Showing papers in "Experimental and Therapeutic Medicine in 2021"

COVID-19 and its consequences on mental health (Review)

Abstract: As one year is approaching since the beginning of the Coronavirus disease 2019 (COVID-19) pandemic, it is important to acknowledge the detrimental effect that it is having on mental health at the individual, societal and public health levels. The current review presents the direct and indirect psychological impact of COVID-19 on the general public, as well as on vulnerable groups, including the elderly, the young, healthcare professionals, people with pre-existing mental health issues, those infected by COVID-19, homeless people and refugees. Important findings are discussed in the present review, including the social stigma in older people associated with portraying COVID-19 as the disease of the elderly, and the limited psychological impact of COVID-19 in the severely mentally ill, alongside the response of the mental healthcare systems globally to this unparalleled public health crisis. The important lessons to be learnt so far can help formulate individual mental health recommendations, as well as improved intervention and prevention public health strategies.

PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review).

Abstract: Renal cell carcinoma (RCC) accounts for over 90% of all renal malignancies, and mainly affects the male population. Obesity and smoking are involved in the pathogenesis of several systemic cancers including RCC. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway regulates cell growth, differentiation, migration, survival, angiogenesis, and metabolism. Growth factors, hormones, cytokine and many extracellular cues activate PI3K/AKT/mTOR. Dysregulation of this molecular pathway is frequently reported in human cancers including RCC and is associated with aggressive development and poor survival rate. mTOR is the master regulator of cell metabolism and growth, and is activated in many pathological processes such as tumour formation, insulin resistance and angiogenesis. mTOR inhibitors are used at present as drug therapy for RCC to inhibit cell proliferation, growth, survival, and the cell cycle. Temsirolimus and everolimus are two mTOR inhibitors that are currently used for the treatment of RCC. Drugs targeting the PI3K/AKT/mTOR signalling pathway may be one of the best therapeutic options for RCC.

The complex relationship between infertility and psychological distress (Review)

Abstract: Infertility is defined as the inability to procreate, or carry or deliver a baby naturally. The majority of specialists describe infertility as being unable to get pregnant after having tried for at least one year. The relationship between infertility and psychological stress is complex. On the one hand, infertile couples are subject to greater stress and have a greater risk of developing psychological disorders compared with normal, healthy couples. On the other hand, high levels of psychological distress have been indicated to increase infertility. Therefore, in the present review, the main factors that may lead to increased stress in couples who try to conceive, psychological stress as the reason for infertility, and the therapies that can help decrease psychological distress and increase chances of pregnancy are underlined. In addition to the psychological side effects that may occur from infertility itself, a range of other side effects can be caused by hormones and drugs used to treat infertility. Additionally, problem during erection and ejaculation can cause of psychological distress, which can lead to infertility among men. Psychotherapy is the main intervention recommended for couples who suffer from any form of infertility. Ideally, counselling should begin before patients start any medical intervention to help with their infertility.

Multifactorial expression of IL-6 with update on COVID-19 and the therapeutic strategies of its blockade (Review)

Abstract: Interleukin 6 (IL-6), a cytokine produced by various cells of the human body (macrophages, lymphocytes, astrocytes, ischemic myocytes, endothelial cells) has both pro-inflammatory and anti-inflammatory properties, being a key component in regulating various physiologic and pathological processes. The structure of this molecule and the receptor system it possesses are important due to the different activities that IL-6 can exert; through trans-signaling pro-inflammatory activities are mediated, while through classic signaling, IL-6 is responsible for anti-inflammatory and regenerative activities. IL-6 signaling is involved in coronary artery disease and the global COVID-19 pandemic. This proatherogenic cytokine reaches elevated serum levels in the cytokine storm generated by SARS-CoV-2, and is also associated with smoking or obesity-classic cardiovascular risk factors which promote inflammatory states. IL-6 levels are proportionally correlated with dyslipidemia, hypertension and glucose dysregulation, and they are associated with poor outcomes in patients with unstable angina or acute myocardial infarction. IL-6 targeting for treatment development (not only) in cardiovascular disease and COVID-19 is still a matter of ongoing research, although tocilizumab has proven to be effective in reducing the proatherogenic effects of IL-6 and is suggested to improve COVID-19 patient survival.

The new WHO classification of gastrointestinal neuroendocrine tumors and immunohistochemical expression of somatostatin receptor 2 and 5.

