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Graphical abstract, Highlights • Skin cancer is a fatal public health concern rising continuously all over the world. • Several environmental and genetic risk factors are associated with cutaneous carcinogenesis. • Use of nanocarriers for targeted delivery of anticancer agents is the most advanced approach. • Polymeric structures are suitable for tumor selective delivery of drugs, genes and imaging agents. • Polymeric micro/nanostructures have successfully used for combination anticancer therapies., Background Skin cancer has been the leading type of cancer worldwide. Melanoma and non-melanoma skin cancers are now the most common types of skin cancer that have been reached to epidemic proportion. Based on the rapid prevalence of skin cancers, and lack of efficient drug delivery systems, it is essential to surge the possible ways to prevent or cure the disease. Aim of review Although surgical modalities and therapies have been made great progress in recent years, however, there is still an urgent need to alleviate its increased burden. Hence, understanding the precise pathophysiological signaling mechanisms and all other factors of such skin insults will be beneficial for the development of more efficient therapies. Key scientific concepts of review In this review, we explained new understandings about onset and development of skin cancer and described its management via polymeric micro/nano carriers-based therapies, highlighting the current key bottlenecks and future prospective in this field. In therapeutic drug/gene delivery approaches, polymeric carriers-based system is the most promising strategy. This review discusses that how polymers have successfully been exploited for development of micro/nanosized systems for efficient delivery of anticancer genes and drugs overcoming all the barriers and limitations associated with available conventional therapies. In addition to drug/gene delivery, intelligent polymeric nanocarriers platforms have also been established for combination anticancer therapies including photodynamic and photothermal, and for theranostic applications. This portfolio of latest approaches could promote the blooming growth of research and their clinical availability.

Amyloid-β (Aβ) accumulating is considered as a causative factor for formation of senile plaque in Alzheimer’s disease (AD), but its mechanism is still elusive. The Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), a key redox cofactor for energy metabolism, is reduced in AD. Accumulative evidence has shown that the decrease of α-secretase activity, a disintegrin and metalloprotease domain 10 (ADAM10), is responsible for the increase of Aβ productions in AD patient’s brain. Here, we observe that the activity of α-secretase ADAM10 and levels of Nmnat2 are significantly decreased, meanwhile there is a simultaneous elevation of Aβ in Tg2576 mice. Over-expression of Nmnat2 increases the mRNA expression of α-secretase ADAM10 and its activity and inhibits Aβ production in N2a/APPswe cells, which can be abolished by Compound C, an AMPK antagonist, suggesting that AMPK is involved in over-expression of Nmnat2 against Aβ production. The further assays demonstrate that Nmnat2 activates AMPK by up-regulating the ratio of NAD+/NADH, moreover AMPK agonist AICAR can also increase ADAM10 activity and reduces Aβ1-40/1-42. Taken together, Nmnat2 suppresses Aβ production and up-regulates ADAM10 in AMPK activity-dependent manner, suggesting that Nmnat2 may serve as a new potential target in arresting AD.

Obesity is considered as a risk factor for chronic health diseases such as heart diseases, cancer, and diabetes 2. Reduced physical activities, lifestyle, poor nutritional diet, and genetics are among the risk factors associated with the development of obesity. In recent years, several studies have explored the link between the gut microbiome and the progression of diseases including obesity, with the shift in microbiome abundance and composition being the main focus. The alteration of gut microbiome composition affects both nutrients metabolism and specific gene expressions thereby disturbing body physiology. Specifically, the abundance of fiber-metabolizing microbes is associated with weight loss and that of protein and fat-metabolizing bacteria with weight gain. Various internal and external factors such as genetics, maternal obesity, mode of delivery, breastfeeding, nutrition, antibiotic use, and the chemical compounds present in the environment are known to interfere with the richness of the gut microbiota (GM), thereby influencing weight gain/loss and ultimately the development of obesity. However, the effectiveness of each factor in potentiating the shift in microbes' abundance to result in significant changes that can lead to obesity is not yet clear. In this review, we will highlight the factors involved in shaping gut microbiota, their influence on obesity and possible interventions. Understanding the influence of these factors on the diversity of the GM and how to improve their effectiveness on disease conditions could be key in the treatment of metabolic diseases.

