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Mitochondria, as “power house of the cell”, are crucial players in cell pathophysiology. Beyond adenosine triphosphate (ATP) production, they take part in a generation of reactive oxygen species (ROS), regulation of cell signaling and cell death. Dysregulation of mitochondrial dynamics may lead to cancers and neurodegeneration; however, the fusion/fission cycle allows mitochondria to adapt to metabolic needs of the cell. There are multiple data suggesting that disturbed mitochondrial homeostasis can lead to Parkinson’s disease (PD) development. 2-methoxyestradiol (2-ME), metabolite of 17β-estradiol (E2) and potential anticancer agent, was demonstrated to inhibit cell growth of hippocampal HT22 cells by means of nitric oxide synthase (NOS) production and oxidative stress at both pharmacologically and also physiologically relevant concentrations. Moreover, 2-ME was suggested to inhibit mitochondrial biogenesis and to be a dynamic regulator. This review is a comprehensive discussion, from both scientific and clinical point of view, about the influence of 2-ME on mitochondria and its plausible role as a modulator of neuron survival., Ministry of Science and Higher Education, Poland

Questions: What airway clearance techniques and exercise regimens are used by adults with cystic fibrosis (CF) in Australia when well or unwell? What proportion of these adults believe that exercise can be used as a substitute for traditional airway clearance techniques, and how have they come to this belief? What type of exercise is used as a substitute for traditional airway clearance techniques? Design: Cross-sectional survey at 13 CF centres in Australia, using a purpose-designed questionnaire. Participants: Six hundred and ninety-two adults with CF completed the questionnaire. Outcome measures: The questionnaire included questions about: the participants' current use of traditional airway clearance techniques and exercise, when well and unwell; and beliefs regarding the use of exercise as a substitute for traditional airway clearance techniques. Results: Coughing, huffing and positive expiratory pressure were the most commonly used airway clearance techniques. Walking, jogging and lifting weights were the most commonly used forms of exercise. Overall, 43% of participants believed that exercise could be used as a substitute for traditional airway clearance techniques, with 44% having substituted exercise for traditional airway clearance techniques in the previous 3 months. Personal experience was the most commonly reported factor influencing participants' beliefs about the use of exercise as a substitute for traditional airway clearance techniques. Conclusion: Exercise is commonly used as a substitute for traditional airway clearance techniques. Physiotherapists should advise patients that whilst there is some research suggesting a possible mechanism for exercise as a form of airway clearance, there are currently no medium-term to long-term data supporting exercise as a stand-alone form of airway clearance. These results suggest that future research to investigate the clinical effectiveness of exercise as a substitute for traditional airway clearance techniques should be a priority. Registration: ACTRN12616000994482. Key words: Cystic fibrosis, Exercise, Physical therapy modalities, Respiratory therapy

Introduction: Limited evidence has been shown on ways to optimize the mechanical design of machines in order to minimize knee loads. Objective: This study compared six computer simulated models of open kinetic knee extension exercises for patellofemoral pressure and tibiofemoral forces. Methods: A musculoskeletal model of the lower limb was developed using six different cam radius to change resistive forces. A default machine, a constant cam radius, a torque-angle model, a free-weight model and two optimized models were simulated. Optimized models reduced cam radius at target knee flexion angles to minimize knee forces. Cam radius, human force, tibiofemoral compressive and shear force, and patellofemoral pressure were compared for the six models using data from five knee flexion angles. Results: Large reductions in cam radius comparing the free-weight model to other models (73-180%) were limited to the large human force for the constant cam model to other models (9-36%). Larger human force (13 -36%) was estimated to perform knee extension using a constant cam radius compared other models without large effects in knee joint forces. Conclusion: Changes in cam design effected human without a potential impact in knee loads. Resumo Introdução: As evidências são limitadas quanto às formas de otimização do arranjo mecânico das máquinas a fim de minimizar as forças na articulação do joelho. Objetivo: O presente estudo comparou seis modelos de extensão de joelhos realizados em cadeia cinética aberta sob a pressão aplicada nas articulações patelofemoral e tibiofemoral. Métodos: Um modelo do sistema musculo-esquelético do membro inferior foi desenvolvido utilizando seis desenhos de roldana com o objetivo de alterar as forças resistivas. Uma máquina referência foi utilizada, uma com uma roldana concêntrica, um modelo baseado na relação torque-ângulo dos extensores do joelho, um modelo de peso livre e dois modelos otimizando a aplicação de cargas foram simulados. A otimização foi aplicada visando reduzir o raio da roldana excêntrica e minimizar as forças aplicadas no joelho. O raio da roldana, a força produzida pelo executante, as forças compressivas e de cisalhamento nas articulações tibiofemoral e a pressão na articulação patelofemoral foram comparadas para os seis modelos de máquina utilizando cinco ângulos de flexão do joelho. Resultados: Reduções no raio da roldana foram observadas comparando o modelo de peso livre com os demais modelos (73-180%). Maior força produzida foi observada para o modelo de roldana constante comparado aos demais modelos (9-36%). Maior força produzida foi estimada para realizar a extensão do joelho utilizando a roldana constante comparada com os demais modelos (13-36%) sem efeitos sobre as forças no joelho. Conclusão: O arranjo mecânico das máquinas alterou a força produzida pelo executante sem afetar as forças aplicadas no joelho.

La linfocitopenia T CD4 idiopática (LCI) es un síndrome clínico inusual que se caracteriza por un déficit de células T CD4+ circulantes en ausencia de infección por VIH u otra condición de inmunosupresión. Los pacientes con dicha enfermedad pueden presentarse asintomáticos o con infecciones oportunistas, las más frecuentes son por criptococo, micobacterias o virales como herpes zoster. Presentamos el caso de un hombre de 32 años, sin antecedentes, en quien se descartó infección por retrovirus, con recuento de linfocitos T CD4+ menor a 300 células/m3; se diagnosticó LCI posterior al diagnóstico de criptococomas cerebrales mediante hallazgos imagenológicos los cuales fueron congruentes con estudios microbiológicos.

Introduction: Antibiotic-resistance is a phenomenon by which bacteria manage to survive antimicrobial treatment; with incidence in intra and extra hospital environments such as: water sources, agricultural / livestock sector and fomites. Aim: To describe bacteria present in high circulation fomites in a central-western region of Colombia, with their phenotypic sensitivity profile and presence of genes beta-lactamases (TEM, OXA3 and SHV). Methodology: We isolate bacterial strains from banknotes, escalator handrails and ATM buttons. We evaluated its phenotypic sensitivity profile by minimal inhibitory concentration automated technique using Vitek 2® and presence of genes for beta-lactamases type TEM-full, OXA-3 and SHV-full by conventional PCR. Results: A total of 30 isolates were obtained; Acinetobacter baumannii complex, was the most common; banknotes were the form with the highest number of isolates and resistance. Of the total isolates, 53% carried at least one of the genes studied. Phenotypically, gram-negative bacteria were identified with resistance against: Imipinem, Piperacillin / Tazobactam, Colistin, Ceftazidime, Tigecycline and Ceftriaxone; Gram-positive bacteria with resistance to: Quinupristin / Dalfopristin, Minocycline, Tetracycline, Teicoplanin, Nitrofuratoin, Oxacillin, Clindamycin, Trimethropine-sulfamethoxazole, and Minocycline. Conclusion: Taking into account the circulation of strains with these resistances, it is important to educate the community to avoid the acquisition or spread of infections due to the inappropriate handling of this type of inanimate elements.

La tuberculosis (TB) es una de las enfermedades infecciosas con mayor carga de morbimortalidad a nivel mundial, la presentación pulmonar es la forma más común, sin embargo, las manifestaciones extrapulmonares, especialmente las osteoarticulares, pueden ser difíciles de diagnosticar debido a sus síntomas inespecíficos sugestivos de otras entidades como neoplasias o enfermedades infiltrativas, lo que hace de su diagnóstico un reto clínico. Está enfermedad esta asociada a múltiples factores de riesgo como inmunosupresión, contacto cercano con pacientes con tuberculosis, hacinamiento, residir en zona endémica, entre otros. A continuación, se presentan dos casos de pacientes pediátricos sin compromiso inmune que cursaron con cuadros sugestivos de neoplasias musculoesqueleticas, con hallazgos imagenológicos congruentes, pero con estudios microbiológicos positivos para TB.

