particularly AG, could be promising alternative therapies for treating ALD. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disease that mainly occurs due to the cellular inflammatory response and the destruction of joint cartilage. Natural eggshell membrane (NEM), a byproduct of egg processing, might be a promising knee OA treatment because of its anti-inflammatory properties and resemblance to synovial membrane components. Therefore, we aimed to study the anti-inflammatory effects of NEM in OA, utilizing both in vitro experiments with primary chondrocytes and in vivo studies with a surgical rat model of knee OA. In vitro studies showed that NEM treatment improved cell viability in chondrocytes exposed to interleukin-1α by upregulating chondrogenic genes and inhibiting enzymes that degrade the extracellular matrix (ECM). Furthermore, the anti-inflammatory effects of NEM were observed in chondrocytes induced by lipopolysaccharide. Administering NEM orally for 56 days after OA surgery resulted in enhanced joint swelling reduction and improved mobility in animal models, as well as an increase in bone density and cartilage compressive strength in a concentration-dependent manner. It inhibited inflammatory markers (5-lipoxygenase and prostaglandin E2) and extracellular matrix (ECM)-degrading enzymes (MMP-2 and MMP-9) in both the cartilage and synovium. Simultaneously, there was an upregulation in the expression of chondrogenic genes (Sox9, aggrecan, and Col-2). The histopathological and immunohistochemical analyses demonstrated that NEM's anti-inflammatory, anti-apoptotic, and chondrogenic properties contributed to the mitigation of joint degradation and synovial inflammation. Therefore, NEM is a potential alternative or functional food agent that addresses both anti-inflammatory and chondroprotective aspects in OA. [ABSTRACT FROM AUTHOR]

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment. [ABSTRACT FROM AUTHOR]

Trachinotus ovatus is an economically important mariculture fish, and hypoxia has become a critical threat to this hypoxia-sensitive species. However, the molecular adaptation mechanism of T. ovatus liver to hypoxia remains unclear. In this study, we investigated the effects of acute hypoxic stress (1.5 ± 0.1 mg·L−1 for 6 h) and re-oxygenation (5.8 ± 0.3 mg·L−1 for 12 h) in T. ovatus liver at both the transcriptomic and metabolic levels to elucidate hypoxia adaptation mechanism. Integrated transcriptomics and metabolomics analyses identified 36 genes and seven metabolites as key molecules that were highly related to signal transduction, cell growth and death, carbohydrate metabolism, amino acid metabolism, and lipid metabolism, and all played key roles in hypoxia adaptation. Of these, the hub genes FOS and JUN were pivotal hypoxia adaptation biomarkers for regulating cell growth and death. During hypoxia, up-regulation of GADD45B and CDKN1A genes induced cell cycle arrest. Enhancing intrinsic and extrinsic pathways in combination with glutathione metabolism triggered apoptosis; meanwhile, anti-apoptosis mechanism was activated after hypoxia. Expression of genes related to glycolysis, gluconeogenesis, amino acid metabolism, fat mobilization, and fatty acid biosynthesis were up-regulated after acute hypoxic stress, promoting energy supply. After re-oxygenation for 12 h, continuous apoptosis favored cellular function and tissue repair. Shifting from anaerobic metabolism (glycolysis) during hypoxia to aerobic metabolism (fatty acid β-oxidation and TCA cycle) after re-oxygenation was an important energy metabolism adaptation mechanism. Hypoxia 6 h was a critical period for metabolism alteration and cellular homeostasis, and re-oxygenation intervention should be implemented in a timely way. This study thoroughly examined the molecular response mechanism of T. ovatus under acute hypoxic stress, which contributes to the molecular breeding of hypoxia-tolerant cultivars. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is characterized by progressive cartilage destruction and synovitis; however, there are no approved disease-modifying OA drugs. Krill oil (KO) has been reported to possess anti-inflammatory properties and alleviate joint pain in knee OA, indicating its potential to target the inflammatory mechanism of OA. Therefore, the anti-OA effects of KO were investigated in primary chondrocytes and a surgical rat model of knee OA. The oral administration of KO at 200 and 100 mg/kg for 8 weeks improved joint swelling and mobility in the animal model and led to increased bone mineral density and compressive strength in the cartilage. The oral KO doses upregulated chondrogenic genes (type 2 collagen, aggrecan, and Sox9), with inhibition of inflammation markers (5-lipoxygenase and prostaglandin E2) and extracellular matrix (ECM)-degrading enzymes (MMP-2 and MMP-9) in the cartilage and synovium. Consistently, KO treatments increased the viability of chondrocytes exposed to interleukin 1α, accompanied by the upregulation of the chondrogenic genes and the inhibition of the ECM-degrading enzymes. Furthermore, KO demonstrated inhibitory effects on lipopolysaccharide-induced chondrocyte inflammation. Histopathological and immunohistochemical analyses revealed that KO improved joint destruction and synovial inflammation, probably due to the anti-inflammatory, anti-apoptotic, and chondrogenic effects. These findings suggest the therapeutic potential of KO for knee OA. [ABSTRACT FROM AUTHOR]

Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth–death regulation. [ABSTRACT FROM AUTHOR]

Hypoxia-induced vascular endothelial dysfunction (VED) is a significant contributor to several severe human diseases, including heart disease, stroke, dementia, and cancer. However, current treatment options for VED are limited due to the lack of understanding of the underlying disease mechanisms and therapeutic leads. We recently discovered a heat-stable microprotein in ginseng, called ginsentide TP1, that has been shown to reduce vascular dysfunction in cardiovascular disease models. In this study, we use a combination of functional assays and quantitative pulsed SILAC proteomics to identify new proteins synthesized in hypoxia and to show that ginsentide TP1 provides protection for human endothelial cells against hypoxia and ER stress. Consistent with the reported findings, we also found that hypoxia activates various pathways related to endothelium activation and monocyte adhesion, which in turn, impairs nitric oxide (NO) synthase activity, reduces the bioavailability of NO, and increases the production of reactive oxygen species that contribute to VED. Additionally, hypoxia triggers endoplasmic reticulum stress and initiates apoptotic signaling pathways associated with cardiovascular pathology. Treatment with ginsentide TP1 reduced surface adhesion molecule expression, prevented activation of the endothelium and leukocyte adhesion, restored protein hemostasis, and reduced ER stress to protect against hypoxia-induced cell death. Ginsentide TP1 also restored NO signaling and bioavailability, reduced oxidative stress, and protected endothelial cells from endothelium dysfunction. In conclusion, this study shows that the molecular pathogenesis of VED induced by hypoxia can be mitigated by treatment with ginsentide TP1, which could be one of the key bioactive compounds responsible for the "cure-all" effect of ginseng. This research may lead to the development of new therapies for cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Quercetin is a natural flavonoid widely found in natural fruits and vegetables. Recent studies have shown that quercetin mediates multiple beneficial effects in a variety of organ damage and diseases, and is considered a healthcare supplement with health-promoting potential. Male infertility is a major health concern, and testicular damage from multiple causes is an important etiology. Previous studies have shown that quercetin has a protective effect on reproductive function. This may be related to the antioxidant, anti-inflammatory, and anti-apoptotic biological activities of quercetin. Therefore, this paper reviews the mechanisms by which quercetin exerts its pharmacological activity and its role in testicular damage induced by various etiologies. In addition, this paper compiles the application of quercetin in clinical trials, demonstrating its practical effects in regulating blood pressure and inhibiting cellular senescence in human patients. However, more in-depth experimental studies and clinical trials are needed to confirm the true value of quercetin for the prevention and protection against testicular injury. [ABSTRACT FROM AUTHOR]