Abstract: The 2019 World Health Organization (WHO) classification of gastrointestinal tumors defines well-differentiated grade 3 neuroendocrine tumors, the mixed neuroendocrine-non-neuroendocrine tumors (MiNENs) and classifies goblet cell carcinoid as goblet cell adenocarcinoma. The expression of somatostatin receptors (SSTRs) is the foundation for somatostatin analogue therapy. At present, there are only a few studies that have analyzed the immunohistochemical reactivity of SSTRs in gastrointestinal neuroendocrine neoplasms (NENs). The aim of the present study was to evaluate the immunohistochemical expression of SSTR2 and SSTR5 in gastrointestinal NENs and goblet cell adenocarcinomas and the correlation of these markers with clinical and morphological factors. The study included 67 patients with NENs and 4 patients with adenocarcinoma ex-goblet cell carcinoid diagnosed between January 2008 and December 2018. Tumors were reclassified according to the 2019 WHO classification. Immunohistochemical staining for chromogranin A, synaptophysin, Ki-67, p53, SSTR2, and SSTR5 were performed in all the cases. The results showed that, G1 and G2 neuroendocrine tumors were more common SSTR2-positive in comparison with G3 carcinomas (P<0.0001). In addition, 33.3% of neuroendocrine carcinomas and 2 cases of low-grade adenocarcinoma ex-goblet cell carcinoid were SSTR2-positive. Neuroendocrine carcinomas had significantly lower SSTR2 and SSTR5 expression compared with well-differentiated neuroendocrine tumors (P=0.0130; P=0.0437, respectively). The SSTR2 expression in the early tumor stages was 100%, more often than in advanced stages (55.6%; P=0.0011). The results demonstrated the decrease in SSTR2 expression with increasing malignancy and tumor stage. The SSTR2-positive expression in neuroendocrine carcinomas and adenocarcinoma ex-goblet cell carcinoid provides evidence for the benefits of somatostatin analog treatment associated with surgery and chemotherapy.

Autophagy-related signaling pathways are involved in cancer (Review).

Abstract: Autophagy is a self-digestion process in cells that can maintain energy homeostasis under normal circumstances. However, misfolded proteins, damaged mitochondria and other unwanted components in cells can be decomposed and reused via autophagy in some specific cases (including hypoxic stress, low energy states or nutrient deprivation). Therefore, autophagy serves a positive role in cell survival and growth. However, excessive autophagy may lead to apoptosis. Furthermore, abnormal autophagy may lead to carcinogenesis and promote tumorigenesis in normal cells. In tumor cells, autophagy may provide the energy required for excessive proliferation, promote the growth of cancer cells, and evade apoptosis caused by certain treatments, including radiotherapy and chemotherapy, resulting in increased treatment resistance and drug resistance. On the other hand, autophagy leads to an insufficient nutrient supply in cancer cells and the destruction of energy homeostasis, thereby inducing cancer cell apoptosis. Therefore, understanding the mechanism of the double-edged sword of autophagy is crucial for the treatment of cancer. The present review summarizes the signaling pathways and key factors involved in autophagy and cancer to provide possible strategies for treating tumors.

Effectiveness of COVID-19 vaccines and their challenges (Review).

Abstract: At the end of 2019, a new disease recognized such as severe acute respiratory syndrome (SARS), was reported in Wuhan, China. This disease was caused by an unknown SARS coronavirus 2 (SARS-CoV-2); a virus is characterized by high infectivity among humans. In some cases, this disease can be asymptomatic, while in other cases can induce flu-like symptoms or acute respiratory distress syndrome, pneumonia and death. For this reason, the World Health Organization and Public Health Emergency of International Concern declared a pandemic status in January 2020. Currently, numerous countries have been involved in the development of effective vaccines to protect humans against SARS-CoV-2 infection. The present review will discuss the four vaccines, AZD1222 (AstraZeneca or Vaxzevria), Janssen (Ad26.COV2.S), Moderna/mRNA-1273 and BioNTech/Fosun/Pfizer BNT162b1, that are currently in use worldwide to understand their efficacy, but also evaluate the difficulties and challenges of vaccine development. Although several questions should be addressed regarding these vaccines, the current review will examine the viral elements used in the coronavirus-19 vaccine that can play a crucial role in inducing a strong immune response, as well as the different adverse effects that they can cause to individuals.

Impact of adipose tissue in chronic kidney disease development (Review).

Abstract: Obesity is a worldwide pandemic health issue. Obesity is associated with the pathogenesis of type 2 diabetes, hypertension, dyslipidemia, cardiovascular diseases, cancer, and kidney diseases. This systemic disease can affect the kidneys by two mechanisms: Indirectly through diabetes mellitus (DM) and hypertension and directly through adipokines secreted by adipose tissue. Obesity is a risk factor for chronic kidney disease (CKD), which is associated with an increased risk of morbidity and mortality among the adult population. Increased visceral adipose tissue leads to renal glomerular hyperfiltration and hyperperfusion, which may lead to glomerular hypertrophy, proteinuria, and CKD development. Adipokines are hormones produced by fat tissue. They are involved in energy homeostasis, sugar and fat metabolism, reproduction, immunity, and thermogenesis control. Hormones and cytokines secreted by adipose tissue contribute to the development and progression of CKD. Decreased serum or urinary adiponectin levels are specific in diabetic and non-diabetic CKD patients, while leptin presents increased levels, and both are associated with the development of glomerulopathy. Excessive adipose tissue is associated with inflammation, oxidative stress (OS), insulin resistance and activation of the renin angiotensin-aldosterone system (RAAS). Therefore, adipose tissue dysfunction plays an important role in the development of CKD.

Graphene oxide induces dose-dependent lung injury in rats by regulating autophagy.