In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

Ever reports showed that PCNP is associated with human cancers including neuroblastoma and lung cancer. However, the role and underlying molecular mechanism of PCNP in ovarian cancer have not been plenty elucidated. Herein, we first investigated the expression of PCNP in ovarian cancer tissues and cells, the effects of PCNP in ovarian cancer proliferation, apoptosis, migration and invasion, and determined the molecular mechanism of PCNP in ovarian cancer progression. The results indicated that PCNP was significantly overexpressed in human ovarian cancer tissues and cells, and related to poor prognosis in ovarian cancer patients. In addition, we also detected that PCNP promoted ovarian cancer cells growth, migration and invasion, as well as inhibited ovarian cancer cells apoptosis. Mechanistically, PCNP binding to β‐catenin promoted β‐catenin nuclear translocation and further activated Wnt/β‐catenin signalling pathway. Moreover, PCNP regulated the expression of genes involved in EMT and further triggered EMT occurrence. Conclusionally, PCNP may promote ovarian cancer progression through activating Wnt/β‐catenin signalling pathway and EMT, acting as a novel and promising target for treating ovarian cancer.

Background Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingolipids and produced by sphingosine kinases (SphK1 and SphK2). SphK1/S1P pathway is implicated in the progression of chronic kidney disease. However, the role of SphK1/S1P pathway in renal injury in hypertension has not been reported. This study tested the hypothesis that SphK1/S1P pathway mediates the kidney damage in DOCA-salt hypertensive mice. Methods Male wild type (WT) C57BL6 and SphK1 knockout (KO) mice were subjected to unilateral nephrectomy, subcutaneous implant containing 50 mg of deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water for 7 weeks. At the end of experiments, blood pressure data, 24 h urine and kidney samples were collected. Renal mRNA levels of SphK1 were measured by real-time RT-PCR. Markers for fibrogenesis and immune cell infiltration in kidneys were detected using Western blot and immunohistochemistray analysis, respectively. The glomerular morphological changes were examined in kidney tissue slides stained with Periodic-Acid Schiff. Four groups were studied: wild type control (WT-C), WT-DOCA, KO-C and KO-DOCA. Results The renal SphK1 mRNA expression was significantly upregulated in WT-DOCA mice, whereas this upregulation of renal SphK1 mRNA was blocked in KO-DOCA mice. There was no difference in DOCA-salt-induced hypertension between WT and KO mice. The urinary albumin was increased in both DOCA-salt groups. However, the albuminuria was significantly lower in KO-DOCA than in WT-DOCA group. There were increases in glomerulosclerosis indices in both DOCA-salt groups, whereas the increases were also significantly lower in KO-DOCA than in WT-DOCA mice. Renal protein levels of α-smooth muscle actin were upregulated in both DOCA-salt groups, but the increase was significant lower in KO-DOCA than in WT-DOCA group. The increased staining areas of collagen detected by Sirius Red-staining in kidney tissue sections were also attenuated in KO-DOCA compared with WT-DOCA mice. In contrast, the increased infiltration of CD43+ (a T cell marker) or CD68+ (a macrophage marker) cells in DOCA-salt kidneys showed no significant difference between WT-DOCA and KO-DOCA mice. Conclusions SphK1/S1P signaling pathway mediates kidney damage in DOCA-salt hypertensive mice independent of blood pressure and immune modulation.

Since the end of 2019, a new type of coronavirus pneumonia (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout the world. Previously, there were two outbreaks of severe coronavirus caused by different coronaviruses worldwide, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This article introduced the origin, virological characteristics and epidemiological overview of SARS-CoV-2, reviewed the currently known drugs that may prevent and treat coronavirus, explained the characteristics of the new coronavirus and provided novel information for the prevention and treatment of COVID-19.

Plasmacytoma variability translocation 1 (PVT1), an oncogene, has been reported to be highly expressed in many tumors, including human glioma, gastric cancer, and non-small cell lung cancer. Functionally, it could also regulate the development of tumor cells. However, its specific roles and pathogenesis in human gliomas are still not clear. This study investigated the function and mechanism of PVT1 knockdown in the proliferation and malignant transformation of human gliomas. We first examined the expression levels of PVT1 and miR-424 in human glioma tissues and cell lines. We also used gene manipulation techniques to explore the effects of PVT1 knockdown on cell viability, migration, invasion, and miR-424. We found that PVT1 knockdown effectively inhibited cell viability, migration, and invasion of human glioma cells and increased miR-424 expression. Based on the negative correlation between PVT1 and miR-424, we then confirmed the direct interaction between PVT1 and miR-424 using RNA immunoprecipitation (RIP) and luciferase reporter assays. Further, we established a xenograft nude mouse model to determine the role and mechanism of PVT1 on tumor growth in vivo. In addition, PVT1 knockdown was shown to promote miR-424 in vivo. In summary, the present study demonstrated that PVT1 knockdown could negatively regulate miR-424 to inhibit human glioma cell activity, migration, and invasiveness. PVT1 knockdown could negatively regulate miR-424 to inhibit cellular activity, migration, and invasiveness in human gliomas, which explained the oncogenic mechanism of PVT1 in human gliomas. It also suggested that PVT1 might be a novel therapeutic target for human gliomas.