Antioxidant therapy is an effective approach for treating diseases in which oxidative stress is involved in the onset of symptoms. This approach aims to rapidly replenish the antioxidant substances in the body when they are depleted due to excess oxidative stress. Importantly, a supplemented antioxidant must specifically eliminate harmful reactive oxygen species (ROS) without reacting with physiologically beneficial ROS, which are important to the body. In this regard, typically used antioxidant therapies can be effective, but may cause adverse effects due to their lack of specificity. We believe that Si-based agents are epoch-making drugs that can overcome these problems associated with current antioxidative therapy. These agents alleviate the symptoms of oxidative-stress-associated diseases by generating large amounts of the antioxidant hydrogen in the body. Moreover, Si-based agents are expected to be highly effective therapeutic drug candidates because they have anti-inflammatory, anti-apoptotic, and antioxidant effects. In this review, we discuss Si-based agents and their potential future applications in antioxidant therapy. There have been several reports of hydrogen generation from silicon nanoparticles, but unfortunately, none have been approved as pharmaceutical agents. Therefore, we believe that our research into medical applications using Si-based agents is a breakthrough in this research field. The knowledge obtained thus far from animal models of pathology may greatly contribute to the improvement of existing treatment methods and the development of new treatment methods. We hope that this review will further revitalize the research field of antioxidants and lead to the commercialization of Si-based agents. [ABSTRACT FROM AUTHOR]

Prohibitins (PHBs) are a highly conserved class of proteins and have an essential role in transcription, epigenetic regulation, nuclear signaling, mitochondrial structural integrity, cell division, and cellular membrane metabolism. Prohibitins form a heterodimeric complex, consisting of two proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2). They have been discovered to have crucial roles in regulating cancer and other metabolic diseases, functioning both together and independently. As there have been many previously published reviews on PHB1, this review focuses on the lesser studied prohibitin, PHB2. The role of PHB2 in cancer is controversial. In most human cancers, overexpressed PHB2 enhances tumor progression, while in some cancers, it suppresses tumor progression. In this review, we focus on (1) the history, family, and structure of prohibitins, (2) the essential location-dependent functions of PHB2, (3) dysfunction in cancer, and (4) the promising modulators to target PHB2. At the end, we discuss future directions and the clinical significance of this common essential gene in cancer. [ABSTRACT FROM AUTHOR]

Acute ultraviolet (UV)-B radiation is the major external factor causing photodamage. In this study, we aimed to determine the effects of Dendrobium nobile Lindl. polysaccharides (DNPs) on photodamage in HaCaT keratinocytes after UVB irradiation and the underlying mechanisms. We found that DNPs significantly attenuated the decline in the viability and proliferation of HaCaT cells after UVB irradiation. Moreover, DNPs scavenged reactive oxygen species (ROS), improved the activities of endogenous antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, and reduced the levels of malondialdehyde, while partially attenuating cell cycle arrest, suggesting their antioxidant and anti-apoptotic properties. The mitogen-activated protein kinase (MAPK) pathway was found to be important for the attenuation of UVB-induced photodamage in the HaCaT cells. Furthermore, DNPs exerted cytoprotective effects by downregulating UVB-induced ROS-mediated phosphorylation of MAPKs, including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase, and by inhibiting p53 expression as well as the apoptotic cascade response. Therefore, DNPs ameliorated UVB-induced oxidative damage and apoptosis in HaCaT cells via the regulation of MAPKs. Our findings thus highlight the Dendrobium nobile Lindl polysaccharides as promising therapeutic candidates for UVB-induced photodamage. [ABSTRACT FROM AUTHOR]

Ardisia silvestris is a traditional medicinal herb used in Vietnam and several other countries. However, the skin-protective properties of A. silvestris ethanol extract (As-EE) have not been evaluated. Human keratinocytes form the outermost barrier of the skin and are the main target of ultraviolet (UV) radiation. UV exposure causes skin photoaging via the production of reactive oxygen species. Protection from photoaging is thus a key component of dermatological and cosmetic products. In this research, we found that As-EE can prevent UV-induced skin aging and cell death as well as enhance the barrier effect of the skin. First, the radical-scavenging ability of As-EE was checked using DPPH, ABTS, TPC, CUPRAC, and FRAP assays, and a 3-(4-5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assay was used to examine cytotoxicity. Reporter gene assays were used to determine the doses that affect skin-barrier-related genes. A luciferase assay was used to identify possible transcription factors. The anti-photoaging mechanism of As-EE was investigated by determining correlated signaling pathways using immunoblotting analyses. As-EE had no harmful effects on HaCaT cells, according to our findings, and As-EE revealed moderate radical-scavenging ability. With high-performance liquid chromatography (HPLC) analysis, rutin was found to be one of the major components. In addition, As-EE enhanced the expression levels of hyaluronic acid synthase-1 and occludin in HaCaT cells. Moreover, As-EE dose-dependently up-regulated the production of occludin and transglutaminase-1 after suppression caused by UVB blocking the activator protein-1 signaling pathway, in particular, the extracellular response kinase and c-Jun N-terminal kinase. Our findings suggest that As-EE may have anti-photoaging effects by regulating mitogen-activated protein kinase, which is good news for the cosmetics and dermatology sectors. [ABSTRACT FROM AUTHOR]