Abstract: Graphene is a two-dimensional structured material with a hexagonal honeycomb lattice composed of carbon atoms. The biological effects of graphene oxide (GO) have been extensively investigated, as it has been widely used in biological research due to its increased hydrophilicity/biocompatibility. However, the exact mechanisms underlying GO-associated lung toxicity have not yet been fully elucidated. The aim of the present study was to determine the role of GO in lung injury induction, as well as its involvement in oxidative stress, inflammation and autophagy. The results revealed that lower concentrations of GO (5 and 10 mg/kg) did not cause significant lung injury, but the administration of GO at higher concentrations (50 and 100 mg/kg) induced lung edema, and increased lung permeability and histopathological lung changes. High GO concentrations also induced oxidative injury and inflammatory reactions in the lung, demonstrated by increased levels of oxidative products [malondialdehyde(MDA) and 8-hydroxydeoxyguanosine (8-OHdG)] and inflammatory factors (TNF-α, IL-6, IL-1β and IL-8). The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CLQ) inhibited autophagy in the lung and attenuated GO-induced lung injury, as demonstrated by a reduced lung wet-to-dry weight ratio, lower levels of protein in the bronchoalveolar lavage fluid, and a reduced lung injury score. Furthermore, 3-MA and CLQ significantly reduced the levels of MDA, 8-OHdG and inflammatory factors in lung tissue, suggesting that autophagy also mediates the development of oxidative injury and inflammation in the lung. Finally, autophagy was directly inhibited in BEAS-2B cells by short hairpin RNA-mediated autophagy protein 5 (ATG5) knockdown, which were then treated with GO. Cell viability, as well as the extent of injury (indicated by lactate dehydrogenase level) and oxidative stress were determined. The results revealed that ATG5 knockdown-induced autophagic inhibition significantly decreased cellular injury and oxidative stress, suggesting that autophagy induction is a key event that leads to lung injury during exposure to GO. In conclusion, the findings of the present study indicated that GO causes lung injury in a dose-dependent manner by inducing autophagy.

MicroRNA-432-5p inhibits cell migration and invasion by targeting CXCL5 in colorectal cancer.

Abstract: MicroRNAs (miRNAs) play an important role in the occurrence and development of colorectal cancer (CRC) Evidence shows that miR-432-5p expression is decreased in various tumors and cancer cell lines miR-432-5p can inhibit tumor invasion and metastasis, but its role in colorectal cancer is unclear The present study demonstrated that miR-432-5p expression was decreased in colorectal cancer tissue and cell lines, and is negatively associated with invasion classification, lymph node metastasis and Tumor-Node-Metastasis stage Kaplan-Meier survival analysis showed that low miR-432-5p expression was associated with a poor survival rate in patients with CRC In addition, SW480 and HT-29 cells transfected with miR-432-5p mimics had decreased migration and invasion abilities, whereas miR-432-5p inhibitors had the opposite effect The expression of C-X-C motif chemokine ligand 5 (CXCL5), a direct target of miR-432-5p, was negatively associated with miR-432-5p expression When CXCL5 was introduced into miR-432-5p mimic-transfected SW480 and HT-29 cells, miR-432-5p-mediated inhibition of CRC migration and invasion was reversed Thus, the present results suggest that miR-432-5p can inhibit the migration and invasion of CRC cells by targeting CXCL5

COVID-19 and post-traumatic stress disorder: The perfect 'storm' for mental health (Review).

Abstract: Since its outbreak, in December, 2019, in the Chinese city of Wuhan, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an ongoing global pandemic. Due to the novel antigenic properties of this virus, the world population could not develop immunity effectively and this led to the subsequent spread of COVID-19. This caused an unprecedented emergency situation with significant negative effects on health and well-being both on an individual and societal level. Apart from health, economic and social consequences, the impact of this pandemic on mental health is increasingly being reported in the scientific literature. The present review aimed to provide a comprehensive discussion of the possible neurological and neuropsychiatric manifestations of SARS-CoV-2, together with the related underlying molecular pathways. In addition, the present review focused on populations which are at a higher risk of developing psychiatric disturbances due to the COVID-19 pandemic and discussed possible routes of clinical management and therapeutics to minimize the burden associated with psychiatric disorders. Moreover, research findings exploring the prevalence of COVID-19-related post-traumatic stress disorder (PTSD) symptoms across vulnerable groups, including children, adolescents and COVID-19 survivors are presented, with particular emphasis on those with severe disease who required hospitalization and/or intensive care unit admission. Based on the available literature, the identification of potential determinants associated with PTSD across the different populations is underlined. Lessons learnt from the pandemics across the globe together with the ongoing research on COVID-19 and its impact on mental health, highlight the utmost importance for evidence-based, proactive and targeted interventions in high-risk groups aiming to mitigate the risks and manage vulnerabilities.

Fatty acids and their role in type-2 diabetes (Review).