Una vacuna para COVID 19 es una necesidad urgente de la comunidad global. El justificado temor por la premura con la cual se han desarrollado las evaluaciones de candidatos vacunales para COVID 19 no debe evitar un análisis racional, detallado e integral de los pasos que se deben cumplir y superar para dar licencia a una vacuna

Resumen Objetivo: describir las características socio-demográficas, presentación clínica y condiciones extrínsecas que pueden favorecer el desarrollo de la pitiriasis versicolor. Material y métodos: estudio observacional descriptivo, de corte transversal y prospectivo, en el que se incluyeron pacientes con diagnóstico clínico y micológico de pitiriasis versicolor entre enero y diciembre de 2018, que asistieron al Hospital Universitario Centro Dermatológico Federico Lleras Acosta. Resultados: se incluyeron un total de 42 pacientes con diagnóstico de pitiriasis versicolor confirmado por examen directo, el 62% fueron hombres con una edad promedio de 33 años. La localización más común fue el tórax anterior (68%) y posterior (65%), en fototipos III y IV (78.5%), con una tonalidad hipocrómica. El 28% presentaron cuadros recurrentes, con síntomas hasta 7 años antes de la consulta. El signo de Besnier fue positivo en el 95% de los casos. El 64% refirió antecedente personal de hiperhidrosis y el 67% practicaba algún deporte como buceo, natación o gimnasia. Discusión: la identificación de las condiciones extrínsecas presentes esta población permite orientar medidas de prevención para evitar recurrencias de pitiriasis versicolor. Los viajes a lugares de clima cálido y la práctica de deportes son factores que favorecen el desarrollo de la micosis. En las formas clínicas atípicas se sugiere realizar siempre el examen micológico directo para confirmar el diagnóstico. El signo de Besnier es una maniobra útil para el diagnóstico clínico de la pitiriasis versicolor, particularmente cuando el acceso al examen directo es limitado. Abstract Objective: to describe the sociodemographic aspects, clinical presentation and extrinsic conditions that may increase the risk of developing pityriasis versicolor. Materials and methods: a descriptive, cross-sectional and prospective observational study was conducted. Patients with clinical and mycological diagnosis of ptyriasis versicolor were included from january to december 2018 who attended to the Hospital Universitario Centro Dermatológico Federico Lleras Acosta. Results: a total of 42 patients were included in the study, all of them had confirmed mycological diagnosis of pityriasis versicolor. The most common location of the lesions was the anterior thorax (68%) and posterior thorax (65%), in III and IV phototypes (78.5%) with a hypochromic color. 28% had recurrent infection, with symptoms mean of 7 years before the consultation. The Besnier sign was positive in 95% of cases, 64% reported personal history of hyperhidrosis and 67% practiced some sports: diving, swimming and gymnastics. Discussion: recognizing extrinsic conditions that may increase the risk of developing pitiraisis versicolor in this population allows identifying control measures to prevent a relapse. The main factors involved in the development of pitiraisis versicolor were traveling to places with high temperatures and sport practice. In atypical clinical presentation it is mandatory to perform the mycological direct test to confirm the diagnosis. The Besnier sign is a useful method for the clinical diagnosis of pityriasis versicolor, particularly when access to direct examination is limited.

Objetivo: Aislar STEC en las heces del ganado bovino en el municipio de Ulloa, Valle del Cauca y detectar factores de virulencia asociados con la patogénesis. Materiales y métodos: Se tomaron 21 muestras provenientes de bovinos, las cuales fueron tomadas directamente del recto del animal mediante hisopos. Las muestras se procesaron hasta obtener colonias puras a las cuales se les evaluó la presencia de los genes stx1, stx2, eae, saa y hlyA mediante PCR y posteriormente, se evaluó el efecto citotóxico de las muestras positivas sobre células Vero (ATCC-CCL-81.4). Resultados: De las 21 muestras de heces de bovinos,12 presentaron bacterias con uno o ambos genes stx. Se obtuvieron 106 aislamientos totales de STEC y se observaron diferencias en cuanto a la presencia y ausencia de los genes de virulencia evaluados en los aislamientos de cada bovino, obteniendo cinco combinaciones de genes. 48 aislamientos presentaron únicamente el gen stx2 y 58 presentaron tanto el gen stx1 como el gen stx2; de los 106 aislamientos, se detectaron 44 con el gen hlyA y 57 con el gen saa. Conclusiones: Todos los sobrenadantes de STEC analizados mostraron actividad citotóxica sobre las células Vero, mientras que en ausencia de STEC las células formaron monocapa después de 48 h de incubación. Este trabajo es el primer reporte en Colombia que aporta información sobre la presencia de STEC en el ganado bovino, la presencia de factores de virulencia y el potencial efecto citotóxico que poseen estas cepas nativas.

Dysregulated expression of microRNAs (miRNAs or miRs) has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). However, their underlying role in the complication of detrusor fibrosis remains poorly understood. Therefore, this study aimed to examine the potential functional relevance of miR-363 in detrusor fibrosis of rats with streptozotocin (STZ)-induced T2DM through the predicted target gene collagen type I alpha 2 (Col1a2). Immunohistochemical analysis found an increase in the positive expression of collagen type III alpha 1 (Col3a1) and Col1a2 in detrusor tissues, where miR-363 expression was decreased. Next, gain- and loss-of-function experiments were performed to clarify the effects of miR-363 and Col1a2 on the activities of bladder detrusor cells. Of note, binding affinity between miR-363 and Col1a2 was verified by a dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. Upregulated miR-363 inhibited Col1a2 expression, which led to increased expression of B-cell lymphoma 2 (Bcl-2) and Smad7 and accelerated cell viability, along with decreases in cell apoptosis and Col3a1, Bcl-2-associated X protein (Bax), transforming growth factor (TGF)-β1, and Smad4 expressions. In conclusion, miR-363 upregulation reduces detrusor fibrosis in rats with STZ-induced T2DM through suppression of the TGF-β1/Smad signaling pathway by targeting Col1a2. Therefore, our study provided further insights for the development of new therapeutic targets for T2DM., Graphical Abstract, miR-363 can inhibit Col1a2, which promotes viability and reduces apoptosis of detrusor cells in rats with STZ-induced T2DM through the inhibition of the TGF-β1/Smad signaling pathway, which ultimately leads to the alleviation of detrusor fibrosis. This study provides new evidence regarding the functional actions of miR-363 in T2DM.

Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the "hallmarks of cancer." Their expression is dysregulated in cancer, and they are "misused" to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same "profibrotic" ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).

Background: Musculoskeletal pain (MSP) conditions are common in the educational leaning environment and are often associated with poor ergonomic conditions. Objective: This study investigated the prevalence, pattern and possible risk factors of MSP among undergraduate students of occupational therapy and physiotherapy in a South African university. Methods: A cross-sectional survey using an internet-based self-designed electronic questionnaire was used to obtain information about participants’ socio-demography, ergonomic hazards, MSP, and relevant personal information. Descriptive statistics, chi-square, and logistic regression were used in analyzing the data. Results: There were 145 participants (females 115 (79.3%); physiotherapy (74) 51.03%), making 36.7% of the present undergraduate student population in the two departments. The most prevalent ergonomic work hazards were prolonged sitting (71.7%) and repetitive movements (53.8%). The 12 months prevalence of MSP among the students was 89.7%. The pattern of MSP revealed that pain on the neck region was most prevalent (66.2%) followed by pain in the low back region (64.4%). Duration of daily travels and participation in regular exercise activities were significantly associated with the prevalence of MSP. Logistic model explained 23.6% of the variance in prevalence of MSP and correctly classified 94.1% of cases ([Formula: see text], [Formula: see text]). The right-handed students were 0.13 times more likely to present with MSP than left-handed students. Also, students who exercised regularly were 9.47 times less likely to present with MSP. Conclusion: MSP is highly prevalent among health science undergraduates and is significantly associated with sedentary postures and inadequacy in structured physical activity participation.

Objective: This study investigated the limits of stability (LOS) and the movement patterns during reaching by applying the Multi-Directional Reach Test (MDRT) in children with Down syndrome (DS) aged 7–12 years old. Methods: Thirty children with DS and 30 age and gender typical development (TD) matched children, aged 7–12 years old were recruited. Each child was asked to reach as far as possible during standing in four directions using a self-selected movement pattern. The movement patterns were classified by two experienced pediatric physical therapists. Results: The reach distance in children with DS aged 7–9 years old was significantly shorter than TD children aged 7–9 years old for the forward and backward directions. Also, the reach distance in DS children aged 7–9 years old was significantly smaller than that of TD children aged 10–12 years old for all directions. For children with DS aged 10–12 years old, the reach distance was significantly less than that of TD children only in the backward direction. All children with DS in this study adopt a hip and mixed strategy during forward and backward reaching. In contrast, TD children adopt an adult-like movement pattern. Conclusion: The boundary of stability in an anteroposterior (AP) direction of children with DS aged 7–12 years old was lesser than the matched TD children, especially for the backward direction. These findings may assist therapists in detecting postural control and balance problems in children with DS.