Aloesone is a major metabolic compound in Aloe vera, which has been widely used as a food source and therapeutic agent in several countries. Our recent study demonstrated that aloesone has anti-epileptic effects on glutamate-induced neuronal injury by suppressing the production of reactive oxygen species (ROS). Unless ROS are naturally neutralized by the endogenous antioxidant system, they lead to the activation of inflammation, polarization, and apoptosis. This study aimed to identify the multiple beneficial effects of aloesone and explore its molecular mechanism in macrophages. Hence, the murine macrophage cell line RAW264.7 was pretreated with aloesone and then exposed to lipopolysaccharides (LPS). The results demonstrated that aloesone, within a dosage range of 0.1–100 µM, dramatically decreased the LPS-induced elevation of ROS production, reduced nitric oxide (NO) release, inhibited the M1 polarization of RAW264.7 cells, and prevented cells from entering the LPS-induced early and late phases of apoptosis in a dose-dependent manner. Simultaneously, aloesone significantly decreased the mRNA expression of inflammation-related genes (iNOS, IL-1ꞵ, TNF-α) and increased the expression of antioxidant enzymes (Gpx-1 and SOD-1). The core genes HSP90AA1, Stat3, Mapk1, mTOR, Fyn, Ptk2b, and Lck were closely related to these beneficial effects of aloesone. Furthermore, immunofluorescence staining and flow cytometry data confirmed that aloesone significantly repressed the activation of mTOR, p-mTOR, and HIF-1α induced by LPS and inhibited the protein expression of TLR4, which is the target of LPS. In conclusion, aloesone demonstrated multiple protective effects against LPS-induced oxidative stress, inflammation, M1 polarization, and apoptosis in macrophages, suggesting its potential as a prodrug. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the protective function and mechanism of TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) from skipjack tuna cardiac arterial bulbs on skin photoaging using UVB-irradiated HaCaT cell model. The present results indicated that TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) had significant cytoprotective effect on UVB-irradiated HaCaT cells (p < 0.001). Hoechst 33342 staining showed that apoptosis of UV-irradiated HaCaT cells could be significantly reduced by the treatment of TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM); JC-1 staining showed that TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) could protect HaCaT cells from apoptosis by restoring mitochondrial membrane potential (MMP); Furthermore, TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) could significantly down-regulate the ratio of Bax/Bcl-2 and reduce the expression level of the apoptosis-executing protein Caspase-3 by decreasing the expression of protein Caspase-8 and Caspase-9 (p < 0.05). The action mechanism indicated that TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) could up-regulate the expression levels of Nrf2, NQO1 and HO-1 (p < 0.05), which further increased the activity of downstream proteases (SOD, CAT and GSH-Px), and scavenged reactive oxygen species (ROS) and decreased the intracellular levels of malondialdehyde (MDA). In addition, molecular docking indicated that TCP3 (PKK) and TCP6 (YEGGD) could competitively inhibit the Nrf2 binding site because they can occupy the connection site of Nrf2 by binding to the Kelch domain of Keap1 protein. TCP9 (GPGLM) was inferred to be non-competitive inhibition because it could not bind to the active site of the Kelch domain of Keap1 protein. In summary, the antioxidant peptides TCP3 (PKK), TCP6 (YEGGD) and TCP9 (GPGLM) from cardiac arterial bulbs of skipjack tuna can effectively protect HaCaT cells from UVB-irradiated damage and can be used in the development of healthy and cosmetic products to treat diseases caused by UV radiation. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is characterized by impaired tear dynamics, leading to complex pathophysiological conditions. (PEG)-BHD1028, a peptide agonist to AdipoRs, was evaluated as a potential therapeutic agent for DED based on the reported physiological function of adiponectin, including anti-inflammation and epithelial protection. Therapeutic effects of (PEG)-BHD1028 were evaluated in experimentally induced EDE with 0.001%, 0.01%, and 0.1% (PEG)-BHD1028 in mice and 0.1%, 0.2%, and 0.4% in rabbits for 10 days. In the rabbit study, 0.05% cyclosporine was also tested as a comparator. The results from the mouse study revealed significant improvement in tear volumes, tear breakup time (TBUT), inflammation, and corneal severity score (CSS) within 10 days at all (PEG)-BHD1028 concentrations. In the rabbit study, the tear volume and TBUT significantly increased in (PEG)-BHD1028 groups compared with vehicle and 0.05% cyclosporine groups. The CSS, apoptosis rate, and corneal thickness of all (PEG)-BHD1028 and 0.05% cyclosporine groups were significantly improved relative to the vehicle group. The immune cell counts of 0.2% and 0.4% (PEG)-BHD1028 treated groups were significantly lower than those of the vehicle group. These results represent the potential of (PEG)-BHD1028 as an effective therapeutic agent for DED. [ABSTRACT FROM AUTHOR]

The important factors in the pathogenesis of neurodegenerative disorders include oxidative stress and neuron-glia system inflammation. Vignae Radiatae Semen (VRS) exhibits antihypertensive, anticancer, anti-melanogenesis, hepatoprotective, and immunomodulatory properties. However, the neuroprotective effects and anti-neuroinflammatory activities of VRS ethanol extract (VRSE) remained unknown. Thus, this study aimed to investigate the neuroprotective and anti-inflammatory activities of VRSE against hydrogen peroxide (H2O2)-induced neuronal cell death in mouse hippocampal HT22 cells and lipopolysaccharide (LPS)-stimulated BV2 microglial activation, respectively. This study revealed that VRSE pretreatment had significantly prevented H2O2-induced neuronal cell death and attenuated reactive oxygen species generations in HT22 cells. Additionally, VRSE attenuated the apoptosis protein expression while increasing the anti-apoptotic protein expression. Further, VRSE showed significant inhibitory effects on LPS-induced pro-inflammatory cytokines in BV2 microglia. Moreover, VRSE pretreatment significantly activated the tropomyosin-related kinase receptor B/cAMP response element-binding protein, brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2, and heme oxygenase-1 signaling pathways in HT22 cells exposed to H2O2 and inhibited the activation of the mitogen-activated protein kinase and nuclear factor-κB mechanism in BV2 cells stimulated with LPS. Therefore, VRSE exerts therapeutic potential against neurodegenerative diseases related to oxidative stress and pathological inflammatory responses. [ABSTRACT FROM AUTHOR]

Alcohol and drug overdoses cause liver diseases such as cirrhosis, hepatitis, and liver cancer globally. In particular, an overdose of acetaminophen (APAP), which is generally used as an analgesic and antipyretic agent, is a major cause of acute hepatitis, and cases of APAP-induced liver damage are steadily increasing. Potential antioxidants may inhibit the generation of free radicals and prevent drug-induced liver damage. Among plant-derived natural materials, radishes (RJ) and turnips (RG) have anti-inflammatory, anticancer, and antioxidant properties due to the presence of functional ingredients, such as glucosinolate and isothiocyanate. Although various functions have been reported, in vivo studies on the antioxidant activity of radishes are insufficient. Therefore, we aim to evaluate the hepatoprotective effects of RG and RJ in APAP-induced liver-damaged mice. RG and RJ extracts markedly improved the histological status, such as inflammation and infiltration, of mice liver tissue, significantly decreased the levels of alanine transaminase, aspartate aminotransferase, and malondialdehyde, and significantly increased the levels of glutathione, superoxide dismutase and catalase in the APAP-induced liver-damaged mice. In addition, RG and RJ extracts significantly increased the expression of Nrf-2 and HO-1, which are antioxidative-related factors, and regulated the BAX and BCL-2, thereby showing anti-apoptosis activity. These results indicated that RG and RJ extracts protected mice against acute liver injury, attributed to a reduction in both oxidative stress and apoptosis. These findings have clinical implications for the use of RG and RJ extracts as potential natural candidates for developing hepatoprotective agents. [ABSTRACT FROM AUTHOR]