Abstract: Age, lifestyle and diet are major risk factors for the onset of type 2 diabetes mellitus (T2DM). Insulin resistance (IR) and β-cell dysfunction underlie the pathophysiology of T2DM. Diabetic populations are also prone to lipid and lipoprotein abnormalities as an indirect effect of IR on key metabolic enzymes. However, recent studies suggested that lipid changes may not only be a consequence of impaired glucose metabolism but also a causative factor. Fatty acids (FAs) influence translocation of glucose transporters and insulin receptor binding and signalling, in addition to cell membrane fluidity and permeability. It is thus suggested that FAs may have an essential role in the development of IR and T2DM. Specific combinations of FAs within phospholipids and triglycerides were indicated to exhibit the strongest associations with the risk of T2DM. The aim of the present review was to investigate the role of FAs in the pathogenesis of T2DM, as it has yet to be fully elucidated.

Upregulating miR-27a-3p inhibits cell proliferation and inflammation of rheumatoid arthritis synovial fibroblasts through targeting toll-like receptor 5.

Abstract: Rheumatoid arthritis (RA) is a serious chronic inflammatory disease and synovial fibroblasts (SFs) serve a vital role in the pathogenesis and progression of RA. Current studies have demonstrated that dysregulation of microRNAs is involved in RA etiopathogenesis. The present study aimed to investigate the role of microRNA (miR)-27a-3p in RASFs, as well as its molecular mechanism. RASFs were isolated from synovial tissues from patients with RA. Expression of miR-27a-3p and toll-like receptor 5 (TLR5) was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation, apoptosis and inflammatory response were measured with MTT assay, flow cytometry and ELISA kits, respectively. The target binding between miR-27a-3p and TLR5 was predicted on DIANA TOOLS software, and confirmed by dual-luciferase reporter assay and Biotin-coupled miRNA pull-down assay. Expression of miR-27a-3p was downregulated and TLR5 was upregulated in synovial tissues and RASFs isolated from patients with RA. Functionally, upregulating miR-27a-3p may promote the apoptosis rate of RASFs and suppress cell proliferation and secretions of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. TLR5 was validated as a downstream target for miR-27a-3p in RASFs, and its expression was negatively regulated by miR-27a-3p. Silencing TLR5 in RASFs may exert similar effects to miR-27a-3p-overexpression; whereas, restoring TLR5 counteracted the suppression of miR-27a-3p-overexpression on RASF proliferation and inflammation, as well as the promotion on apoptosis. miR-27a-3p upregulation may suppress RA progression by inhibiting RASFs proliferation and inflammation through targeting TLR5.

Mechanism of circadian regulation of the NRF2/ARE pathway in renal ischemia-reperfusion.

Abstract: The nuclear erythroid 2-related factor 2 (NRF2)/antioxidant response element (ARE) pathway has been shown to provide strong protection against oxidative stress injury induced by renal ischemia-reperfusion (IR). However, the endogenous regulatory mechanism of the NRF2/ARE pathway in renal IR injury is incompletely understood. A rat model of renal IR was established by occlusion of the bilateral renal pedicle for 45 min, followed by reperfusion for 24 h. Renal injury was assessed by light microscopy and levels of serum creatinine, blood urea nitrogen and neutrophil gelatinase-associated lipocalin was measured using enzyme-linked immunosorbent assay. Renal oxidative stress was also evaluated by measuring superoxide dismutase and malondialdehyde in renal tissues. Protein expression levels of brain and muscle ARNT-like 1 (BMAL1), nuclear factor erythroid 2-related factor 2 (NRF2), NAD(P)H dehydrogenase [quinone] 1 (NQO1), glutamate-cysteine ligase modifier (GCLM) and heme oxygenase 1 (HO1) in the kidney were determined by western blotting and immunohistochemistry. Reverse transcription-quantitative PCR was used to evaluate rhythmic transcription of the core clock genes (CLOCK and BMAL1) and the NRF2 gene. The nature of the binding of BMAL1 to the promoter regions in the NRF2 gene was assessed by chromatin immunoprecipitation assays in rat kidneys. BMAL1 was found to bind to the promoter of the NRF2 gene through an E-BOX element associated with strongly rhythmic activation of NRF2 in both the normal kidney and those exposed to IR. The ARE-regulated anti-oxidative stress protein was affected by the circadian rhythm of the NRF2 gene. As the NRF2 level was at a circadian nadir, the expression of the proteins NQO1, GCLM and HO1 was weakened, resulting in more serious renal oxidative stress injury and pathological and functional impairment induced by IR. It can be concluded that the circadian rhythm of the NRF2/ARE pathway controlled by the circadian clock is essential for regulating antioxidant stress in renal IR injury, which might prompt new therapeutic strategies associated with the diurnal variability of human kidney disease, including renal transplantation.

Novel applications of platelet concentrates in tissue regeneration (Review)

Abstract: Numerous studies have explored the suitability of biocompatible materials in regenerative medicine. Platelet concentrates are derived from centrifuged blood and are named according to their biological characteristics, such as platelet-rich plasma, platelet-rich fibrin and concentrated growth factor. Platelet concentrates have gained considerable attention in soft and hard tissue engineering. Indeed, multiple components of autologous platelet concentrates, such as growth factors, fibrin matrix and platelets, serve essential roles in wound healing. Current studies are focused on cutting-edge strategies to meet the requirements for tissue restoration by improving the properties of autologous platelet concentrates. In the present review, applications of platelet concentrates for tissue engineering are discussed, presenting a selection of recent advances and novel protocols. In addition, several aspects of these strategies, such as the advantages of lyophilized platelet concentrates and the combination of platelet concentrates with biomaterials, stem cells or drugs are discussed. The present review aims to summarize novel strategies using platelet concentrates to improve the outcomes of wound healing.