Background/Objective: To date, a validated Chinese (Mandarin) six-minute walk test (6MWT) translated instruction is not available. Translation of the Chinese 6MWT instruction is done in an ad hoc manner within the Chinese-speaking populations. This study aimed to develop a set of valid and reliable Chinese (Mandarin) instructions of the 6MWT. Methods: Translation was performed from the original English instruction via the recommended “Process of translation and adaptation of instruments” by the World Health Organization to generate the Chinese instructions. The Chinese instructions were tested with 52 healthy adult participants for its validity. Each participant underwent three 6MWTs and a cardiopulmonary exercise test. Randomization allowed participants to undergo the walk test in both the original English and the new Chinese instructions. Face and content validity, intra-rater and inter-rater reliability of the Chinese instructions of the 6MWT were established through the translation process. Criterion validity was established by analyzing the results of the 6MWT and cardiopulmonary exercise test. Results: Intraclass correlation coefficient for inter-rater reliability was excellent ([Formula: see text], 95% confidence [Formula: see text]–1.000). Similarly, the intra-rater reliability across the three raters was high (R1: [Formula: see text], 95% confidence interval [Formula: see text]–1.000; R2: [Formula: see text], 95% [Formula: see text]–1.000; R3: [Formula: see text], 95% [Formula: see text]–1.000). The 6-min walk distances collected from the Chinese and English instructed trials correlated positively with the maximal oxygen consumption ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]). Conclusion: This is the first study to develop and validate the Chinese (Mandarin) instructions of the 6MWT, and the translation is as reliable and valid as the original English instructions.

Instrumented gait analysis allows for the identification of walking parameters to predict cognitive decline and the worsening of dementia. The aim of this study was to perform a meta-analysis to better clarify which gait parameters are affected or modified with the progression of the dementia in a larger sample, as well as which gait assessment conditions (single-task or dual-task conditions) would be more sensitive to reflect the influence of dementia. Literature searches were conducted with the keywords “quantitative gait” OR “gait analysis” AND “dementia” AND “single-task” AND “dual-task,” and for “quantitative gait” OR “gait analysis” AND “dementia” AND “fall risk” on PubMed, EMBASE, the Cochrane Library, Scopus, and Web of Science. The results were used to perform a systematic review focussing on instrumental quantitative assessment of the walking of patients with dementia, during both single and dual tasks. The search was performed independently by two authors (C. R. and C. M.) from January 2018 to April 2020 using the PICOS criteria. Nine publications met the inclusion criteria and were included in the systematic review. Our meta-analysis showed that during a single task, most of the spatiotemporal parameters of gait discriminated best between patients with dementia and healthy controls, including speed, cadence, stride length, stride time, stride time variability, and stance time. In dual tasks, only speed, stride length, and stride time variability discriminated between the two groups. In addition, compared with spatial parameters (e.g. stride length), some temporal gait parameters were more correlated to the risk of falls during the comfortable walking in a single task, such as cadence, stride time, stride time variability, and stance time. During a dual task, only the variability of stride time was associated with the risk of falls.

Context: Consumption of khat leaves has been disseminated worldwide with the migration of its users from Arabia and Africa. Despite numerous reports regarding the associations of khat chewing with serious health impacts, a significant number of people worldwide uses khat daily, especially in its origin countries. The risk of co-administration of khat and drugs (prescription and over the-counter medications) is high among these individuals, leading to increase probability of adverse khat-drug interactions. The likelihood of khat-drug interactions could be higher than drug-drug interactions because drugs usually contain single chemical entities while almost all herbs (including khat) contain mixtures of pharmacologically active constituents. Aims: To review the literatures on how khat interacts with some drugs and whether it is favorable or not. Methods: The study was conducted as a systematic review. The electronic literature searches were made in Google search engine to access publications from databases like PubMed, Google Scholar, and Cochrane using the keywords ‘khat’, ‘Catha edulis’ in combination with the terms ‘drug interaction’, ‘adverse-effects’, ‘side effects’, ‘adverse drug reaction’, ‘safety’, and ‘toxicity’ to identify relevant articles. Results: A total of 250 articles was identified, and these articles were checked in terms of title, abstract, and content according to inclusion and exclusion criteria. Finally, 18 articles were included in the study. The khat use significantly interact with most drugs and may cause unpredictable pharmacological sequences. Conclusions: Healthcare providers suggest patients` khat abstinence during medication process. Future studies need to investigate the khat- clinical drugs interactions especially with chronic used drugs.

Context: Almost one year after the onset of COVID-19 pandemic in Wuhan, China and still no specific therapy has emerged, counting millions of dead worldwide. The association of an uncontrolled SARS-CoV-2 replication and host-dependent mechanisms in COVID-19 pathogenesis suggest that any therapeutic strategy must combine antiviral drugs and adjuvant therapy to modulate the host’s responses. Owing to the multiplicity of mechanisms involved in COVID-19 pathogenic expressions, such as severe hypoxia, excessive inflammatory reaction and impaired immune response, an emerging therapeutic paradigm is the searching for agents acting as multifunctional drugs. Methylene blue (MB), the antique medication, seems to meet the above criterion. Aims: To summarize the probable beneficial effects of MB against COVID-19 supported by a discussion of the drug mechanisms of action counteracting the pathogenic mechanisms of the disease. Methods: PubMed, Google Scholar, and Scopus databases were used to collect the biomedical research on MB, and the discussed dataset finally included 150 published articles. Those COVID-19 pathogenic pathways possibly targeted by MB were critically appraised. Results: It was found that MB may act as multimodal agent by targeting simultaneously several pathogenic mechanisms of COVID-19 as hypoxic damage, hyper-inflammatory reaction and death signaling activation. It also may act as a virucidal agent by preventing virus-induced metabolic re-orientation. Its high safety profile, low cost, along with the mechanisms discussed herein might be essential criteria to test MB as an adjuvant therapy against COVID-19. Conclusions: Overall, this critical review provides theoretical grounds for MB clinical evaluation in the therapeutic management of SARS-CoV-2 infection.

Context: Oxidative stress and formation of advanced glycation end products (AGEs), due to glycation of proteins, lipids and nucleic acids are characteristic in diabetic patients. Palmatine, a protoberberine alkaloid bioactive isolated from Coscinium fenestratum (CF) stem extract, which previously has shown to possess antidiabetic and antioxidant properties and to be able to protect the kidney and liver in a STZ-diabetic induced rat model. Aims: To evaluate the in vitro and in vivo antioxidant and anti-AGE activity of palmatine. Methods: In vitro and in vivo studies were conducted to measure radical scavenging, reducing power, inhibition of lipid peroxidation, carbonyl trapping and metal ion chelation. In vitro antiglycation activity was done using bovine serum albumin-methylglyoxal (BSA-MGO), bovine serum albumin – glucose (BSA-GLU) and glycated hemoglobin. In vivo antioxidant and antiglycation activity were used to evaluate liver and kidney extracted from STZ-induced diabetic rat after treatment with palmatine. Results: The results showed palmatine blocked the formation of AGE as shown by the results of BSA-GLU, BSA-MGO, glycated hemoglobin and inhibited the free radicals generated by DPPH, nitric oxide, hydrogen peroxide, lipid peroxidation, FRAP and metal ion chelating. It was able to stimulate in vivo the activity of catalase, super oxide dismutase and glutathione peroxidase. Conclusions: Palmatine possess antioxidant and antiglycation properties, the mechanism of action seems to be via the blockage of free radical formation, decreasing of reactive carbonyl. Further research is ongoing to determine the effect of palmatine on glyoxalase 1 and aldose reductase pathway and interaction with receptor for AGE.