Hydrogen sulfide (H2S), as one of the three known gaseous signal transduction molecules in organisms, has attracted a surging amount of attention. H2S is involved in a variety of physiological and pathological processes in the body, such as dilating blood vessels (regulating blood pressure), protecting tissue from ischemia-reperfusion injury, anti-inflammation, carcinogenesis, or inhibition of cancer, as well as acting on the hypothalamus and pancreas to regulate hormonal metabolism. The change of H2S concentration is related to a variety of endocrine disorders, and the change of hormone concentration also affects the synthesis of H2S. Understanding the effect of biosynthesis and the concentration of H2S on the endocrine system is useful to develop drugs for the treatment of hypertension, diabetes, and other diseases.

Respiratory diseases are leading causes of death and disability around the globe, with a diverse range of health problems. Treatment of respiratory diseases and infections has been verified to be thought-provoking because of the increasing incidence and mortality rate. Hydrogen sulfide (H2S) is one of the recognized gaseous transmitters involved in an extensive range of cellular functions, and physiological and pathological processes in a variety of diseases, including respiratory diseases. Recently, the therapeutic potential of H2S for respiratory diseases has been widely investigated. H2S plays a vital therapeutic role in obstructive respiratory disease, pulmonary fibrosis, emphysema, pancreatic inflammatory/respiratory lung injury, pulmonary inflammation, bronchial asthma and bronchiectasis. Although the therapeutic role of H2S has been extensively studied in various respiratory diseases, a concrete literature review will have an extraordinary impact on future therapeutics. This review provides a comprehensive overview of the effective role of H2S in respiratory diseases. Besides, we also summarized H2S production in the lung and its metabolism processes in respiratory diseases.

Nazeer Hussain Khan,1,2 Shao-Feng Duan,3 Dong-Dong Wu,1,4 Xin-Ying Ji1,4,5 1Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 2School of Life Sciences, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 3Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, Henan, 475004, People’s Republic of China; 4School of Basic Medical Sciences, Henan University College of Medicine, Kaifeng, Henan, 475004, People’s Republic of China; 5Kaifeng Key Laboratory of Infection and Biological Safety, Henan University College of Medicine, Kaifeng, Henan, 475004, People’s Republic of ChinaCorrespondence: Dong-Dong Wu; Xin-Ying Ji Email ddwubiomed2010@163.com; 10190096@vip.henu.edu.cnAbstract: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in women globally. In 2018, 2.1 million new cases were reported, with 627,000 deaths. Pakistan has the highest incidence rate of breast cancer among Asian countries: one in every nine women has a lifetime risk of being diagnosed with breast cancer. By reason of many misconceptions about the etiology of the disease and socioeconomic factors, Pakistani women have very low rates of early detection and diagnose breast cancer at advance stages with fewer chances of survival. The key to cure the breast cancer is early diagnosis. The aim of current review is to highlight the factors leading to the delays in early presentation of breast cancer in Pakistani women and to summarize possible recommendations for educating women about early diagnosis along with palliative care facilities for patients suffering from breast cancer. Furthermore, this study appeals to both the general public and government in the belief that better reporting and awareness campaigns may bring more women to clinics for early diagnosis.Keywords: breast cancer, health budget, Pakistani women, better reporting; awareness campaigns

Hydrogen sulfide (H2S) has long been considered as a toxic gas, but as research progressed, the idea has been updated and it has now been shown to have potent protective effects at reasonable concentrations. H2S is an endogenous gas signaling molecule in mammals and is produced by specific enzymes in different cell types. An increasing number of studies indicate that H2S plays an important role in cardiovascular homeostasis, and in most cases, H2S has been reported to be downregulated in cardiovascular diseases (CVDs). Similarly, in preclinical studies, H2S has been shown to prevent CVDs and improve heart function after heart failure. Recently, many H2S donors have been synthesized and tested in cellular and animal models. Moreover, numerous molecular mechanisms have been proposed to demonstrate the effects of these donors. In this review, we will provide an update on the role of H2S in cardiovascular activities and its involvement in pathological states, with a special focus on the roles of exogenous H2S in cardiac protection.