Liver injury is a significant public health issue nowadays. Shibi tea is a non-Camellia tea prepared from the dried leaves of Adinandra nitida, one of the plants with the greatest flavonoid concentration, with Camellianin A (CA) being the major flavonoid. Shibi tea is extensively used in food and medicine and has been found to provide a variety of health advantages. The benefits of Shibi tea and CA in preventing liver injury have not yet been investigated. The aim of this study was to investigate the hepatoprotective effects of extract of Shibi tea (EST) and CA in mice with carbon tetrachloride (CCl4)-induced acute liver injury. Two different concentrations of EST and CA were given to model mice by gavage for 3 days. Treatment with two concentrations of EST and CA reduced the CCl4-induced elevation of the liver index, liver histopathological injury score, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Western blotting and immunohistochemical analysis demonstrated that EST and CA regulated the oxidative stress signaling pathway protein levels of nuclear factor E2-related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1), the expression of inflammatory cytokines, the phosphorylated nuclear factor-kappaB p65 (p-NF-κB)/nuclear factor-kappaB p65 (NF-κB) ratio, the phospho-p44/42 mitogen-activated protein kinase (p-MAPK), and the apoptosis-related protein levels of BCL2-associated X (Bax)/B cell leukemia/lymphoma 2 (Bcl2) in the liver. Taken together, EST and CA can protect against CCl4-induced liver injury by exerting antioxidative stress, anti-inflammation, and anti-apoptosis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common age-related neurodegenerative disease that strikes millions worldwide. Herein, we demonstrate a new approach based on network target to identify anti-AD compounds from Danshen. Network pharmacology and molecular docking were employed to establish the DS-AD network, which mainly involved apoptosis of neuron cells. Then network scoring was confirmed via Connectivity Map analysis. M308 (Danshenxinkun D) was an anti-AD candidate with a high score (p < 0.01). Furthermore, we conducted ex vivo experiments with H2O2-treated PC12 cells to verify the neuroprotective effect of Salvia miltiorrhiza-containing plasma (SMP), and UPLC-Q-TOF/MS and RT-qPCR were performed to demonstrate the anti-AD activity of M308 from SMP. Results revealed that SMP could enhance cell viability and level of acetylcholine. AO/EB staining and Mitochondrial membrane potential (MMP) analysis showed that SMP significantly suppressed apoptosis, which may be due to anti-oxidative stress activity. Moreover, the effects of M308 and SMP on expressions of PSEN1, DRD2, and APP mRNA were consistent, and M308 can significantly reverse the expression of PSEN1 and DRD2 mRNA in H2O2-treated PC12 cells. The strategy based on the network could be employed to identify anti-AD compounds from Chinese herbs. Notably, M308 stands out as a promising anti-AD candidate for development. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have become a serious healthcare problem worldwide and there is no efficacious cure. However, regulating the fate of stem cells is an effective way to treat these neurological diseases. In previous work, stemazole was reported to maintain the survival of human neural stem cells in the absence of growth factors and to have therapeutic effects on neurodegenerative diseases. However, although it is a promising small molecule, the molecular mechanisms against apoptosis are ambiguous. In this study, tandem mass tag (TMT)-based proteomics were performed to obtain whole protein expression profiles of human neural stem cells in different groups under extreme conditions. Bioinformatics analysis based on protein–protein interaction (PPI) network construction, gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were adopted to explore crucial proteins and possible pharmacological mechanisms. A total of 77 differentially expressed proteins were identified, comprising 38 upregulated proteins and 39 downregulated proteins. Combined with a diseases database of Alzheimer's disease (AD), caspase-2 (CASP2), PKA C-alpha (PRKACA), fibronectin (FN1), large neutral amino acid transporter small subunit 1 (SLC7A5), which are involved in cell proliferation and apoptosis, this was further validated by enzyme activity assay and molecular docking, and regarded as putative targets regulated by stemazole. The present results give an insight into this small molecule and a better understanding for further elucidating the underlying mechanisms in the treatment of stem cells and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer’s disease and Parkinson’s disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Microglia-induced inflammatory signaling and neuronal oxidative stress are mutually reinforcing processes central to the pathogenesis of neurodegenerative diseases. Recent studies have shown that extracts of dried Pheretima aspergillum (Lumbricus) can inhibit tissue fibrosis, mitochondrial damage, and asthma. However, the effects of Lumbricus extracts on neuroinflammation and neuronal damage have not been previously studied. Therefore, to evaluate the therapeutic potential of Lumbricus extract for neurodegenerative diseases, the current study assessed the extract's anti-inflammatory and antioxidant activities in BV2 microglial cultures stimulated with lipopolysaccharide (LPS) along with its neuroprotective efficacy in mouse hippocampal HT22 cell cultures treated with excess glutamate. Lumbricus extract dose-dependently inhibited the LPS-induced production of multiple proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β) and reversed the upregulation of proinflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2). Lumbricus also activated the antioxidative nuclear factor erythroid 2-relayed factor 2/heme oxygenase-1 pathway and inhibited LPS-induced activation of the nuclear factor-κB/mitogen-activated protein kinases/NOD-like receptor family pyrin domain containing 3 inflammatory pathway. In addition, Lumbricus extract suppressed the glutamate-induced necrotic and apoptotic death of HT22 cells, effects associated with upregulated expression of antiapoptotic proteins, downregulation of pro-apoptotic proteins, and reduced accumulation of reactive oxygen species. Chromatography revealed that the Lumbricus extract contained uracil, hypoxanthine, uridine, xanthine, adenosine, inosine, and guanosine. Its effects against microglial activation and excitotoxic neuronal death reported herein support the therapeutic potential of Lumbricus for neurodegenerative diseases.