Diabetic nephropathy is a serious complication of diabetes. Hyperoside has been widely reported to ameliorate diabetes-associated disease. The current study is designed to explore the mechanism of hyperoside in diabetic nephropathy. In the present study, high glucose was used to treat podocytes. Diabetic nephropathy mice models were established by high-fat feeding followed by multiple low dose injections of streptozocin. Western blot analysis was conducted for detection of extracellular matrix accumulation, inflammatory response and cell apoptosis. We found out that hyperoside improved high glucose-induced cell injury. Additionally, hyperoside prevented mice with diabetic nephropathy from diabetic symptoms and renal dysfunction. Mechanistically, hyperoside inhibited the mRNA and protein expression of APC. MiR-499-5p was found to be an upstream negative mediator of APC, and hyperoside induced the upregulation of miR-499-5p. MiR-499-5p bound with the 3' untranslated region of APC to inhibit its expression. Finally, rescue assays revealed that the suppressive effects of miR-499-5p overexpression on renal dysfunction were rescued by upregulation of APC in mice with diabetic nephropathy. In conclusion, these findings indicated that hyperoside ameliorates diabetic nephropathy via targeting the miR-499-5p/APC axis, suggesting that hyperoside may offer a potential tactic for diabetic nephropathy treatment.

Context: Immunotherapy, by directing the immune response against tumor cells, complements the oncological therapy along with conventional treatments. Thus, the monoclonal antibody nimotuzumab blocks the binding of epidermal growth factor to its receptor, interfering with cell proliferation in epithelial tumors, such as those of the head and neck. Aims: To evaluate the safety of nimotuzumab after concluded the clinical trials in epithelial tumors of the head and neck, analyzing the relation with the therapeutic compliance for the patients. Methods: A retrospective descriptive study was carried out, characterizing nine patients with epithelial tumors of the head and neck, who continued to use nimotuzumab after concluding clinical trials; and evaluating adverse effects according to severity, intensity, causality, and frequency, thus establishing the safety of this medicine. The compliance of nimotuzumab therapy was analyzed, by reviewing the administration intervals to the received doses. A descriptive statistical analysis was performed. Results: In the studied sample men predominated (eight patients: 88.89%), without significance differences in age and race. All were diagnostic with epidermal carcinomas, predominated the good differentiated (six patients: 66.67%). Five adverse effects were detected in two old patients (all not serious, light or moderate, and possible or probable, occasional or frequent), evaluating to nimotuzumab as safe medication. There was inadequate therapeutic compliance to treatment, not relation with the presented adverse effects. Conclusions: Nimotuzumab represented a safe drug after concluded the clinical trials in patients with epithelial tumors of the head and neck, without relation with the existed inadequate therapeutic compliance.

Alzheimer's disease (AD) accounts for the majority of dementia among the elderly. In addition to cognitive impairment, behavioral and psychological symptoms (BPSD) such as depression tendency and increased aggression impose a great burden on the patient. However, there is still no rational therapeutic drug for BPSD. Recently, we developed a novel AD therapeutic candidate, SAK3, and demonstrated that it improved cognitive dysfunction in AppNL-G-F/NL-G-F knock-in (NL-G-F) mice. In this study, we investigated whether acute SAK3 administration improved BPSD in addition to cognitive improvement. Acute SAK3 administration improved BPSD, including anxiolytic and depressive-like behaviors, and ameliorated aggressive behaviors. Furthermore, continuous SAK3 administration improved anxiolytic and depressive-like behaviors. Intriguingly, the anti-anxiolytic and cognitive improvement lasted two weeks after the withdrawal of SAK3, whereas the anti-depressive action did not. Taken together, SAK3 had comprehensive beneficial effects on BPSD behavior.

Context: One of the world’s most widespread and frequent liver diseases is the non-alcoholic fatty liver disease (NAFLD). Aims: To evaluate the preventives activities of Ruzu herbal bitters (RHB), which is an anti-obesity therapeutic concoction used widely in Nigeria on high–fat diet (HFD) induced NAFLD in albino Wistar rats. Methods: A total number of twenty-five rats were isolated and divided equally into five groups. Group 1, the normal control group was placed on normal rat diet and normal saline (1 mL/kg body weight daily) for twelve weeks. The remaining four groups 2-5 were placed on HFD for twelve weeks; adding to the following treatment schedules by oral gavage: group 2 received pioglitazone 4 mg/kg daily, group 3 received RHB 0.6 mL/kg daily, group 4 received normal saline 1 mL/kg daily and group 5 received fenofibrate 10 mg/kg daily (s.c). The animals were sacrificed and biochemical markers of liver function, lipid profile, glycemic index, and histopathological assessment of the liver of the rats were determined. Results: Rat treated with RHB and other treated groups significantly (p

The balance of Th17/Treg plays an important role in hepatic ischemia–reperfusion (I/R) injury. Glycolysis and glutaminolysis for energy metabolism governs the differentiate of CD 4+ T-cells to Th17/Treg. Metformin can regulate glucose metabolism in the liver, but its protective effect on I/R liver injury and its effect on Th17/Treg balancestill unknown. In this study, the I/R liver injury rat model and the primary hepatocyte hypoxia/reoxygenation injury model were established. The biochemical indexes, inflammatory factor indexes, Th17/Treg balance and energy metabolism were evaluated. RNA-seq and gene knockout cells were used to investigated the target protein of metformin. The results showed that metformin could effectively improve liver injury caused by I/R, significantly inhibit the glycolysis, improve the Th17/Treg balance, and inhibit the expression of inflammatory factors. RNA-seq results showed that TIGAR was a possible regulatory site of metformin. However, the protective effect and the regulating effect of Th17/Treg balance by metformin in TIGAR knock-out cells were disappeared. In conclusion, metformin could regulate TIGAR inhibit glycolysis then regulate Th17/Treg balance, inhibit the release of liver inflammatory factors, and finally play a role in inhibiting the occurrence of liver injury caused by ischemia-reperfusion.

Context: Medicinal plants are a highly sought-after alternative to current pharmaceutical drugs because they can be locally cultivated, inexpensive and possess minimal adverse effects. Given that Terminalia phanerophlebia (TP) possesses many useful properties and plays a role in modulating lethal diseases, the cytotoxic effect should be evaluated before its application for therapeutic use. Aims: To investigate the oxidative effect and molecular mechanisms of TP on human embryonic kidney (HEK293) cells. Methods: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and adenosine triphosphate (ATP) assays were used to determine the cell viability whilst the thiobarbituric acid reactive species (TBARS) assay was used to detect lipid peroxidation. Endogenous antioxidants, catalase, superoxide dismutase, glutathione peroxidase, heat shock protein 70 and nuclear factor erythroid 2-related factor 2 (Nrf2), were used as oxidative stress markers and were detected via western blotting. Results: A decrease in cell viability with an IC50 of 1.36 mg/mL and ATP were noted. The concentration of malondialdehyde (MDA) increased significantly (p

We performed clinical retrospective study in female cancer patients and fundamental experiments in mice, in order to clarify risk factors for paclitaxel-induced peripheral neuropathy (PIPN). In the clinical study, 131 of 189 female outpatients with cancer undergoing paclitaxel-based chemotherapy met inclusion criteria. Breast cancer survivors (n = 40) showed significantly higher overall PIPN (grades 1–4) incidence than non-breast cancer survivors (n = 91). Multivariate sub-analyses of breast cancer survivors showed that 57 years of age or older and endocrine therapy before paclitaxel treatment were significantly associated with severe PIPN (grades 2–4). The age limit was also significantly correlated with overall development of severe PIPN. In the preclinical study, female mice subjected to ovariectomy received repeated administration of paclitaxel, and mechanical nociceptive threshold was assessed by von Frey test. Ovariectomy aggravated PIPN in the mice, an effect prevented by repeated treatment with 17β-estradiol. Repeated administration of thrombomodulin alfa (TMα), known to prevent chemotherapy-induced peripheral neuropathy in rats and mice, also prevented the development of PIPN in the ovariectomized mice. Collectively, breast cancer survivors, particularly with postmenopausal estrogen decline and/or undergoing endocrine therapy, are considered a PIPN-prone subpopulation, and may require non-hormonal pharmacological intervention for PIPN in which TMα may serve as a major candidate.