Molecular mechanisms of opioid tolerance: From opioid receptors to inflammatory mediators (Review).

Abstract: Opioids are considered the most effective analgesics for the treatment of both acute and chronic pain. However, prolonged opioid use can induce a certain level of tolerance to its analgesic effects, leading to a reduction in its effectiveness, addiction and abuse. A better understanding of the mechanisms underlying opioid tolerance may provide insights into this phenomenon and aid in the development of novel methods to combat the side effects of opioid tolerance. The present review focused on two major contributors to tolerance, opioid receptors and inflammatory mediators. The molecular mechanisms involved in the desensitization of the opioid receptors were briefly described, including their phosphorylation, internalisation and recycling. Subsequently, the effects of Toll like receptor 4/NOD-like receptor family pyrin domain containing 3-mediated proinflammatory responses in opioid tolerance were discussed, aiming in supporting the identification of novel therapeutic targets.

Challenges of phototherapy for neonatal hyperbilirubinemia (Review).

Abstract: Phototherapy is universally recognized as the first option for treating neonatal jaundice due to its unparalleled efficiency and safety in reducing the high serum free bilirubin levels and limiting its neurotoxic effects. However, several studies have suggested that phototherapy may elicit a series of short- and long-term adverse reactions associated with pediatric diseases, including hemolysis, allergic diseases, DNA damage or even cancer. The aim of the present review was to summarize the etiology, mechanism, associated risks and therapeutic strategies for reducing high neonatal serum bilirubin levels. In order to shed light on the negative effects of phototherapy and to encourage implementation of a reasonable and standardized phototherapy scheme in the clinic, the present review sought to highlight the current understanding of the adverse reactions of phototherapy, as it is necessary to further study the mechanism underlying the development of the adverse effects of phototherapy in infants in order to explore novel therapeutic alternatives.

Lactobacillus spp. reduces ethanol‑induced liver oxidative stress and inflammation in a mouse model of alcoholic steatohepatitis

Abstract: Alcoholic steatohepatitis (ASH) is a complex multifactorial disease that can lead to liver fibrosis and cirrhosis if not treated promptly. Alcohol-induced oxidative stress and inflammation are the main factors that cause steatohepatitis and liver injury; however, probiotic bacteria in the gastrointestinal tract have been revealed to regulate immune responses and reduce oxidative stress, suggesting that functional probiotics could help to prevent ASH and liver injury. Despite numerous reports on the interactions between ASH and probiotics, the mechanisms underlying probiotic-mediated liver protection remain unknown. Therefore, the aim of the present study was to screen probiotics with high antioxidant capacity and investigate the ability of different probiotic combinations to reduce alcoholic liver disease (ALD) in a mouse model. It was identified that Lactobacillus plantarum (TSP05), Lactobacillus fermentum (TSF331) and Lactobacillus reuteri (TSR332) neutralized free radicals and displayed high antioxidant activity in vitro. In addition, these three functional probiotic strains protected mice from alcohol-induced liver injury in vivo. Mice treated with the probiotics demonstrated significantly lower alanine aminotransferase, aspartate aminotransferase and triglyceride levels, which were associated with the downregulation of the proinflammatory cytokines TNF-α and IL-6. Furthermore, probiotic treatment upregulated glutathione and glutathione peroxidase activity, which are bioindicators of oxidative stress in the liver. Collectively, the present results indicated that Lactobacillus strains TSP05, TSF331 and TSR332 reduced oxidative stress and inflammatory responses, thus preventing ASH development and liver injury.

Metformin attenuates H 2 O 2 ‑induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway

Abstract: Osteoporosis is a common metabolic disease that has a high incidence in postmenopausal women. Studies have indicated that oxidative damage plays an important role in the development of postmenopausal osteoporosis. Metformin has been showed to have the ability to relieve excessive oxidation. The aim of the present was to determine the therapeutic effect and potential mechanism of metformin in postmenopausal osteoporosis. Oxidative damage was stimulated in vitro by the addition of H2O2 to MC3T3-E1 cells and a mouse menopausal model was also constructed. Cell viability and flow cytometry experiments were performed to determine the effects of H2O2 and metformin treatment on apoptosis. Mitochondrial membrane potential was tested by JC-1 assays. Western blotting was used to detect the expression of mitochondrial apoptosis markers and antioxidant enzymes. Small interfering RNA was used to knockdown sirtuin3 (SIRT3), which was verified at the mRNA and protein levels. Bilateral ovariectomy was used to prepare menopausal mice, which were analyzed using micro-computed tomography. The results indicated that metformin is able to repair mitochondrial damage and inhibit the apoptosis of osteoblasts induced by H2O2, and also reverse bone mass loss in ovariectomized mice. Western blotting results demonstrated the involvement of SIRT3 in the production of antioxidant enzymes that are essential in protecting against mitochondrial injury. In addition, experiments with SIRT3 knockdown indicated that metformin reverses H2O2-induced osteoblast apoptosis by upregulating the expression of SIRT3 via the PI3K/AKT pathway. The results of the present reveal the pathogenesis of oxidative damage and the therapeutic effect of metformin in postmenopausal osteoporosis. They also suggest that SIRT3 is a potential drug target in the treatment of osteoporosis, with metformin being a candidate drug for modification and/or clinical application.