Various research works have piled up conflicting evidence questioning the effect of oxidative stress in cancer. Reactive oxygen and nitrogen species (RONS) are the reactive radicals and nonradical derivatives of oxygen and nitrogen. RONS can act as a double-edged weapon. On the one hand, RONS can promote cancer initiation through activating certain signal transduction pathways that direct proliferation, survival, and stress resistance. On the other hand, they can mitigate cancer progression via their resultant oxidative stress that causes many cancer cells to die, as some recent studies have proposed that high RONS levels can limit the survival of cancer cells during certain phases of cancer development. Similarly, eukaryotic translation initiation factors are key players in the process of cellular transformation and tumorigenesis. Dysregulation of such translation initiation factors in the form of overexpression, downregulation, or phosphorylation is associated with cancer cell’s altering capability of survival, metastasis, and angiogenesis. Nonetheless, eIFs can affect tumor age-related features. Data shows that alternating the eukaryotic translation initiation apparatus can impact many downstream cellular signaling pathways that directly affect cancer development. Hence, researchers have been conducting various experiments towards a new trajectory to find novel therapeutic molecular targets to improve the efficacy of anticancer drugs as well as reduce their side effects, with a special focus on oxidative stress and initiation of translation to harness their effect in cancer development. An increasing body of scientific evidence recently links oxidative stress and translation initiation factors to cancer-related signaling pathways. Therefore, in this review, we present and summarize the recent findings in this field linking certain signaling pathways related to tumorigeneses such as MAPK and PI3K, with either RONS or eIFs.

Hydrogen sulfide (H2S) plays a key role in the regulation of physiological processes in mammals. The decline in H2S level has been reported in numerous renal disorders. In animal models of renal disorders, treatment with H2S donors could restore H2S levels and improve renal functions. H2S donors suppress renal dysfunction by regulating autophagy, apoptosis, oxidative stress, and inflammation through multiple signaling pathways, such as TRL4/NLRP3, AMP-activated protein kinase/mammalian target of rapamycin, transforming growth factor-β1/Smad3, extracellular signal-regulated protein kinases 1/2, mitogen-activated protein kinase, and nuclear factor kappa B. In this review, we summarize recent developments in the effects of H2S donors on the treatment of common renal diseases, including acute/chronic kidney disease, renal fibrosis, unilateral ureteral obstruction, glomerulosclerosis, diabetic nephropathy, hyperhomocysteinemia, drug-induced nephrotoxicity, metal-induced nephrotoxicity, and urolithiasis. Novel H2S donors can be designed and applied in the treatment of common renal diseases.

Melanoma is the deadliest skin tumor and is prone to distant metastases. The incidence of melanoma has increased rapidly in the past few decades, and current trends indicate that this growth is continuing. This study was aimed to explore the molecular mechanisms of melanoma pathogenesis and discover underlying pathways and genes associated with melanoma. We used high-throughput expression data to study differential expression profiles of related genes in melanoma. The differentially expressed genes (DEGs) of melanoma in GSE15605, GSE46517, GSE7553, and the Cancer Genome Atlas (TCGA) datasets were analyzed. Differentially expressed genes (DEGs) were identified by paired t-test. Then the DEGs were performed cluster and principal component analyses and protein-protein interaction (PPI) network construction. After that, we analyzed the differential genes through bioinformatics and got hub genes. Finally, the expression of hub genes was confirmed in the TCGA databases and collected patient tissue samples. Total 144 up-regulated DEGs and 16 down-regulated DEGs were identified. A total of 17 gene ontology analysis (GO) terms and 11 pathways were closely related to melanoma. Pathway of pathways in cancer was enriched in 8 DEGs, such as junction plakoglobin (JUP) and epidermal growth factor receptor (EGFR). In the PPI networks, 9 hub genes were obtained, such as loricrin (LOR), filaggrin (FLG), keratin 5 (KRT5), corneodesmosin (CDSN), desmoglein 1 (DSG1), desmoglein 3 (DSG3), keratin 1 (KRT1), involucrin (IVL), and EGFR. The pathway of pathways in cancer and its enriched DEGs may play important roles in the process of melanoma. The hub genes of DEGs may become promising melanoma candidate genes. Five key genes FLG, DSG1, DSG3, IVL, and EGFR were identified in the TCGA database and melanoma tissues. The results suggested that FLG, DSG1, DSG3, IVL, and EGFR might play important roles and potentially be valuable in the prognosis and treatment of melanoma. These hub genes might well have clinical significance as diagnostic markers.

Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H2S in the liver are summarized and the role and mechanism of H2S in liver health and disease are further discussed.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Peptide V3 has shown anti-angiogenic and anti-tumor effects on S180 and H22 xenografts in nude mice. However, the detailed mechanism of action of peptide V3 has not yet been fully elucidated. In the present study, the effects of peptide V3 on the growth of human HCC cells were examined both in vitro and in vivo. Our results showed that peptide V3 inhibited the proliferation, viability, migration, and invasion of human HCC cells. However, no obvious effect was observed in HL-7702 cells. Peptide V3 increased the apoptosis and decreased the protein levels of H-RAS, phospho (p)-RAF, p-MEK, and p-extracellular signal-regulated protein kinase (ERK) in human HCC cells. Peptide V3 suppressed the growth of human HCC xenografts by down-regulating angiogenesis and up-regulating apoptosis. In conclusion, peptide V3 could inhibit the growth of human HCC by inhibiting the Ras/Raf/MEK/ERK signaling pathway. Novel peptides and modification strategies could be designed and applied for the treatment of different types of cancer.