Gabapentinoids such as gabapentin and pregabalin, which bind specifically to the α2δ subunit of voltage-gated Ca2+ channels, are used for first-line treatment of neuropathic pain. Here, we examined the analgesic effect of mirogabalin besilate (referred to simply as mirogabalin), a novel gabapentinoid, focusing on its action on the spinal cord and the descending noradrenergic pain inhibitory system. When administered systemically (10 and 30 mg/kg, intraperitoneally (i.p.)) and locally (10 and 30 μg, intracerebroventricularly (i.c.v.) or intrathecally (i.t.)) to mice, mirogabalin was found to exert analgesic effects on thermal (plantar test) and mechanical (von Frey test) hypersensitivity developing after partial sciatic nerve ligation. Notably, its analgesic effects (30 mg/kg, i.p. and 30 μg, i.c.v.) disappeared in mice pretreated with yohimbine hydrochloride (3 μg, i.t.). Moreover, in mice harboring a mutation in the α2δ-1 subunit resulting in substitution of arginine at position 217 with alanine to prevent gabapentinoid binding (R217A mutant mice), the analgesic effects of pregabalin and mirogabalin (30 μg, i.c.v., respectively) on mechanical hypersensitivity were almost completely suppressed. These results clearly demonstrate that mirogabalin also operates via the descending noradrenergic system, and that binding to the α2δ-1 subunit supraspinally is essential for the pain relief effect of gabapentinoids.

Context: Colorectal and breast cancer are of particular cellular preventive concern. WIDR cells are an indicator of colorectal cancer development, while HTB and 4T1 cells are involved in breast cancer. The Chromolaena odorata was reported to interfere with the growth of the three cancer cells. Aims: To evaluate the bioactivity of C. odorata against the cytotoxicity of colorectal and breast cancer cells. Methods: Ethanol extract of C. odorata leaves was examined to find chemical compounds by GC-MS, quality of antioxidants by DPPH assay, and antioxidants quantity by flavonoids and phenolic assay, whereas ionic values were evaluated by the multi-tester meter also cytotoxicity on the WiDr, HTB, and 4T1 cancer cells by MTT assay. Results: C. odorata contained six antioxidant compounds with quality above 80%. Alpha-amyrin has the most retention time of 38.112 min. The C.odorata had an antioxidant rate (IC50) higher than vitamin C. Total flavonoids (72%) higher than total phenolic (28%), and both have a significant impact on the WiDr, HTB, and 4T1 cancer cells (p0.05).The C. odorata had a higher cytotoxicity effect on the 4TI and HTB cells in breast cancer than WiDr cancer cells in colorectal cancer. Conclusions: The C. odorata has significant antioxidant quality and quantity with a stable ionic value also has a cytotoxic effect on the WIDR, HTB, and 4T1 cancer cells.

Context: Diabetes mellitus (DM) is a metabolic hyperglycemia disease caused by abnormalities in insulin secretion and the highest increase in diabetes sufferers that occurred in Southeast Asian countries, including Indonesia. The sikkam leaf (Bischofia javanica) ethanolic extract contains many secondary metabolites, and some of them are quercetin and gallic acid, which have the potential to be used as antidiabetic. Aims: To analyze apoptosis via cytochrome c in aortic tissue of DM after giving B. javanica leaves. Methods: The treatment group consisted of G0: Negative control, G1: Positive control (alloxan induction + standard feed), G2: Alloxan induction + 300 mg/kg BW of B. javanica leaves ethanol extract, G3: Alloxan induction + 600 mg/kg BW of B. javanica leaves ethanol extract, G4: Induction of alloxan + ethanol extract of B. javanica leaves 900 mg/kg BW and G5: Induction of alloxan + glibenclamide 0.5 mg/kg BW. Fourteen days later, the rats were dissected, and the aortic tissue was analyzed for apoptosis by tunnel assay and cytochrome c by immunohistochemistry. Results: There was a statistically significant difference (p

Paeoniflorin-6′-O-benzene sulfonate (CP-25) is a derivative of Paeoniflorin. We investigate beneficial effect of CP-25 on methotrexate (MTX) induced nephrotoxicity in rats. Plasma blood urea nitrogen (Bun), plasma creatinine (CREA), urine CREA and protein in the rats were quantitatively measured. Renal tissues were pathologically observed, and apoptosis was detected. Apoptosis related proteins and organic anion transporter-3 (OAT3) expression were determined by western blotting analysis. MTX induced nephrotoxicity and hematotoxicity in rats with abnormal levels of serum Bun, serum CERA, 24 h urine protein excretion, white blood cells, platelets, plateletcrit and abnormal renal pathological appearance. Either pre-treatment or treatment of CP-25 restored normal levels of hematological and renal function parameters, and improved histopathology in rats treated with MTX. CP-25 prevented MTX induced apoptosis of renal tubular cells, and the effect was further confirmed by its regulatory effects on abnormal expression of Bax, cleaved-caspase-3, cleaved-caspase-8, Cyt-c, Bcl-2. The other important finding is co-administration of CP-25 with MTX significantly increased MTX renal excretion in the damaged rats, and the effect is supposed to be linked with its regulation on abnormal renal OAT3 expression. Taken together, CP-25 shows well protective activity against MTX induced nephrotoxicity, and this effect is via its anti-apoptosis and detoxification properties.

Context: Previously, we investigated the relationship between the nature of the substituent at the 5-position of the uracil ring and the action of the corresponding uracil derivatives on immortalized lung cells. In the present study, we analyzed the impact of some 6-substituted uracil-derivatives on the regeneration potential of the lung cells (LC). Aims: To evaluate uracil derivatives capable of stimulating lung cell proliferation to create drugs that accelerate lung regeneration. Methods: The level of cell proliferation, maximum tolerated dose, and toxic effect of 6-substituted uracil derivatives (9 compounds) were studied on the immortalized lung epithelial cells and compared with the known drug 6-methyluracil. Results: The maximum tolerated dose of compounds for the LC line depends on the chemical structure of the compounds. The highest level of cell proliferation and tolerated was demonstrated when was used 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil. Conclusions: 3-methyl-6-cyclopropyluracil and 1-butyl-6-methyluracil exhibit a high proliferative activity in vitro so they could be recommended for additional studies of regenerative activity in vivo.

Hydroxyl radical (•OH) production in the rat striatum during carbon monoxide (CO) poisoning, which inhibits complex IV, was enhanced synergistically by malonate, a mitochondrial complex II inhibitor, but not N-methyl-4-phenylpyridinium or NaCN, complex I and IV inhibitors, respectively. No such enhancement appeared in the case of NaCN combined with malonate. Intrastriatal dopamine, which is involved in •OH production by malonate, did not synergistically enhance CO-induced •OH production. Diphenyleneiodonium, a nonselective NADPH oxidase inhibitor, partly suppressed the potentiation of CO-induced •OH production by malonate. Impairment of mitochondrial functions might potentiate oxidative stress and intensify CO toxicity in the brain.

This study was explored the renoprotective effect of Tongxinluo (a Traditional Chinese Medicine) on diabetic kidney disease and its underlying mechanism. The results revealed significant (p

The progressive degeneration of the excitable cells of the ear depends on the sustained excitation of the voltage-sensitive sodium channels, so the negative pharmacological modulation could be a rational therapeutic strategy against the damage of these cells. The objective was to demonstrate the effectiveness of Vinpocetine (VPC), a potent sodium channel blocker, as a treatment for acquired sensorineural hearing loss. A phase II, longitudinal and prospective open clinical study, was conducted over a period of 12 months with patients older than 18 years, to demonstrate the effectiveness of Vinpocetine (VPC) as a treatment for acquired sensorineural hearing loss, using evoked potentials, otoacoustic emissions, audiometry and logoaudiometry, analyzing the results at 6 and 12 months of treatment with Vinpocetine (30 mg/day in 3 doses). It was observed that from 0 to 6 months there was hearing impairment (which was already expected due to the age of the patients). From 6 to 12 months and from 0 to 12 months there were significant differences with a tendency towards improvement, indicating that the aforementioned deterioration not only stopped, but that with the use of vinpocetine, the hearing capacity improved. It is concluded that Vinpocetine helps to stop hearing impairment and even improve hearing.