The aim of this study was to assess the anti-inflammatory and anti-apoptotic effects of KIOM-2015EW, the hot-water extract of maple leaves in hyperosmolar stress (HOS)-induced human corneal epithelial cells (HCECs). HCECs were exposed to hyperosmolar medium and exposed to KIOM-2015EW with or without the hyperosmolar media. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 production and apoptosis were observed, and the activation of mitogen-activated protein kinases (MAPKs) including extracellular signal regulated kinase (ERK), p38 and c-JUN N-terminal kinase (JNK) signaling and nuclear factor (NF)-κB was confirmed. Compared to isomolar medium, the induction of cell cytotoxicity significantly increased in HCECs exposed to hyperosmolar medium in a time-dependent manner. KIOM-2015EW-treatment significantly reduced the mRNA and protein expression of pro-inflammatory mediators and apoptosis. KIOM-2015EW-treatment inhibited HOS-induced MAPK signaling activation. Additionally, the HOS-induced increase in NF-κB phosphorylation was attenuated by KIOM-2015EW. The results demonstrated that KIOM-2015EW protects the ocular surface by suppressing inflammation in dry eye disease, and suggest that KIOM-2015EW may be used to treat several ocular surface diseases where inflammation plays a key role. [ABSTRACT FROM AUTHOR]

Nawrot-PorAlthough cisplatin is an anticancer drug that has activity against malignant tumor, it often causes nephrotoxicity. Previous reports have confirmed that the saponins from the leaves of P. quinquefolium (PQS) exerted many pharmacological activities. However, the renoprotective effects of PQS were still unknown. The purpose of the present research was to discuss renoprotective effect of PQS in a mouse model of cisplatin-induced acute kidney injury (AKI). The levels of blood urea nitrogen (BUN) and serum creatinine (CRE) were evidently increased in cisplatin-intoxicated mice, which were reversed by PQS. Renal oxidative stress, evidenced by increased malondialdehyde (MDA) level and decline of glutathione (GSH) and superoxide dismutase (SOD) activities, was significantly alleviated by PQS pretreatment. The suppression of inflammatory response by PQS was realized through the decrease the mRNA expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in kidney tissues, which were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Simultaneously, the overexpression of cytochrome P450 E1 (CYP2E1) and heme oxygenase-1 (HO-1) were attenuated by PQS. Furthermore, the effects of Western blotting demonstrated that PQS administration significantly suppressed the protein expression levels of nicotinamide adenine dinucleotide phosphate oxidase type 4 (Nox4), cleaved Caspase-3, cleaved Caspase-9, Bax, nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), suggesting the inhibition of apoptosis and inflammation response. Overall, PQS may possess protective effects in cisplatin-induced AKI through suppression of oxidative stress, inflammation and apoptosis.ąbka. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats) combined with pronuclear microinjection has become the most effective method for producing transgenic animals. However, the relatively low embryo developmental rate limits its application. In the current study, it was observed that 10−7 M melatonin is considered an optimum concentration and significantly promoted the in vitro development of murine microinjected pronuclear embryos, as indicated by the increased blastocyst rate, hatching blastocyst rate and blastocyst cell number. When these blastocysts were implanted into recipient mice, the pregnancy rate and birth rate were significantly higher than those of the microinjected control, respectively. Mechanistic studies revealed that melatonin treatment reduced reactive oxygen species (ROS) production and cellular apoptosis during in vitro embryo development and improved the quality of the blastocysts. The implantation of quality-improved blastocysts led to elevated pregnancy and birth rates. In conclusion, the results revealed that the anti-oxidative and anti-apoptotic activities of melatonin improved the quality of microinjected pronuclear embryos and subsequently increased both the efficiency of embryo implantation and the birth rate of the pups. Therefore, the melatonin supplementation may provide a novel alternative method for generating large numbers of transgenic mice and this method can probably be used in human-assisted reproduction and genome editing. [ABSTRACT FROM AUTHOR]

Chum salmon skin gelatin, de-isoflavoned soy protein, and casein were hydrolyzed at two degrees of hydrolysis. Genistein, the prepared hydrolysates, and genistein-hydrolysate combinations were assessed for their proliferative and anti-apoptotic effects on human osteoblasts (hFOB 1.19) to clarify potential cooperative effects between genistein and these hydrolysates in these two activities. Genistein at 2.5 μg/L demonstrated the highest proliferative activity, while the higher dose of genistein inhibited cell growth. All hydrolysates promoted osteoblast proliferation by increasing cell viability to 102.9%–131.1%. Regarding etoposide- or NaF-induced osteoblast apoptosis, these hydrolysates at 0.05 g/L showed both preventive and therapeutic effects against apoptosis. In the mode of apoptotic prevention, the hydrolysates decreased apoptotic cells from 32.9% to 15.2%–23.7% (etoposide treatment) or from 23.6% to 14.3%–19.6% (NaF treatment). In the mode of apoptotic rescue, the hydrolysates lessened the extent of apoptotic cells from 15.9% to 13.0%–15.3% (etoposide treatment) or from 13.3% to 10.9%–12.7% (NaF treatment). Gelatin hydrolysates showed the highest activities among all hydrolysates in all cases. All investigated combinations (especially the genistein-gelatin hydrolysate combination) had stronger proliferation, apoptotic prevention, and rescue than genistein itself or their counterpart hydrolysates alone, suggesting that genistein cooperated with these hydrolysates, rendering greater activities in osteoblast proliferation and anti-apoptos [ABSTRACT FROM AUTHOR]

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

The protective effects of vitamin D (VitD) in different diseases were studied. The liver is of great interest, especially with the presence of VitD receptors. A high-fat diet (HFD) is associated with many diseases, including liver injury. Consumption of saturated fatty acids triggers hepatic apoptosis and is associated with increased inflammation. We aimed in this study to investigate the protective effects of VitD on hepatic molecular apoptotic changes in response to an HFD in rats. Forty male Wistar albino rats were used and divided into four groups: control, HFD, control + VitD, and VitD-supplemented HFD (HFD + VitD) groups. After six months, the rats were sacrificed, and the livers were removed. RNA was extracted from liver tissues and used for the quantitative real-time RT-PCR of different genes: B-cell lymphoma/leukemia-2 (BCL2), BCL-2-associated X protein (Bax), Fas cell surface death receptor (FAS), FAS ligand (FASL), and tumor necrosis factor α (TNF-α). The results showed that an HFD increased the expression of the pro-apoptotic genes Bax, FAS, and FASL, and reduced the expression of the anti-apoptotic gene BCL2. Interestingly, a VitD-supplemented HFD significantly increased the BCL2 expression and decreased the expression of all pro-apoptotic genes and TNFα. In conclusion, VitD has a protective role against hepatic molecular apoptotic changes in response to an HFD.