Background: Melanoma is the most deadly tumor in skin tumors and is prone to distant metastases. The incidence of melanoma has increased rapidly in the past few decades, and current trends indicate that this growth is continuing. This study was aimed to explore the molecular mechanisms of melanoma pathogenesis and discover underlying pathways and genes associated with melanoma.Methods: We used high-throughput expression data to study differential expression profiles of related genes in melanoma. The differentially expressed genes (DEGs) of melanoma in GSE15605, GSE46517, GSE7553 and the Cancer Genome Atlas (TCGA) datasets were analyzed. Differentially expressed genes (DEGs) were identified by paired t-test. Then the DEGs were performed cluster and principal component analyses and protein–protein interaction (PPI) network construction. After that, we analyzed the differential genes through bioinformatics and got hub genes. Finally, the expression of hub genes was confirmed in the TCGA databases and collected patient tissue samples.Results: Total 144 up-regulated DEGs and 16 down-regulated DEGs were identified. A total of 17 gene ontology analysis (GO) terms and 11 pathways were closely related to melanoma. Pathway of pathways in cancer was enriched in 8 DEGs, such as junction plakoglobin (JUP) and epidermal growth factor receptor (EGFR). In the PPI networks, 9 hub genes were obtained, such as loricrin (LOR), filaggrin (FLG), keratin 5 (KRT5), corneodesmosin (CDSN), desmoglein 1 (DSG1), desmoglein 3 (DSG3), keratin 1 (KRT1), involucrin (IVL) and EGFR. The pathway of pathways in cancer and its enriched DEGs may play important roles in the process of melanoma. The hub genes of DEGs may become promising melanoma candidate genes. Five key genes FLG, DSG1, DSG3, IVL and EGFR were identified in the TCGA database and melanoma tissues.Conclusions: The results suggested that FLG, DSG1, DSG3, IVL and EGFR might play important roles and potentially be valuable in the prognosis and treatment of melanoma.

This study aims to discuss the effect of triptolide (TPL) on rheumatoid arthritis (RA) and the mechanism related to osteoclast precursor (OCP) and osteoclast (OC). TNF-transgenic RA mice were treated with different doses of TPL by gavage. After the administration was finished, the curative effects were evaluated and compared, and the OCP apoptosis rates, the OC number, and the OC differentiation ability in vitro were detected. Finally, splenocytes of wild-type mice were cultured in vitro and induced to differentiate into OCP, and the cell apoptosis rate, cIAP2, and apoptotic effectors expression level were detected after cIAP2 overexpression and TPL administration. After TPL administration, the RA symptoms in the TPL groups were all better, the apoptosis rate of OCP was higher, and the amount of OC in vitro were lower than that in the control group (all P < 0.05), and all of the changes in the high-dose group were more obvious than the low-dose group. In splenocytes cells cultured in vitro, cIAP2 overexpression could decrease the apoptosis rate of OCPs and increase the OC number, and TPL treatment could down-regulate the cIAP2 and promote OCP apoptosis and OC reduction. In conclusion, TPL could induce OCP apoptosis and inhibit OC formation to effectively treat RA by mediating cIAP2 degradation.

Aim. This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson’s disease (PD) and providing theoretical guidance for the prevention and treatment of PD. Methods. Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method. Results. (1) Risk factors of PD include dairy products, pesticides, traumatic brain injury, and obesity. Protective factors include alcohol, tobacco, coffee, black tea, and physical activity. (2) Physical activity can reduce the risk and improve symptoms of PD and the beneficial forms of physical activity, including running, dancing, traditional Chinese martial arts, yoga, and weight training. (3) Different forms of physical activity alleviate the symptoms of PD through different mechanisms, including reducing the accumulation of α-syn protein, inflammation, and oxidative stress, while enhancing BDNF activity, nerve regeneration, and mitochondrial function. Conclusion. Physical activity has a positive impact on the prevention and treatment of PD. Illustrating the molecular mechanism of physical activity-induced protective effect on PD is an urgent need for improving the efficacy of PD therapy regimens in the future.

Objective The objective was to explore the association of methylene tetrahydrofolate reductase ( MTHFR) C667T and A1298C and reduced folate carrier 1 ( RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China. Methods Two hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment. Results We detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity. Conclusions In Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.