Knockdown of lncRNA NEAT1 expression inhibits cell migration, invasion and EMT by regulating the miR‑24‑3p/LRG1 axis in retinoblastoma cells

Abstract: Retinoblastoma (RB) is the most common primary intraocular cancer type that occurs during retinal development in childhood. Previous studies have reported that long non-coding RNAs (lncRNAs) are involved in the development of RB. Therefore, the aim of the present study was to investigate the effects and underlying regulatory mechanisms of nuclear paraspeckle assembly transcript 1 (NEAT1) in RB. The expression levels of NEAT1, microRNA (miR)-24-3p and leucine-rich-α-2-glycoprotein (LRG1) were detected using reverse transcription-quantitative PCR (RT-qPCR). Moreover, the protein expression levels of LRG1, matrix metalloproteinase 9, N-cadherin and E-cadherin were detected via western blotting. Furthermore, cell migration and invasion abilities were evaluated via Transwell assays. The targeting relationships between miR-24-3p and NEAT1 or LRG1 were predicted using online software and confirmed via dual-luciferase reporter assay. In the present study, NEAT1 and LRG1 were upregulated, and miR-24-3p was downregulated in RB tissues and cells compared with the corresponding healthy tissues and cells. Moreover, miR-24-3p was identified as a target of NEAT and LRG1 was demonstrated to be a direct target gene of miR-24-3p. Knockdown of NEAT1 or LRG1 significantly suppressed RB cell migration and invasion ability, while the effects were reversed by an miR-24-3p inhibitor. In addition, the downregulation of LRG1 caused by miR-24-3p was restored following the overexpression of NEAT1 in RB cells. It was also demonstrated that NEAT1 knockdown inhibited the epithelial-to-mesenchymal transition (EMT) pathway by inhibiting the expression of LRG via targeting miR-24-3p. In conclusion, the present results suggest that silencing of NEAT1 suppresses cell migration, invasion and the EMT process by downregulating LRG1 expression via sponging miR-24-3p in RB, thus indicating that NEAT1 may be a potential candidate for RB treatment.

Therapeutic potential of interleukin-15 in cancer (Review).

Abstract: The immune system is dysfunctional in cancer, and therapeutic approaches designated to restore immunity and increase long-term overall survival are desirable. The role of immunotherapy is to trigger the immune system to recognize and destroy tumor cells. Interleukin-15 (IL-15) is a member of the common gamma-chain (γc) cytokines that promote the differentiation and expansion of T cells, B cells and natural killer (NK) cells, leading to enhanced antitumor responses. This suggests that IL-15 is a promising candidate for anticancer therapy. Renewed interest in cancer immunotherapy has led to an increased number of preclinical studies and clinical trials that have investigated the reliability and potency of IL-15-based agents, not only as single therapy, but also in combination with others. This review provides a description of these studies which show the advantages and disadvantages of IL-15 as an immunotherapeutic agent. We present here the role of IL-15 and pharmacologically improved IL-15 superagonists as a single treatment or in combination with other therapeutic agents.

Relationship between oxidative stress and nuclear factor-erythroid-2-related factor 2 signaling in diabetic cardiomyopathy (Review).

Abstract: Diabetic cardiomyopathy (DCM) is the leading cause of death worldwide, and oxidative stress was discovered to serve an important role in the pathophysiology of the condition. An imbalance between free radicals and antioxidant defenses is known to be associated with cellular dysfunction, leading to the development of various types of cardiac disease. Nuclear factor-erythroid-2-related factor 2 (NRF2) is a transcription factor that controls the basal and inducible expression levels of various antioxidant genes and other cytoprotective phase II detoxifying enzymes, which are ubiquitously expressed in the cardiac system. Kelch-like ECH-associated protein 1 (Keap1) serves as the main intracellular regulator of NRF2. Emerging evidence has revealed that NRF2 is a critical regulator of cardiac homeostasis via the suppression of oxidative stress. The activation of NRF2 was discovered to enhance specific endogenous antioxidant defense factors, one of which is antioxidant response element (ARE), which was subsequently illustrated to detoxify and counteract oxidative stress-associated DCM. The NRF2 signaling pathway is closely associated with the development of various types of cardiac disease, including ischemic heart disease, heart failure, myocardial infarction, atrial fibrillation and myocarditis. Therefore, it is hypothesized that drugs targeting this pathway may be developed to inhibit the activation of NRF2 signaling, thereby preventing the occurrence of DCM and effectively treating the disease.

Characteristics of the intestinal microbiome in ankylosing spondylitis.