Casein and soy protein were digested by papain to three degrees of hydrolysis (DH) 7.3%-13.3%, to obtain respective six casein and soy protein hydrolysates, aiming to clarify their in vitro proliferation and anti-apoptosis towards a human osteoblastic cell line (hFOB1.19 cells). Six casein and soy protein hydrolysates at five levels (0.01-0.2 mg/mL) mostly showed proliferation as positive 17β-estradiol did, because they conferred the osteoblasts with cell viability of 100%-114% and 104%-123%, respectively. The hydrolysates of higher DH values had stronger proliferation. Casein and soy protein hydrolysates of the highest DH values altered cell cycle progression, and enhanced cell proportion of S-phase from 50.5% to 56.5% and 60.5%. The two also antagonized etoposide- and NaF-induced osteoblast apoptosis. In apoptotic prevention, apoptotic cells were decreased from 31.6% to 22.6% and 15.6% (etoposide treatment), or from 19.5% to 17.7% and 12.4% (NaF treatment), respectively. In apoptotic reversal, soy protein hydrolysate decreased apoptotic cells from 13.3% to 11.7% (etoposide treatment), or from 14.5% to 11.0% (NaF treatment), but casein hydrolysate showed no reversal effect. It is concluded that the hydrolysates of two kinds had estradiol-like action on the osteoblasts, and soy protein hydrolysates had stronger proliferation and anti-apoptosis on the osteoblasts than casein hydrolysates. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is characterized by impaired tear dynamics, leading to complex pathophysiological conditions. (PEG)-BHD1028, a peptide agonist to AdipoRs, was evaluated as a potential therapeutic agent for DED based on the reported physiological function of adiponectin, including anti-inflammation and epithelial protection. Therapeutic effects of (PEG)-BHD1028 were evaluated in experimentally induced EDE with 0.001%, 0.01%, and 0.1% (PEG)-BHD1028 in mice and 0.1%, 0.2%, and 0.4% in rabbits for 10 days. In the rabbit study, 0.05% cyclosporine was also tested as a comparator. The results from the mouse study revealed significant improvement in tear volumes, tear breakup time (TBUT), inflammation, and corneal severity score (CSS) within 10 days at all (PEG)-BHD1028 concentrations. In the rabbit study, the tear volume and TBUT significantly increased in (PEG)-BHD1028 groups compared with vehicle and 0.05% cyclosporine groups. The CSS, apoptosis rate, and corneal thickness of all (PEG)-BHD1028 and 0.05% cyclosporine groups were significantly improved relative to the vehicle group. The immune cell counts of 0.2% and 0.4% (PEG)-BHD1028 treated groups were significantly lower than those of the vehicle group. These results represent the potential of (PEG)-BHD1028 as an effective therapeutic agent for DED.

Several studies have been shown that accelerated apoptosis is involved in post-exercise lymphocytopenia and tissue damage after high-intensity exercise. Ganoderma tsugae (GT) is one of the well-known medicinal mushrooms that possess various pharmacological functions. This mushroom has traditionally been used for health promotion purposes. This study investigates the hepatoprotective effects of GT on exhaustive exercise-induced liver damage. Twenty-four male Sprague-Dawley rats were randomly divided into four groups and designated as exhaustive exercise only (E), exhaustive exercise with low dosage (EL), medium dosage (EM) and high dosage (EH) GT at 0, 0.1875, 0.9375 and 1.875 g/kg/day, respectively. After 30 days all rats were euthanized immediately after an exhaustive running challenge on a motorized treadmill. The rat livers were immediately harvested. Evidence of apoptotic liver cell death was revealed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspases mediated cascade events. DNA fragmentation, an apoptosis process, can be examined using TUNEL assay. A few TUNEL-positive hepatocytes, compared to the exercise only group, were observed in the livers from exhaustive animals supplemented with GT. Immunoblot analysis also showed that caspase-6-mediated specific cleavage of lamin A/C was increased significantly in the livers of group E, but was significantly decreased in the EM and EH groups. Our observations demonstrate that GT possesses anti-apoptotic and hepatoprotective potential after exhaustive exercise. [ABSTRACT FROM AUTHOR]

Organisms and their cells are constantly exposed to environmental fluctuations. Among them are stressors, which can induce macromolecular damage that exceeds a set threshold, independent of the underlying cause. Stress responses are mechanisms used by organisms to adapt to and overcome stress stimuli. Different stressors or different intensities of stress trigger different cellular responses, namely induce cell repair mechanisms, induce cell responses that result in temporary adaptation to some stressors, induce autophagy or trigger cell death. Studies have reported life-prolonging effects of a wide variety of so-called stressors, such as oxidants, heat shock, some phytochemicals, ischemia, exercise and dietary energy restriction, hypergravity, etc. These stress responses, which result in enhanced defense and repair and even cross-resistance against multiple stressors, may have clinical use and will be discussed, while the emphasis will be on the effects/cross-effects of oxidants. [ABSTRACT FROM AUTHOR]

Ultraviolet radiation is a major environmental harmful factor on human skin. In this paper, we investigate the potential mechanism of Houttuynia cordata extract on UVB-induced HaCaT keratinocyte cell death and inflammation. We found that Houttuynia cordata ethyl acetate extract fraction (HC-EA) protected against UVB-induced cell damage. The HPLC results indicate that quercitrin and hyperoside are the major polyphenolics in HC-EA and are responsible for providing protection against UVB-induced cell death. These responses were associated with the regulation of caspase-9 and caspase-3 activation, which rescued HaCaT cells from UVB-induced apoptosis. In addition, HC-EA, quercitrin, and hyperoside attenuated UVB-induced inflammatory mediators, including IL-6, IL-8, COX-2, and iNOS. Furthermore, the treatment of cells with HC-EA and its active compounds abolished intracellular ROS and increased levels of heme oxygenase-1 and superoxide dismutase. UVB-induced ROS production mediated Akt and mitogen activated protein kinases (MAPKs) pathways, including p38, ERK, and JNK. Our results show HC-EA, quercitrin, and hyperoside decreased UVB-induced p38 and JNK phosphorylation, while increasing ERK and Akt phosphorylation. MAPKs and Akt mediated cell survival and death were confirmed by specific inhibitors to Akt and MAPKs. Thus, HC-EA, which contains quercitrin and hyperoside, protected keratinocyte from UVB-induced oxidative damage and inflammation through the modulation of MAPKs and Akt signaling. [ABSTRACT FROM AUTHOR]