Sepsis is the leading cause of death for critically ill patients in recent years. Dendritic cells (DCs) are important antigen-presenting cells and play a key role in immune response by regulating the innate and adaptive immunity. The number of DCs, the differentiation of monocytes into DCs, and the levels of surface molecules associated with the function of DCs are changed in the development of sepsis. There are many mechanisms involved in the alterations of DCs during sepsis, including the induction of apoptosis, reactive oxygen species generation, activation of the Wnt signaling pathway, epigenetic regulation, and variation in Toll-like receptor-dependent signaling. In this review, we present the classifications of DC subsets and mechanisms involved in the alterations of DCs in sepsis, as well as further discuss the therapeutic strategies targeting DCs in sepsis to improve the aberrant immune response and prolong the life during sepsis progression.

// Wei-dong Qin 1 , Guo-liang Liu 2 , Juan Wang 3 , Hao Wang 1 , Jian-ning Zhang 1 , Fan Zhang 1 , Yang Ma 1 , Xin-ying Ji 2 , Chen Li 1 and Ming-xiang Zhang 4 1 Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China 2 The Henan Provincial Key Engineering Laboratory of Antibody Drugs, School of Medicine, Henan University, Kaifeng, Henan, China 3 Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong, China 4 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China Correspondence to: Wei-dong Qin, email: // Ming-xiang Zhang, email: // Keywords : diabetic cardiomyopathy, poly(ADP-ribose) polymerase 1, hyperglycemia, inflammatory response, apoptosis, Pathology Section Received : September 26, 2015 Accepted : March 14, 2016 Published : March 24, 2016 Abstract Diabetic cardiomyopathy (DCM) is characterized by structural alterations such as cardiomyocyte hypertrophy, necrosis and focal fibrosis. Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme which can be activated by DNA damage and plays a critical role in various diseases. We hypothesized that PARP-1 may play an important role in DCM and that its inhibition may protect cardiomyocytes from inflammation and apoptosis in DCM. H9c2 cardiomyocytes were treated with normal glucose, mannitol or high glucose (HG). Male C57BL/6 mice or PARP-1-/- mice were treated with streptozotocin (STZ) by intraperitoneal injection for 5 consecutive days to induce diabetes. In vitro, HG stimulation induced oxidative stress and DNA damage and increased PARP-1 expression and activity. Compared with the control, pretreatment with PARP-1 siRNA significantly reduced HG-induced inflammatory response, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 secretion, and intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) expression. PARP-1 inhibition reduced HG-induced cardiomyocyte apoptosis through downregulation of cleaved caspases and activation of IGF-1R/Akt pathway. In vivo, hyperglycemia increased the protein expression of nitrotyrosine and PARP-1 as well as PARP-1 activity. PARP-1 gene deletion significantly improved cardiac dysfunction and reduced inflammatory response and apoptosis. This work demonstrated the critical role of PARP-1 in diabetic heart injury, and suggested that PARP-1 inhibition may be a feasible strategy for the treatment of DCM.

PCNP is associated with human cancers including neuroblastoma and lung cancer. However, the role and underlying molecular mechanism of PCNP have not been plenty elucidated. Herein, we first investigated the effects of PCNP in ovarian cancer proliferation, apoptosis, migration and invasion and determined the molecular mechanism of PCNP in ovarian cancer progression. The results indicated that PCNP was significantly overexpressed in human ovarian cancer tissues and cells, and related to poor prognosis in ovarian cancer patients. In addition, we also detected that PCNP promoted ovarian cancer cells growth, migration and invasion, as well as inhibited ovarian cancer cells apoptosis. Mechanistically, PCNP bound to β-catenin, promoted β-catenin nuclear translocation and further activated Wnt/β-catenin signaling pathway. Moreover, PCNP regulated the expression of genes involved in EMT and further triggered EMT occurrence. Together, these results summarized that PCNP/β-catenin axis may promote ovarian cancer progression, supplying a novel and promising targets to improve prognosis and treat ovarian cancer. Funding Statement: The research was supported by two National Natural Science Foundation of China (81670088, 81602708) and Henan Provincial Science and Technology Department International Cooperation Project (172102410019). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: This study was reviewed and approved by the Ethical Board at Henan University. All animal procedures were manipulated with the approval of the Medical and Research Ethics Committee of Henan University Medical School.