QUESTION: What are the relative effects of group-based exercise, individual exercise and home-based exercise on clinical outcomes and costs in patients with subacromial pain?DESIGN: Multicentre, three-arm, randomised controlled trial with concealed allocation and intention-to-treat analysis.PARTICIPANTS: A total of 208 patients referred to municipal rehabilitation for management of subacromial pain in six municipalities in the Central Denmark Region.INTERVENTIONS: Patients were randomly allocated to group-based exercise rehabilitation (GE), individual exercise rehabilitation (IE) or home exercise rehabilitation (HE) for a period of 8 weeks.OUTCOME MEASURES: The primary outcome measure was the shortened version of the Disabilities of the Arm, Shoulder and Hand questionnaire (Quick-DASH). The secondary outcome measures included the EQ-5D-5L index, pain intensity, fear avoidance, psychological wellbeing, and the participant's perception of improvement and satisfaction. Healthcare and productivity costs were extracted from national health and social registers.RESULTS: There was no important between-group difference in Quick-DASH scores at 6 months: adjusted mean differences GE minus IE -2 (95% CI -9 to 5), GE minus HE -2 (95% CI -9 to 5) and HE minus IE 1 (95% CI -6 to 7). The estimates of the between-group differences were able to exclude any clinically important differences in the three regimens' effects on health benefits according to the EQ-5D-5L index and other secondary outcomes. The total average costs were highest for the IE group and lowest for the HE, but not statistically different across groups.CONCLUSION: In people with subacromial pain, group-based exercise, individually supervised exercise and home-based supervised exercise regimens have similar benefits. The home exercise intervention was associated with lowest costs.TRIAL REGISTRATION: ClinicalTrials.gov: NCT03055117.

We previously reported that brotizolam, but not suvorexant, delayed recovery from isoflurane anesthesia in mice. However, the effects of hypnotics may be altered by the circadian rhythm. Locomotor activity was measured using sighted (ICR and C57BL/6J) and blind (FVB/N and C3H/HeN) mice, and the effects of hypnotics on isoflurane anesthesia were compared during the light and dark periods. In sighted mice, recovery induced by brotizolam was delayed in the light period, while that by suvorexant was delayed in the dark period. In C57BL/6J mice, delayed recovery induced by brotizolam was marked, and that by suvorexant was observed in the light and dark periods. Locomotor activity was low in the last 6 h of the dark period in blind mice, and was similar to that in the light period. In blind mice, delayed recovery induced by brotizolam was identical in both periods, while suvorexant did not influence recovery from isoflurane anesthesia. These results suggest that the effects of hypnotics on isoflurane anesthesia are altered by the circadian rhythm and that daily light–dark stimuli may be required for the chronopharmacological effects of hypnotics.

Background Arsenic poisoning affects millions of people. The inorganic forms of arsenic are more toxic. Treatment for arsenic poisoning relies on chelation of extracellularly circulating arsenic molecules by 2,3-dimecaptosuccinic acid (DMSA). As a pharmacological intervention, DMSA is unable to chelate arsenic molecules from intracellular spaces. The consequence is continued toxicity and cell damage in the presence of DMSA. A two-pronged approach that removes extracellular arsenic, while protecting from the intracellular arsenic would provide a better pharmacotherapeutic outcome. In this study, Coenzyme Q10 (CoQ10), which has been shown to protect from intracellular organic arsenic, was administered separately or with DMSA; following oral exposure to sodium meta-arsenite (NaAsO2) – a very toxic trivalent form of inorganic arsenic. The aim was to determine if CoQ10 alone or when co-administered with DMSA would nullify arsenite-induced toxicity in mice. Methods Group one represented the control; the second group was treated with NaAsO2 (15 mg/kg) daily for 30 days, the third, fourth and fifth groups of mice were given NaAsO2 and treated with 200 mg/kg CoQ10 (30 days) and 50 mg/kg DMSA (5 days) either alone or in combination. Results Administration of CoQ10 and DMSA resulted in protection from arsenic-induced suppression of RBCs, haematocrit and hemoglobin levels. CoQ10 and DMSA protected from arsenic-induced alteration of WBCs, basophils, neutrophils, monocytes, eosinophils and platelets. Arsenite-induced dyslipidemia was nullified by administration of CoQ10 alone or in combination with DMSA. Arsenite induced a drastic depletion of the liver and brain GSH; that was significantly blocked by CoQ10 and DMSA alone or in combination. Exposure to arsenite resulted in significant elevation of liver and kidney damage markers. The histological analysis of respective organs confirmed arsenic-induced organ damage, which was ameliorated by CoQ10 alone or when co-administered with DMSA. When administered alone, DMSA did not prevent arsenic-driven tissue damage. Conclusions Findings from this study demonstrate that CoQ10 and DMSA separately or in a combination, significantly protect against arsenic-driven toxicity in mice. It is evident that with further pre-clinical and clinical studies, an adjunct therapy that incorporates CoQ10 alongside DMSA may find applications in nullifying arsenic-driven toxicity.

Kun Yang,1 Rui-Fang Qi,2 Rong-Min Li,2 Yu Zhang,3 Jing-Xia Liu1 1Child Health Care Department, Baoding Children’s Hospital, Baoding, 071000, Hebei Province, People’s Republic of China; 2Endocrinology Department, Baoding Children’s Hospital, Baoding, 071000, Hebei Province, People’s Republic of China; 3Department of Science and Education, Baoding Children’s Hospital, Baoding, 071000, Hebei Province, People’s Republic of ChinaCorrespondence: Rui-Fang QiEndocrinology Department, Baoding Children’s Hospital, 3399 North Hengxiang Street, Lianchi District, Baoding City, 071000, Hebei Province, People’s Republic of ChinaTel +86 312 3377 771Fax +86 312 3377 800Email qiruifang_dr@163.comObjective: The present study was designed to compare the changes in ovarian and uterine parameters in girls with idiopathic central precocious puberty (ICPP) before and after gonadotropin-releasing hormone analogues (GnRHa) treatment to determine which sensitive indexes effectively reflect the therapeutic effect.Methods: Sixty girls diagnosed with ICPP were enrolled in the present study. Relevant data were recorded before treatment. Leuprorelin acetate microspheres were injected at a dose of 30– 180 μg/(kg four weeks). Relevant parameters were measured and recorded every three months. Changes in each parameter were analyzed to evaluate the clinical effect of leuprorelin in the treatment of girls with ICPP.Results: 1) The height grew at a constant rate. 2) The breasts retracted. 3) Changes in pelvic parameters: the volume of the ovary and uterus and major axes of the ovary, uterus, and cervix were reduced; there were no significant changes in vaginal thickness or the uterine fundal–cervical ratio (FCR). 4) Body mass index (BMI) increased.Conclusion: Pelvic ultrasound is helpful in evaluating the efficacy of GnRHA treatment. The changes of ovarian volume and the major axes of the ovary, uterus, cervix can be used as sensitive observation indexes.Keywords: leuprorelin microspheres, idiopathic central precocious puberty in girls, pelvic ultrasound, sensitive indicators

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been the world’s driving fatal bacterial contagious disease globally. It continues a public health emergency, and around one-third of the global community has been affected by latent TB infection (LTBI). This is mostly due to the difficulty in diagnosing and treating patients with TB and LTBI. Exosomes are nanovesicles (40–100 nm) released from different cell types, containing proteins, lipids, mRNA, and miRNA, and they allow the transfer of one’s cargo to other cells. The functional and diagnostic potential of exosomal miRNAs has been demonstrated in bacterial infections, including TB. Besides, it has been recognized that cells infected by intracellular pathogens such as Mtb can be secreting an exosome, which is implicated in the infection’s fate. Exosomes, therefore, open a unique viewpoint on the investigative process of TB pathogenicity. This study explores the possible function of exosomal miRNAs as a diagnostic biomarker. Moreover, we include the latest data on the pathogenic and therapeutic role of exosomal miRNAs in TB.

Systemic lupus erythematosus is a chronic inflammatory disease, in which treatment is still limited due to suboptimal efficacy and toxicities associated with the available therapies. JAK kinases are well known to play an important role in systemic lupus erythematous. There is growing evidence that ROCK kinases are also important in disease development. In this paper, we present the results of the development of CPL409116, a dual JAK and ROCK inhibitor. The studies we performed demonstrate that this molecule is an effective JAK and ROCK inhibitor which efficiently blocks disease progression in NZBWF1/J mouse models of systemic lupus erythematous.