Traumatic optic neuropathy (TON) may cause severe visual loss following direct or indirect head trauma which may result in optic nerve injuries and therefore contribute to the subsequent loss of retinal ganglion cells by inflammatory mediators and reactive oxygen species (ROS). Granulocyte colony-stimulating factor (G-CSF) provides the anti-inflammatory and anti-oxidative actions but has a short half-life and also induces leukocytosis upon typical systemic administration. The purpose of the present study was to investigate the relationship between the anti-oxidative response and neuroprotective effects of long-acting pegylated human G-CSF (PEG-G-CSF) in a rat model of optic nerve crush (ONC). Adult male Wistar rats (150–180 g) were chosen to have a sham operation in one eye and have ONC in the other. PEG-G-CSF or phosphate-buffered saline (PBS control) was immediately administered after ONC by intravitreal injection (IVI). We found the IVI of PEG-G-CSF does not induce systemic leukocytosis, but increases survival of RGCs and preserves the visual function after ONC. TUNEL assays showed fewer apoptotic cells in the retina in the PEG-G-CSF-treated eyes. The number of sorely ED1-positive cells was attenuated at the lesion site in the PEG-G-CSF-treated eyes. Immunoblotting showed up-regulation of p-Akt1, Nrf2, Sirt3, and HO-1 in the ON of the PEG-G-CSF-treated eyes. Our results demonstrated that one IVI of long-acting PEG-G-CSF is neuroprotective in the rONC. PEG-G-CSF activates the p-Akt1/Nrf2/Sirt3 and the p-Akt1/Nrf2/HO-1 axes to provide the antioxidative action and further attenuated RGC apoptosis and neuroinflammation. This provides crucial preclinical information for the development of alternative therapy with IVI of PEG-G-CSF in TON. [ABSTRACT FROM AUTHOR]

Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this combination therapy still needs to be elucidated. A hypoxic–ischemic encephalopathy (HIE) model of neonates, representing cerebral palsy, was prepared and randomly divided into five groups (hUCB+rhEPO combination, hUCB, and rhEPO treatments over HIE, HIE control, and sham). Seven days after, hUCB was administered intraperitoneally and the rhEPO injections were started. Neurobehavioral tests showed the best outcome in the combination therapy group, while the hUCB and rhEPO alone treatments also showed better outcomes compared with the control (p < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy (p < 0.05). The hUCB+rhEPO treatment also showed remarkable increase in phosphorylation of Akt and potentiation of anti-apoptotic responses with decreased Bax and increased Bcl-2 (p < 0.05). Pre-treatment of MK-2206, an Akt inhibitor, for the combination therapy depressed the anti-apoptotic effects. In conclusion, these findings suggest that the therapeutic effect of hUCB therapy might be potentiated by co-administration of rhEPO via augmentation of anti-inflammatory and anti-apoptotic responses related to the phosphorylation of Akt. [ABSTRACT FROM AUTHOR]

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing. [ABSTRACT FROM AUTHOR]

Peptic ulcer has a serious impact on people's health around the world, and traditional medicines can cause adverse reactions. This study investigated the protective effects of tilapia collagen oligopeptides (TCOPs) on gastroduodenal injury. Seventy-two specific pathogen-free (SPF) male Sprague Dawley (SD) rats were randomly divided into six groups according to body weight: normal control group, ethanol group, whey protein group (500 mg/kg BW), and three TCOPs dose groups (250, 500, 1000 mg/kg BW). After intragastric administration for 30 days, the acute gastroduodenal injury was induced by anhydrous ethanol (5 mL/kg, intragastrically) in all groups except the normal control group. Biomarkers in gastric and duodenal tissue and serum were measured. Furthermore, western blot was used to detect the expression of apoptosis-related proteins. The results showed that the administration with TCOPs significantly reduced gastric and duodenal ulcer index, increased gastric juice pH, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, along with the reduction of malondialdehyde (MDA) contents. TCOPs decreased tumor Necrosis Factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase (MPO) levels, while interleukin– 10 (IL-10) levels were increased. Furthermore, pepsinogens 1 (PG1), pepsinogens 2 (PG2), gastrin (GAS), and the pepsinogen ratio (PGR) were decreased, the prostaglandin E2 (PGE2) and NO contents were increased after TCOPs intervention. Moreover, TCOPs up-regulated the expression of Bcl-2 and inhibited the expression of Bax and Caspase-3. In conclusion, TCOPs have protective effects on ethanol-induced gastroduodenal injury through gastrointestinal mucosal microcirculation promotion, antioxidation, anti-inflammation, and anti-apoptosis mechanisms. [ABSTRACT FROM AUTHOR]

Mangosteen has long been utilized as a traditional medicine in Southeast Asia. Diverse extracts of mangosteen pericarp and its bioactive xanthones exhibit various bioactivities. However, the pharmacological potential of mangosteen pericarp water extract (MPW) has not been reported yet. This study used primary cultured rat cortical cells to investigate the effect of MPW on neurotoxicity. We found that MPW inhibited neurotoxicity and production of reactive oxygen species triggered by Aβ(25–35) or excitatory amino acids. MPW inhibited caspase 3 activation and DNA fragmentation in Aβ(25–35)- or N-methyl-D-aspartate-treated cells, suggesting an anti-apoptotic action. Additionally, MPW reduced lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, assuring its antioxidant property. Furthermore, MPW suppressed β-secretase and acetylcholinesterase activities. These findings prompted us to evaluate its effect on memory dysfunction in scopolamine-treated mice using Morris water maze test. Oral administration of MPW at the dosage of 50, 100, or 300 mg/kg for four days significantly decreased the latency time to find the platform and markedly increased the swimming time in the target quadrant. Taken together, our results suggest that MPW exerts memory-enhancing effect through antioxidative neuroprotection and anti-apoptotic action. Accordingly, MPW may have a potential to prevent or treat memory impairment associated with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) are chronic conditions that have drawn robust interest from the scientific community. Phytotherapeutic agents are becoming an important source of chemicals for the treatment and management of NDDs. Various secondary metabolites have been isolated from Melicope lunu-ankenda plant leaves, including phenolic acid derivatives. However, their neuroprotective activity remains unclear. Thus, the aim of this study is to elucidate the in vitro neuroprotective activity of 7-geranyloxycinnamic acid isolated from Melicope lunu-ankenda leaves. The neuroprotective activity was evaluated in differentiated human neuroblastoma (SH-SY5Y) cells by monitoring cell viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Moreover, the potential to impair apoptosis in differentiated cells was investigated employing the Annexin V-FITC assay, acridine orange and propidium iodide (AO/PI) staining, and fluorescence microscopy. Morphological assessment and ultrastructural analysis were performed using scanning and transmission electron microscopy to evaluate the effect of 7-geranyloxycinnamic acid on surface morphology and internal features of the differentiated cells. Pre-treatment of neuronal cells with 7-geranyloxycinnamic acid significantly protected the differentiated SH-SY5Y cells against H2O2-induced apoptosis. Cytoskeleton and cytoplasmic inclusion were similarly protected by the 7-geranyloxycinnamic acid treatment. The present findings demonstrate the neuroprotective potential of 7-geranyloxycinnamic acid against H2O2-induced neurotoxicity in neuronal cells, which is an established hallmark of neuronal disorders. [ABSTRACT FROM AUTHOR]