Tumour necrosis factor‐α‐induced protein 8‐like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of rectal adenocarcinoma is unknown. Our results showed that the expression levels of TIPE2 in human rectal adenocarcinoma tissues were higher than those in adjacent non‐tumour tissues. Overexpression of TIPE2 reduced the proliferation, migration, and invasion of human rectal adenocarcinoma cells and down‐regulation of TIPE2 showed reverse effects. TIPE2 overexpression increased apoptosis through down‐regulating the expression levels of Wnt3a, phospho (p)‐β‐Catenin, and p‐glycogen synthase kinase‐3β in rectal adenocarcinoma cells, however, TIPE2 knockdown exhibited reverse trends. TIPE2 overexpression decreased autophagy by reducing the expression levels of p‐Smad2, p‐Smad3, and transforming growth factor‐beta (TGF‐β) in rectal adenocarcinoma cells, however, TIPE2 knockdown showed opposite effects. Furthermore, TIPE2 overexpression reduced the growth of xenografted human rectal adenocarcinoma, whereas TIPE2 knockdown promoted the growth of rectal adenocarcinoma tumours by modulating angiogenesis. In conclusion, TIPE2 could regulate the proliferation, migration, and invasion of human rectal adenocarcinoma cells through Wnt/β‐Catenin and TGF‐β/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.

MicroRNAs (miRNAs) are small, noncoding RNAs that have tissue- and cell-specific expression. They have the ability to regulate the malignant proliferation and transformation of tumour cells. The research focussed on the expression and role of miR-1297 in melanoma. We firstly found that miR-1297 is up-regulated in melanoma tissues and cell lines. Functionally, phosphatase and tension homology deleted on chromsome ten gene (PTEN) was used as a potential target for miR-1297 and detected using Western blotting and immunohistochemistry (IHC). We then used chemical synthesis of anti-miR1297 to explore the influence on melanoma cells and examined the effects on A375 cell proliferation using MTT and western blotting methods. The results showed that anti-miR-1297 transfected A375 cells could inhibit the growth. Furthermore, transfection with anti-miR-1297 reduced PTEN protein expression and partially restrained A375 cells proliferation, migration and reversed Epithelial-Mesenchymal Transition (EMT) progression. In conclusion, we tentatively put forward that miR-1297 might be the key oncomiR in melanoma, and seed-targeted anti-miR-1297 might serve as a new tactic for miR-1297-based therapies.

Background PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in cell proliferation and tumorigenesis. However, the precise mechanism of action of PCNP in the process of tumor growth has not yet been fully elucidated. Methods ShRNA knockdown and overexpression of PCNP were performed in human neuroblastoma cells. Tumorigenic and metastatic effects of PCNP were examined by tumor growth, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. Results PCNP over-expression decreased the proliferation, migration, and invasion of human neuroblastoma cells and down-regulation of PCNP showed reverse effects. PCNP over-expression increased protein expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase, as well as ratios of B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and Bcl-2-associated death promoter/B-cell lymphoma-extra large in human neuroblastoma cells, however PCNP knockdown exhibited reverse trends. PCNP over-expression increased phosphorylations of extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, as well as decreased phosphorylations of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), nevertheless PCNP knockdown exhibited opposite effects. Furthermore, PCNP over-expression significantly reduced the growth of human neuroblastoma xenograft tumors by down-regulating angiogenesis, whereas PCNP knockdown markedly promoted the growth of human neuroblastoma xenograft tumors through up-regulation of angiogenesis. Conclusions PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma.

The aim of this study was to discuss the new methods of clinical classification and staging of patients with myasthenia gravis (MG) proposed by our group and to summarize the experiences of surgical treatment of MG with a novel incision by cutting the sternum cross-sectionally at the second intercostal level. A retrospective analysis was made for the clinical data from the patients with MG who underwent thymectomy from July 1988 to May 2009. The surgical procedures were designed into three groups, a group with Osserman classification and median incision of the sternum (Group 1), a group with MGFA typing (Myasthenia Gravis Foundation of America) and a small transverse sternal incision at the second intercostal level (Group 2), and a group with new typing and a smaller transverse sternal incision at the second intercostal level (Group 3). Observation of the clinical typing and staging was made in the patients with myasthenia crisis. The parameters such as procedure duration in Group 2 and 3 was significantly lower than those in Group 1 ( P < 0.05). The incidence of myasthenia crisis in Group 3 was significantly lower than that in Groups 2 and 3 ( P < 0.05). The procedure with a smaller transverse sternal incision at the second intercostal level (Group 3) is a safer method for patients with MG. The combination of this procedure with the new typing and staging methods proposed by our group could facilitate the selection of operation indications and opportunity, resulting in the lower incidence of myasthenia crisis and mortality. Our new procedure is well deserved to be a preferential selection by other hospitals.