Abstract: The importance of intestinal microbiota in the development of various systemic diseases has been highlighted over time. Ankylosing spondylitis (AS) is a systemic disease with a complex pathogenesis involving a particular genetic marker and distinctive environmental triggers such as a specific gut dysbiosis. We conducted a prospective case-control study which included 60 subjects from Iasi Rehabilitation Hospital: 28 AS cases and 32 healthy controls. Intestinal microbiota analysis was performed by real-time polymerase chain reaction (qPCR) in stool samples. We performed the quantitative analysis of gut microbiome, focusing both on anti-inflammatory (Bifidobacterium, Lactobacillus, Faecalibacterium prausnitzii) and pro-inflammatory (Bacteroides, Escherichia coli) species. Overall, intestinal bacterial diversity in the AS group was decreased compared to that noted in the control. A significantly decreased level of Clostridium leptum was observed, associated with an increased level of Escherichia coli. We showed correlations between laboratory tests (liver and kidney functional tests, inflammatory syndrome), the presence of HLA-B27, smoker status, the forms of AS with peripheral arthritis vs. pure axial forms and bacterial structures. No significant correlations were shown for disease activity scores, radiological stage of sacroiliitis or for body mass index. Our findings support that the intestinal microbiome in AS patients has a special signature characterized by an inflammatory status. Numerous environmental, genetical, clinical and paraclinical factors can lead to changes in gut bacterial diversity in these cases.

Uveal melanoma diagnosis and current treatment options (Review).

Abstract: Uveal melanoma is a rare condition accounting for only 5% of all primary melanoma cases. Still, it is the most frequently diagnosed primary intraocular malignant tumor in adults. Almost 90% of the tumors involve the choroid and only a small percentage affects the ciliary body or the iris. There is a consistent difference in incidence between different regions with individuals of northern European descent having a significantly higher risk as compared to Hispanics, Asians, and Blacks. Among the many risk factors, mutations in the G protein subunit alpha Q (GNAQ) or G protein subunit alpha 11 (GNA11) genes and different receptors are highly suggestive. While iris melanoma can easily be noticed by the patient itself or diagnosed at a routine slit-lamp evaluation, a consistent percentage of posterior uveal tumors are incidentally diagnosed at funduscopic evaluation as they can evolve silently for years, especially if located in the periphery. Uveal melanoma classifications rely on the tumor size (thickness and basal diameter) and also on intraocular and extraocular extension. The differential diagnosis with pseudomelanomas is carried out according to the tumor aspect and position. Iris melanoma has a better prognosis and a lower mortality rate as compared to choroidal melanoma that has a much higher rate of metastasis (50% of the patients) and a subsequent limited life expectancy from 6 to 12 months. While conservative therapeutic options for the primary tumor, relying on different surgical excision techniques and/or irradiation therapies, offer good local tumor control, the treatment options for metastatic disease, although numerous, are still inadequate in preventing a fatal outcome.

Curcumin ameliorates ischemic stroke injury in rats by protecting the integrity of the blood‑brain barrier

Abstract: The blood-brain barrier (BBB) is critical for proper cerebral homeostasis and its dysfunction during ischemic stroke can result in significant neurological injury. The major goal of the present study was to identify whether curcumin pretreatment possessed protective effects on BBB integrity during the 24 h of acute ischemic brain injury. To investigate the protective effects of curcumin, male Sprague-Dawley rats were divided into multiple groups, including sham, middle cerebral artery occlusion/reperfusion (MCAO/R) vehicle and curcumin pretreated MCAO/R groups. The effects of curcumin were measured by analyzing neurological deficits, infarct size, BBB permeability and expression levels of permeability-related proteins in the brain. It was found that curcumin pretreatment significantly improved neurological scores, decreased infarct size, and protected synaptic remodeling of hippocampal neurons and upregulated the protein expression level of tight junction proteins, ZO-1, occludin and claudin-5 in ischemic rat brains. Furthermore, curcumin pretreatment before stroke was shown to downregulate the phosphorylation of NF-κB and MMP-9, which are central mediators of inflammation. The results from the present study indicated that curcumin pretreatment ameliorated ischemic stroke injury by protecting BBB integrity and synaptic remodeling, as well as inhibiting inflammatory responses.

Updates and new medical treatments for vitiligo (Review)

Abstract: Vitiligo is a multifactorial disease characterized by the loss of skin pigment, which results in achromic macules and patches. There are currently several medical treatments available, which aim to arrest progression and induce skin repigmentation. These treatments alone or combined have exhibited varying degrees of pigmentation, and the majority are safe and effective. All therapies for vitiligo are limited, and no known treatment can consistently produce repigmentation in all patients. Individualized treatment is appropriate according to the location, clinical presentation and the presence of disease activity. The present review summarizes the medical treatments available for vitiligo: Systemic and topic pharmacological therapies, physical and depigmentation treatments. Several treatments are still underway and have not yet been approved. However, due to the promising preliminary results, these are also mentioned in the present review.

Histone demethylase KDM2A: Biological functions and clinical values (Review).