Di Chen, Lina Xiong, Li Zhang, Honglu Yu, Yushuang Xu, Mengmeng Wang, Xin Jiang, Zhifan Xiong Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Zhifan XiongDepartment of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430061, People’s Republic of ChinaTel +86 13517281937Email xiongzhifan@126.comPurpose: The tumor microenvironment (TME) plays a crucial role in the progression and prognosis of gastric cancer (GC). This study investigated TME-associated genes and explored their roles in the GC microenvironment.Methods: A total of 330 GC samples were extracted from TCGA. ESTIMATE and CIBERSORT algorithms were utilized to evaluate the stromal and immune scores of GC samples and the fraction of 22 immune cells infiltrated in the TME. Then, the TME-related differentially expressed genes (DEGs) were determined through integrative analysis. Protein-protein interaction (PPI) network and Cox regression analysis were conducted to analyze DEGs, and CSF1R was determined as the most crucial gene. We further probed the role of CSF1R in the GC microenvironment and evaluated the prognostic value of CSF1R.Results: We identified 560 TME-related DEGs and found CSF1R associated with the development and prognosis of GC. Further analysis showed that CSF1R was involved in immune-related signaling pathways. Furthermore, CIBERSORT analysis revealed that CSF1R expression correlated with several kinds of infiltrating immune cells, including tumor-associated macrophages (TAMs), B cells, NK cells, neutrophils, eosinophils, T cells, dendritic cells, and so on.Conclusion: In summary, CSF1R might take part in the modulation of immune-active status in the GC microenvironment and could be a promising biomarker for GC therapy and prognosis.Keywords: CSF1R, gastric cancer, tumor microenvironment, infiltrating immune cells, ESTIMATE algorithm, CIBERSORT algorithm

Shagufta Naz,1,2 Fawad Ali Shah,1 Humaira Nadeem,1 Sadia Sarwar,1 Zhen Tan,3 Muhammad Imran,1 Tahir Ali,2 Jing Bo Li,2 Shupeng Li4 1Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, 44000, Pakistan; 2Shenzhen University Clinical Research Center for Neurological Diseases, Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, People’s Republic of China; 3Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 4State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of ChinaCorrespondence: Humaira NadeemRiphah Institute of Pharmaceutical Sciences, Riphah International University, G-7/4, 7th Avenue, Islamabad, 44000, PakistanTel +92 51-2891835Fax +92 51-8350180Email humaira.nadeem@riphah.edu.pkShupeng LiState Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of ChinaEmail lisp@pku.edu.cnPurpose: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate this therapeutic failure. The current study demonstrated the synthesis of 2-aminothiazole [S3(a-d) and S5(a-d)] and 2-aminopyridine [S4(a-d) and S6(a-d)] derivatives that can target multiple cellular networks implicated in cancer development.Methods: Biological assays were performed to investigate the antioxidant and anticancer potential of synthesized compounds. Redox imbalance and oxidative stress are hallmarks of cancer, therefore, synthesized compounds were preliminarily screened for their antioxidant activity using DPPH assay, and further five derivatives S3b, S3c, S4c, S5b, and S6c, with significant antioxidant potential, were selected for investigation of in vitro anticancer potential. The cytotoxic activities were evaluated against the parent (A2780) and cisplatin-resistant (A2780CISR) ovarian cancer cell lines. Further, Molecular docking studies of active compounds were performed to determine binding affinities.Results: Results revealed that S3c, S5b, and S6c displayed promising inhibition in cisplatin-resistant cell lines in comparison to parent cells in terms of both resistance factor (RF) and IC50 values. Moreover, S3c proved to be most active compound in both parent and resistant cell lines with IC50 values 15.57 μM and 11.52 μM respectively. Our docking studies demonstrated that compounds S3c, S5b, and S6c exhibited significant binding affinity with multiple protein targets of the signaling cascade.Conclusion: Anticancer activities of compounds S3c, S5b, and S6c in cisplatin-resistant cell lines suggested that these ligands may contribute as lead compounds for the development of new anticancer drugs.Keywords: thiazole, pyridine, antioxidant activity, anticancer activity, molecular docking

Di Zhang,1,* Yafei Guo,2,* Yingli Wang2 1Department of Basic Medicine, Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Traditional Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Di Zhang Email zhangdi0801@live.cnIntroduction: Astragalus is a commonly used traditional Chinese medicine in China, which has been widely applied to enhance the immunomodulatory function of the body. The main bioactive components are complicated. To explore the role of the components, various techniques have been applied in Astragalus extraction. Membrane separation technique featured with green processing condition and high efficiency is of signification interest in the application of Astragalus treatment.Methods: In this study, a new ingredients group A4 was separated from Astragalus using membrane separation technique. The quantification and identification of A4 were achieved by UV-vis spectrometry and UPLC-MS measurements. Pathological approaches along with serum metabolomics were utilized to study the immunoprotective effects of the extracts and explore the underlying mechanisms on metabolic activity.Results: It was observed that A4 could promote the secretion of IL-2 and IFN-γ, stimulate the activated CD4+CD25+ and CD8+ CD25+ T lymphocytes in splenocytes and protect rat spleen to some extent. Seven crucial biomarkers that related to immunity regulations were screened out and identified through serum metabonomic analysis coupled with nuclear magnetic resonance. The enrichment analysis revealed that A4 alleviated the immune dysfunction by modulating amino acid metabolism and energy metabolism for the first time.Conclusion: The new ingredients group A4 isolated from the Astragalus membrane can reduce the immune dysfunction by regulating the amino acid metabolism and energy metabolism of rats.Keywords: Astragalus, membrane separation, immunomodulatory, serum metabolomics

Objective Ovarian tumour domain deubiquitinase with linear linkage specificity (OTULIN) is a potent negative regulator of the nuclear factor-κB (NF-κB) signalling pathway, and it plays a strong neuroprotective role following acute ischemic stroke. Electroacupuncture (EA) is an effective adjuvant treatment for reducing brain injury and neuroinflammation via the inhibition of NF-κB p65 nuclear translocation, but the underlying mechanism is not clear. The present study investigated whether OTULIN was necessary for EA to mitigate brain injury and glial cell activation in a transient middle cerebral artery occlusion (tMCAO) model in rats. Methods An acute ischaemic stroke model was established via tMCAO surgery in Sprague–Dawley (SD) rats. EA was performed once daily at “Baihui (GV 20)”, “Hegu (LI 4)”, and “Taichong (LR 3)” acupoints. The effect of EA on the spatiotemporal expression of OTULIN in the ischaemic penumbra of the cerebral cortex was detected within 7 days after reperfusion. The effects of OTULIN gene silencing on EA neurological deficits, cerebral infarct volume, neuronal damage, the activation of microglia and astrocytes, the contents of tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), and the expression of p-IκBa, IκBa and nucleus/cytoplasm NF-κB p65 protein were assessed. Results EA treatment increased endogenous OTULIN expression, which peaked at 48 h. Enhanced OTULIN was primarily located in neurons, but a small amount of OTULIN was detected in microglia. OTULIN silencing obviously reversed EA neuroprotection, which was demonstrated by worsened neurobehavioural performance, cerebral infarct volume and neuronal injury. The inhibitory effect of EA on the NF-κB pathway was also attenuated by enhanced IκBα phosphorylation and NF-κB p65 nuclear translocation. EA partially inhibited the transformation of microglia and astrocytes from resting states to activated states and reduced the secretion of TNF-α, IL-1β and IL-6. However, these preventive effects were reversed after the silencing of OTULIN expression. Conclusions OTULIN provides a new potential therapeutic target for EA to alleviate acute ischaemic stroke-induced brain injury and the activation of glial cells, which are related to suppression of the NF-κB signalling pathway.

Jie Sun,1,2 Xiaoquan Zhu,3 Yanyang Zhao,3 Qi Zhou,3 Ruomei Qi,3 Hui Liu1,2 1Department of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3The Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hui LiuDepartment of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Dahua Road, Dongcheng District, Beijing, 100730, People’s Republic of ChinaEmail liuhui8140@126.comPurpose: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy. Thirty to forty percent of DLBCL patients still experience relapse or develop refractory disease even with standard immunochemotherapy, leading to a poor prognosis. Currently, although several gene-based classification methods can be used to predict the prognosis of DLBCL, some patients are still unable to be classified. This study was performed to identify a novel prognostic biomarker for DLBCL.Patients and Methods: A total of 1850 B-cell non-Hodgkin lymphoma (B-NHL) patients in 8 independent datasets with microarray gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database and Lymphoma/Leukemia Molecular Profiling Project (LLMPP). The candidate genes were selected through three filters in a strict pipeline. Survival analysis was performed in two independent datasets of patients with both gene expression data and clinical information. Gene set enrichment analysis (GSEA) and the CIBERSORT algorithm were used to explore the biological functions of the genes.Results: We identified 6 candidate genes associated with the clinical outcome of DLBCL patients: CHN1, CD3D, CLU, ICOS, KLRB1 and LAT. Unlike the other five genes, CHN1 has not been previously reported to be implicated in lymphoma. We also observed that CHN1 had prognostic significance in important clinical subgroups; in particular, high CHN1 expression was significantly related to good outcomes in DLBCL patients with the germinal center B-cell-like (GCB) subtype, stage III–IV, or an International Prognostic Index (IPI) score > 2. Multivariate Cox regression analysis of the two datasets showed that CHN1 was an independent prognostic factor for DLBCL. Additionally, GSEA and CIBERSORT indicated that CHN1 was correlated with cell adhesion and T cell immune infiltration.Conclusion: Our data indicate for the first time that high CHN1 expression is associated with favorable outcomes in DLBCL patients, suggesting its potential utility as a prognostic marker in DLBCL.Keywords: CHN1, diffuse large B-cell lymphoma, prognosis, biomarker