Aims: To develop a free accessible online tool to identify the prognostic markers for Merkel cell carcinoma (MCC) and to estimate the significance of interested gene in a cohort of clinical patients. Settings and Design: R package is used to calculate and plot the Kaplan–Meier survival curve. Subjects and Methods: An online search engine was developed by combining MCC datasets with available anatomoclinical data in Gene Expression Omnibus. In current study, genomic expression profile of thirty patients comprising 42985 probes and 21651 genes was evaluated. Patients were divided into first quartile, second quartile, and third quartile. Information about different cancer patients of varying stages (Stage I–IV) was stored using median survival scale of 14.5 months. Data were stored in SQL Server database and hosted on Windows Server 2008 using Apache Tomcat application server. Statistical Analysis Used: Log-rank test was applied and P < 0.05 was considered statistically significant. Results: An Online Survival analysis tool for MCC abbreviating as OSMCC was developed, which can assess the expression level relevance of various genes on the clinical outcome in MCC patients. By OSMCC, the survival curve could be displayed, and the hazard ratio with 95% confidence intervals and log-rank P value can also be calculated. Conclusions: The study demonstrated the ability of OSMCC to identify and analyze transcriptome and clinical datasets for MCC through prognosis significance analysis. So far, OSMCC is the first advanced and specific tool for the prognostic measurement of MCC. Furthermore, OSMCC can prove to be a highly valuable database for the preliminary assessment and identification of potential MCC prognostic biomarkers. OSMCC is accessible at http://bioinfo.henu.edu.cn/MCC/MCCList.jsp.

Alzheimer’s disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβplaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD.

We aim to study the therapeutic effects of HBsAg-activated DCs and cytokine-induced killer (CIK) cells as adoptive immunotherapy in patients with Chronic Hepatitis B (CHB). Autologous HBsAg-activated DC-CIK cells were infused into patients with CHB to evaluate their effect on HBV-DNA, HBsAg, ALT, etc. The viral load in the treatment group decreased significantly (P 0.001), while that in the control group did not decrease (P 0.05). Twenty-one patients (63.6% efficiency) in the treatment group had a viral response (≥2 log decrease in viral load), while four patients (14.8% efficiency) from the control group had a viral response. There were significant differences in the viral responses of the two groups (the control group 63.6% versus the control group 14.8%, P 0.001). We concluded that the immunity was enhanced after HBsAg activation in DCs and CIK cells. Reinfusion of autologous HBsAg-activated DC-CIK cells inhibited HBV proliferation in 21 of 33 (63.6%) patients.

The present study explored the tissue-protective effect of erythropoietin in rats after experimental spinal cord injury (SCI) produced by dropping a weight onto surgically exposed spinal cord. Sixty rats were randomized to sham operation (spinal cord exposure; control), SCI plus intraperitoneal saline injection, or SCI plus intraperitoneal erythropoietin injection. Locomotor function was evaluated with Basso, Beattie and Bresnahan scores 1 day (24 h) and 7 days later, and rats were then killed for analysis of lesion site tissue. Compared with saline-treated SCI rats, erythropoietin-treated SCI rats showed significantly less locomotor dysfunction and faster locomotor recovery. Immunohistochemistry showed that erythropoietin-treated SCI rats had a significantly lower phospho-extracellular signal-regulated kinase (p-ERK) protein expression and a significantly higher mitogen-activated protein kinase phosphatase-1 (MKP-1) protein expression than saline-treated SCI rats. Haematoxylin–eosin staining showed progressive disruption of dorsal white matter and neuron loss after SCI; lesions were less severe and there was more neuron regeneration in the erythropoietin group than in the saline group. It is concluded that erythropoietin reduces pathological changes and SCI severity via down-regulation of p-ERK and up-regulation of MKP-1.

Reprogrammed metabolism is key biochemical characteristic of malignant cells, which represents one of the emerging hallmarks of cancer. Currently, there is rising contemplation on oxidative pentose phosphate pathway (PPP) enzymes as potential therapeutic hits due to their affiliation with tumor metabolism. 6-Phosphogluconate dehydrogenase (6PGD), third oxidative decarboxylase of PPP, has received a great deal of attention during recent years due to its critical role in tumorigenesis and redox homeostasis. 6PGD has been reported to overexpress in number of cancer types and its hyperactivation is mediated through post-transcriptional and post-translational modifications by YTH domain family 2 (YTHDF2), Nrf2 (nuclear factor erythroid 2-related factor 2), EGFR (epidermal growth factor receptor) and via direct structural interactions with ME1 (malic enzyme 1). Upregulated expression of 6PGD provides metabolic as well as defensive advantage to cancer cells, thus, promoting their proliferative and metastatic potential. Moreover, enhanced 6PGD expression also performs key role in development of chemoresistance as well as radiation resistance in cancer. This review aims to discuss the historical timeline and cancer-specific role of 6PGD, pharmacological and genetic inhibitors of 6PGD and 6PGD as prognostic biomarker in order to explore its potential for therapeutic interventions. We anticipate that targeting this imperative supplier of NADPH might serve as tempting avenue to combat the deadly disease like cancer.