Abstract: Histone lysine demethylation modification is a critical epigenetic modification. Lysine demethylase 2A (KDM2A), a Jumonji C domain-containing demethylase, demethylates the dimethylated H3 lysine 36 (H3K36) residue and exerts little or no activity on monomethylated and trimethylated H3K36 residues. KDM2A expression is regulated by several factors, such as microRNAs, and the phosphorylation of KDM2A also plays a vital role in its function. KDM2A mainly recognizes the unmethylated region of CpG islands and subsequently demethylates histone H3K36 residues. In addition, KDM2A recognizes and binds to phosphorylated proteins, and promotes their ubiquitination and degradation. KDM2A plays an important role in chromosome remodeling and gene transcription, and is involved in cell proliferation and differentiation, cell metabolism, heterochromosomal homeostasis and gene stability. Notably, KDM2A is crucial for tumorigenesis and progression. In the present review, the documented biological functions of KDM2A in physiological and pathological processes are comprehensively summarized.

Network pharmacology-based prediction of the active compounds and mechanism of Buyang Huanwu Decoction for ischemic stroke

Abstract: Buyang Huanwu Decoction (BYHWD) is used to promote blood circulation and is widely used in Chinese clinical practice for the treatment and prevention of ischemic cerebral vascular diseases. However, the mechanism and active compounds of BYHWD used to treat ischemic stroke are not well understood. The current study aimed to identify the potential active components of BYHWD and explore its mechanism using network pharmacology and bioinformatics analyses. The compounds of BYHWD were obtained from public databases. Oral bioavailability and drug-likeness were screened using the absorption, distribution, metabolism and excretion (ADME) criteria. Components of BYHWD, alongside the candidate targets of each component and the known therapeutic targets of ischemic stroke were collected. A network of target gene compounds and cerebral ischemia compounds was established using network pharmacology data sources. The enrichment of key targets and pathways was analyzed using STRING and DAVID databases. Moreover, three of key targets [IL6, VEGFA and hypoxia-inducible-factor-1α (HIF-1α)] were verified using western blot analysis. Network analysis determined 102 compounds in seven herbal medicines that were subjected to ADME screening. A total of 42 compounds as well as 79 genes formed the principal pathways associated with ischemic stroke. The 16 key compounds identified were baicalein, beta-carotene, baicalin, kaempferol, luteolin, quercetin, hydroxysafflor yellow A, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin. The core genes in this network were IL6, TNF, VEGFA, HIF-1α, MAPK1, MAPK3, JUN, STAT3, IL1B and IL10. Furthermore, the TNF, IL17, apoptosis, PI3K-Akt, toll-like receptor, MAPK, NF-κB and HIF-1 signaling pathways were identified to be associated with ischemic stroke. Compared with the control group (no treatment), BYHWD significantly inhibited the expression of IL6 and increase the expression of HIF-1α and VEGFA. Network pharmacology analyses can help to reveal close interactions between multi-components and multi-targets and enhance understanding of the potential effects of BYHWD on ischemic stroke.

Quercetin suppresses apoptosis of chondrocytes induced by IL‑1β via inactivation of p38 MAPK signaling pathway

Abstract: The objective of the present study was to investigate the effect of quercetin and evaluate its protective effect on articular cartilage in patients with osteoarthritis (OA), by intervening the p38 pathway. The target factors of quercetin protecting articular cartilage in patients with OA were predicted scientifically and analyzed to predict the possible pathways by using network pharmacology. A pathway predicted to be closely associated with osteoarthritis was chosen for experimental verification in in vitro cells. The optimal intervention drug concentrations were selected by the of Cell Cycle Kit-8 assay, osteoarthritis and inflammatory factors relevant to osteoarthritis, interleukin-1β and tumor necrosis factor-α, were tested by of enzyme-linked immunosorbent assay, and the expression of relevant proteins and mRNA of the p38 signaling pathway was tested by reverse transcription-quantitative PCR and western blotting, following quercetin intervention. It was found that quercetin, at the concentration of 100 umol/l, can decrease inflammatory factors relevant to OA, inhibit the expression of p38, matrix metalloprotease 13 and ADAMTS in the pathway, and promote the expression of collagen Ⅱ. Therefore, it is postulated that quercetin can lower the expression of inflammatory factors in cartilage for the prevention and treatment of OA, and the expression level of relevant factors can be changed positively by blocking the p38 MAPK signaling pathway. Thus, quercetin can promote the repair of degenerative chondrocytes and protect articular chondrocytes.

Diabetic neuropathy: A narrative review of risk factors, classification, screening and current pathogenic treatment options (Review).

Abstract: Diabetic neuropathy (DN) is a frequent complication of diabetes mellitus (DM) with severe consequences as it progresses and influences all human body systems. This review discusses the risk factors for DN, the main characteristics of the clinical forms of DN, the screening methods and the current therapeutic options. Distal symmetric DN is the primary clinical form, and DM patients should be screened for this complication. The most important treatment of DN remains good glucose control, generally defined as HbA1c ≤7%. Symptomatic treatment improves life quality in diabetic patients. Pharmacological agents such as alpha (α)-lipoic acid and benfotiamine have been validated in several studies since they act on specific pathways such as increased oxidative stress (α-lipoic acid exerts antioxidant effects) and the excessive production of advanced glycosylation products (benfotiamine may inhibit their production via the normalization of glucose). Timely diagnosis of DN is significant to avoid several complications, including lower limb amputations and cardiac arrhythmias.