Dahlglud4905

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a frequent cause of autosomal dominant Parkinson's disease (PD) and have been associated with familial and sporadic PD. Reducing the kinase activity of LRRK2 is a promising therapeutic strategy since pathogenic mutations increase the kinase activity. Several small-molecule LRRK2 inhibitors are currently under investigation for the treatment of PD. However, drug discovery and development are always accompanied by high costs and a risk of late failure. The use of already approved drugs for a new indication, which is known as drug repositioning, can reduce the cost and risk. In this study, we applied a structure-based drug repositioning approach to identify new LRRK2 inhibitors that are already approved for a different indication. In a large-scale structure-based screening, we compared the protein-ligand interaction patterns of known LRRK2 inhibitors with protein-ligand complexes in the PDB. The screening yielded 6 drug repositioning candidates. Two of these candidates, Sunitinib and Crizotinib, demonstrated an inhibition potency (IC50) and binding affinity (Kd) in the nanomolar to micromolar range. While Sunitinib has already been known to inhibit LRRK2, Crizotinib is a novel LRRK2 binder. Our results underscore the potential of structure-based methods for drug discovery and development. In light of the recent breakthroughs in cryo-electron microscopy and structure prediction, we believe that structure-based approaches like ours will grow in importance.[This corrects the article DOI 10.1016/j.csbj.2021.06.012.].Background Many people with refugee backgrounds suffer from trauma-related complex social and psychological problems, and compliance with standard psychological treatment tends to be low. More culturally adaptable treatment options seem to be needed. Objective We aimed to investigate whether the music therapy method 'trauma-focused music and imagery' (tr-MI), characterized by a particular focus on arousal and affect regulation, would be equally effective as the standard psychological talk therapies for ameliorating trauma symptoms in Danish refugees. Methods A pragmatic, noninferiority, parallel, randomized controlled trial with six-month follow-up was carried out at three clinics for refugees in the public mental health services of the Psychiatry (DK). Seventy-four adults diagnosed with posttraumatic stress disorder (PTSD) were allocated to either music therapy sessions (tr-MI, N = 39) or psychological treatment as usual (TAU, N = 35). Western classical music, new age music, and music from the participants' o standardized therapy are needed to substantiate the evidence base for tr-MI therapy.A growing amount of evidence has confirmed the crucial role of the prolyl isomerase PIN1 in aging and age-related diseases. However, the mechanism of PIN1 in age-related hearing loss (ARHL) remains unclear. Pathologically, ARHL is primarily due to the loss and dysfunction of hair cells (HCs) and spiral ganglion cells (SGCs) in the cochlea. Therefore, in this study, we aimed to investigate the role of PIN1 in protecting hair cells and auditory HEI-OC1 cells from senescence. Enzyme-linked immunosorbent assays, immunohistochemistry, and immunofluorescence were used to detect the PIN1 protein level in the serum of ARHL patients and C57BL/6 mice in different groups, and in the SGCs and HCs of young and aged C57BL/6 mice. In addition, a model of HEI-OC1 cell senescence induced by H2O2 was used. Adult C57BL/6 mice were treated with juglone, or juglone and NAC, for 4 weeks. Interestingly, we found that the PIN1 protein expression decreased in the serum of patients with ARHL, in senescent HEI-OC1 cells, and in the cochlea of aged mice. Moreover, under H2O2 and juglone treatment, a large amount of ROS was produced, and phosphorylation of p53 was induced. Importantly, PIN1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-α. Overexpression of PIN1 reversed the increased level of p-p53 and rescued HEI-OC1 cells from senescence. Furthermore, PIN1 mediated cellular senescence by the PI3K/Akt/mTOR signaling pathway. In vivo data from C57BL/6 mice showed that treatment with juglone led to hearing loss. Taken together, these findings demonstrated that PIN1 may act as a vital modulator in hair cell and HEI-OC1 cell senescence.Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.Ginseng (Panax ginseng Meyer) is a well-known herbal medicine that has been used for a long time in Korea to treat various diseases. This study investigated the in vitro and in vivo protective effects of red ginseng extract (RGE) and red ginseng oil (RGO). Liver injury was produced in BALB/c mice by 400 mg/kg of acetaminophen intraperitoneal injection. The antioxidant effects of RGE and RGO on the free radicals 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) were measured. In addition, the hepatoprotective activities of RGE and RGO on liver markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress markers, including superoxide dismutase (SOD), catalase (CAT) enzyme activity, and 8-hydroxy-2-deoxyguanosine (8-OHdG) in serum and histopathological analysis, were evaluated. The protective effect of RGO on UV-induced phototoxicity was also evaluated in Balb/c 3T3 mouse fibroblast cell line. RGE and RGO effectively inhibited the radicals DPPH and ABTS compared with ascorbic acid and trolox, respectively. Moreover, RGE and RGO significantly decreased the liver enzyme (ALT and AST) levels, increased the antioxidant enzyme (SOD and CAT) levels, and decreased the DNA oxidation product (8-OHdG) content in mice serum. RGO also exhibited protective effect against UV irradiation compared with chlorpromazine hydrochloride, a known phototoxic drug, in Balb/c 3T3 cell line. RGE and RGO possess antioxidant and hepatoprotective properties in mice, and RGO exerts nonphototoxic activity in Balb/c 3T3 cells.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. BTK inhibitor 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.A major shortcoming of postischemic therapy for myocardial infarction is the no-reflow phenomenon due to impaired cardiac microvascular function including microcirculatory barrier function, loss of endothelial activity, local inflammatory cell accumulation, and increased oxidative stress. Consequently, inadequate reperfusion of the microcirculation causes secondary ischemia, aggravating the myocardial reperfusion injury. ATP-sensitive potassium ion (KATP) channels regulate the coronary blood flow and protect cardiomyocytes from ischemia-reperfusion injury. Studies in animal models of myocardial ischemia-reperfusion have illustrated that the opening of mitochondrial KATP (mito-KATP) channels alleviates endothelial dysfunction and reduces myocardial necrosis. By contrast, blocking mito-KATP channels aggravates microvascular necrosis and no-reflow phenomenon following ischemia-reperfusion injury. Nicorandil, as an antianginal drug, has been used for ischemic preconditioning (IPC) due to its mito-KATP channel-opening effect, thereby limiting infarct size and subsequent severe ischemic insult. In this review, we analyze the protective actions of nicorandil against microcirculation reperfusion injury with a focus on improving mitochondrial integrity. In addition, we discuss the function of mitochondria in the pathogenesis of myocardial ischemia.

chronic kidney disease is an important risk factor for cardiovascular-related morbidity and death. In Ghana, relatively little is known about the prevalence of chronic kidney disease (CKD) in homeless and slum dwellers in the major cities of the country. This study aimed at determining the prevalence of CKD among homeless people in Nima and Agbogbloshie, Accra, Ghana, and to evaluate the association between socio demographic characteristics and CKD.

we recorded information on individuals' socio-demographic characteristics and anthropometric indices, and took blood samples from a total of 512 homeless participants for serum creatinine measurement. Renal function was estimated according to the 4-variable Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (C-G) equations.

participants with normal serum creatinine (SCr), made up of 232 males and 280 females totaling 512 took part in the study. Those with normal glomerular filtration rate (GFR) were 86% and 84.6% by means of the C-G and MDRD equations respectively.