Curcumin is the main secondary metabolite of Curcuma longa and other Curcuma spp, and has been reported to have some potential in preventing and treating some physiological disorders. This study investigated the effect of curcumin in inhibiting high-fat diet and streptozotocin (STZ)-induced hyperglycemia and hyperlipidemia in rats. Twenty-six male Sprague-Dawley (SD) rats (170–190 g) were randomly divided into a standard food pellet diet group (Control group), a high-fat diet and streptozotocin group (HF + STZ group), and a high-fat diet combined with curcumin and STZ group (HF + Cur + STZ group). Compared with the HF + STZ group, the HF + Cur + STZ group exhibited significantly reduced fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (AST), and aspartate transaminase (ALT) levels, as well as liver coefficients. In the livers of these rats, the expression of malondialdehyde (MDA) and Bax was downregulated, whereas that of superoxide dismutase (SOD) and Bcl-2 was upregulated. Moreover, the liver histology of these rats was improved and resembled that of the control rats. These results suggest that curcumin prevents high-fat diet and STZ-induced hyperglycemia and hyperlipidemia, mainly via anti-oxidant and anti-apoptotic mechanisms in the liver. [ABSTRACT FROM AUTHOR]

Background: Most patients with thyroid cancer suffer from salivary gland (SG) dysfunctions after radioiodine (RI) therapy. We investigated the effects of keratinocyte growth factor (KGF)-1 on RI-induced SG dysfunction in an animal model., Methods: Six C57BL/6 mice were assigned to each of the following groups: treatment naïve control group, RI group, and RI+KGF-1 group. Body and SG weights, salivary flow rates, salivary lag times and changes in 99mTc pertechnetate uptake and excretion were measured, and histologic changes were noted. Amylase activities and epidermal growth factor (EGF) concentrations in saliva were also measured. In addition, TUNEL assays were performed and apoptosis-related protein expressions were assessed., Results: RI-induced reductions in salivary flow rates and increases in salivary lag times observed in the RI group were not observed in RI+KGF-1 group. Mice in RI group had higher HIF1a levels than controls, but HIF1a levels in RI+KGF-1 group were similar to those in control group. Furthermore, mice in RI+KGF-1 group had more mucin stained acini and decreased periductal fibrosis than mice in RI group, and tissue remodeling of many salivary epithelial cells (AQP5) and endothelial cells (CD31) were observed in RI+KGF-1 group. Amylase activity and expression in saliva were greater in RI+KGF-1 group than in RI group, and fewer apoptotic cells were observed in RI+KGF-1 group. Furthermore, BCLxl (anti-apoptotic) expression was higher, and Bax (pro-apoptotic) expression was lower in RI+KGF-1 group than in RI group., Conclusions: Local delivery of KGF-1 might prevent RI-induced SG damage by reducing apoptosis.

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer's disease and Parkinson's disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic. [ABSTRACT FROM AUTHOR]

Oxidative stress, which is induced by reactive oxygen species (ROS), causes cellular damage which contributes to the pathogenesis of neurodegenerative diseases. Momordica charantia (MC), a traditional medicinal plant, is known to have a variety of health benefits, such as antidiabetic, anti-inflammatory, and antioxidant effects. However, it is unknown whether MC has protective effects against oxidative stress-induced neuronal cell death. The aim of this study was to investigate the potential action of MC on oxidative stress induced by H2O2. First, we tested whether the pretreatment of Momordica charantia ethanol extract (MCEE) attenuates H2O2-induced cell death in human neuroblastoma SK-N-MC cells. MCEE pretreatment significantly improved cell viability and apoptosis that deteriorated by H2O2. Further, MCEE ameliorated the imbalance between intracellular ROS production and removal through the enhancement of the intracellular antioxidant system. Intriguingly, the inhibition of apoptosis was followed by the blockage of mitochondria-dependent cell death cascades and suppression of the phosphorylation of the mitogen-activated protein kinase signaling (MAPKs) pathway by MCEE. Taken together, MCEE was shown to be effective in protecting against H2O2-induced cell death through its antioxidant and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway. [ABSTRACT FROM AUTHOR]

Heterophyllin B (HB), an active cyclic peptide, is a compound existing in the ethyl acetate extract of Pseudostellaria heterophylla (Miq.) Pax and exhibited the activity of inhibiting the production of NO and cytokines, such as IL-1β and IL-6, in LPS-stimulated RAW 264.7 macrophages. In addition, HB suppressed the production of ROS and the apoptosis induced by LPS in RAW 264.7 macrophages. The underlying mechanism was investigated in the LPS-induced RAW 264.7 cells. The results showed that HB decreased the level of IL-1β and IL-6 expression by qRT-PCR analysis. HB up-regulated the relative ratio of p-AKT/AKT and p-PI3K/PI3K as indicated by western blot analysis. In summary, HB inhibited the LPS-induced inflammation and apoptosis through the PI3K/Akt signaling pathways and represented a potential therapeutic target for treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Although cisplatin is an anticancer drug that has activity against malignant tumor, it often causes nephrotoxicity. Previous reports have confirmed that the saponins from the leaves of P. quinquefolium (PQS) exerted many pharmacological activities. However, the renoprotective effects of PQS were still unknown. The purpose of the present research was to discuss renoprotective effect of PQS in a mouse model of cisplatin-induced acute kidney injury (AKI). The levels of blood urea nitrogen (BUN) and serum creatinine (CRE) were evidently increased in cisplatin-intoxicated mice, which were reversed by PQS. Renal oxidative stress, evidenced by increased malondialdehyde (MDA) level and decline of glutathione (GSH) and superoxide dismutase (SOD) activities, was significantly alleviated by PQS pretreatment. The suppression of inflammatory response by PQS was realized through the decrease the mRNA expression levels of tumor necrosis factor-α ( TNF-α ) and interleukin-1β ( IL-1β ) in kidney tissues, which were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Simultaneously, the overexpression of cytochrome P450 E1 (CYP2E1) and heme oxygenase-1 (HO-1) were attenuated by PQS. Furthermore, the effects of Western blotting demonstrated that PQS administration significantly suppressed the protein expression levels of nicotinamide adenine dinucleotide phosphate oxidase type 4 (Nox4), cleaved Caspase-3, cleaved Caspase-9, Bax, nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), suggesting the inhibition of apoptosis and inflammation response. Overall, PQS may possess protective effects in cisplatin-induced AKI through suppression of oxidative stress, inflammation and apoptosis., Competing Interests: The authors declare no conflict of interest.