Yingchao Fan,* Zhumeng Li,* Liting Wu, Feng Lin, Jinfeng Shao, Xiaoyan Ma, Yonghua Yao, Wenfang Zhuang, Yuan Wang Medical Laboratory, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenfang Zhuang; Yuan WangMedical Laboratory, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, No. 999 Shiguang Road, Yangpu District, Shanghai, 200438, People’s Republic of ChinaEmail wenfangzhuangmed@163.com; tv0801@163.comBackground: Increasing evidences have revealed that solasodine, isolated from Solanum sisymbriifolium fruits, has multiple functions such as anti-oxidant, anti-tumor and anti-infection. However, its role in pancreatic cancer has not been well studied.Methods: To explore the role of solasodine in pancreatic cancer, human pancreatic cell lines including SW1990 and PANC1 were treated with different concentrations of solasodine for 48 h, and cell viability was evaluated by MTT assay, cell invasion and migration were evaluated by Transwell assay. The effect of solasodine on the apoptosis of SW1990 and PANC1 cells was detected by flow cytometry. To further explore the antitumor effect of solasodine in vivo, an SW1990 tumor-bearing mouse model was constructed. The effects of solasodine on cytokines in the serum of SW1990 tumor-bearing mice were also evaluated by ELISA assay.Results: Specifically, in vitro, solasodine could significantly inhibit the proliferation of pancreatic cancer cell lines SW1990 and PANC1 cells. Flow cytometric analysis indicated that solasodine could induce apoptosis of SW1990 and PANC1 cells. Western blot assay indicated that solasodine could significantly inhibit the activation of Cox-2/Akt/GSK3β signal pathway. Meanwhile, the release of Cytochrome c from mitochondria to cytoplasm which can raise the caspases cascade (C-caspase 3 and C-caspase 9) was significantly enhanced by solasodine. In vivo, the results showed that solasodine had potent anti-tumor activities with a lower cytotoxicity. In addition, the serum TNF-α, IL-2 and IFN-γ levels in SW1990 tumor-bearing mice after the treatment of solasodine was significantly increased.Conclusion: Taken together, our results suggested that the solasodine could prevent the progression of pancreatic cancer by inhibiting proliferation and promoting apoptosis, as well as stimulating immunity, suggesting that solasodine might be a potential therapeutic strategy for pancreatic cancer.Keywords: pancreatic cancer, solasodine, Cox-2/Akt/GSK3β signal pathway, apoptosis, apoptosis

Background: The problem of E-waste has assumed great proportions and as a responsible member of the society, the dentist should be aware of the various aspects of E-waste. Objectives: The current study was proposed to assess the improvement in awareness of dental students regarding various aspects of e-waste hazards and management prior and subsequent to an educational intervention session on E waste. Methods: The study was carried amongst 100 first year dental students after prior administrative permission and consent from higher authorities. The knowledge regarding E-waste was assessed by a self-administered questionnaire before and after and educational intervention. After checking for completeness of data, the responses were entered and subjected to descriptive and inferential statistical analysis. Results: Majority 59 (62.1%) knew that improper E-waste disposal posed a serious threat to environment and this score further improved significantly to 90 (94.7%) after the educational intervention. There was a highly statistically significant increase in the knowledge (p

Chen-jian Zhou,1 Hui-jun Wang,2 Chun-yan Zhou,2 Chao-fan Li,2 Ming-Jia Zhu,2 Xiang-jun Qiu2 1Department of Pharmacy, Wenzhou Central Hospital, Wenzhou, 325027, People’s Republic of China; 2School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuSchool of Basic Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A method for the determination of selinexor by UPLC-MS/MS was established to study the effect of posaconazole on the pharmacokinetics of selinexor in rats.Methods: The experiment rats were divided into group A (0.5% CMC-Na) and group B (posaconazole, 20 mg/kg), 6 rats in each group. 30 minutes after administration of 0.5% CMC-Na or posaconazole, all the rats were given selinexor (8 mg/kg), and plasma samples were collected. The plasma samples underwent acetonitrile protein precipitation, and were separated by UPLC on an Acquity UPLC BEH C18 column with gradient elution. Acetonitrile and 0.1% formic acid were used as the mobile phases. The analyte detection was used a Xevo TQ-S triple quadrupole tandem mass spectrometer and multiple reaction monitoring (MRM) for analyte monitoring. We use acetonitrile for protein precipitation.Results: Selinexor had good linearity (1.0– 1000 ng/mL, r2= 0.996 2), and the accuracy and precision, recovery rate and matrix effects(ME) were also met the FDA approval guidelines. Compared with group A, the Cmax, AUC(0−t) and AUC(0−∞) of selinexor in group B increased by 60.33%, 48.28% and 48.27%, and Tmax increased by 53.92%, CLz/F reduced by 32.08%.Conclusion: This bioanalysis method had been applied to the study of drug interactions in rats. It was found that posaconazole significantly increased the concentration of selinexor in rats. Therefore, when selinexor and posaconazole are combined, we should pay attention to the possible drug–drug interactions to reduce adverse reactions.Keywords: UPLC-MS/MS, selinexor, posaconazole, pharmacokinetics, DDIs, rats

Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB1 and CB2, and Δ9-tetrahydrocannabinol activates both of them, providing an analgesic effect but also psychoactive side effects. The psychoactive side effects are considered to be caused by activation of CB1, but not CB2. ABK5 is a CB2 subtype selective agonist that has a very different structure from known cannabinoid receptor agonists. Here, we report anti-inflammatory effects of ABK5 using the T-cell line Jurkat cells, and antinociceptive effect in an inflammatory pain model in rats. Production of the cytokines IL-2 and TNF-α was measured in stimulated Jurkat cells and MOLT-4 cells, and CXCL12-mediated chemotaxis of Jurkat cells was evaluated by a transwell migration assay. Anti-inflammatory and antinociceptive effects of ABK5 were also evaluated in a hindpaw CFA model in rats. ABK5 significantly decreased production of IL-2 and TNF-α measured as both mRNA and protein levels, and reduced chemotaxis towards CXCL12. It also attenuated edema and increased mechanical threshold in the hindpaw of CFA-treated rats. These results suggest that ABK5 is a good lead compound for the development of potential anti-inflammatory and analgesic agents.

BackgroundThe recognition, prevention and treatment of venous thromboembolism (VTE) remains a major challenge in the face of the recent COVID-19 pandemic which has been associated with significant cardiovascular, renal, respiratory and hematologic complications related to hypercoagulability. There has been little literature thus far on the utility of screening ultrasound and the role of the clinical pharmacist in treating these patients.MethodsWe present a prospective pilot program of thirty-one consecutive COVID-19 patients who were provided four extremity screening ultrasounds for VTE on admission. This was coordinated by a clinical pharmacist as part of a multidisciplinary approach. Quantitative and qualitative data were recorded with the goal of describing the utility of the clinical pharmacist in ultrasound screening. Data collected include demographics, information on clinical symptoms or signs at presentation, and laboratory and radiologic results during the hospitalization from each individual electronic medical record.ResultsNine of the thirty-one patients presented with VTE. Of the nine patients, there were twenty-two total clotted vessels, all of which were asymptomatic. The clinical pharmacist, as the coordinator for a multidisciplinary COVID-19 associated coagulopathy management team, drafted a screening and treatment protocol for anticoagulation prophylaxis and therapy of VTE after ultrasound findings.ConclusionVTE screening of hospitalized COVID-19 patients reveals a significant number of asymptomatic VTEs and justifies diagnostic, prophylactic, and treatment measures coordinated by a clinical pharmacist.

Introduction: Subjective well-being (SWB) is known to have tremendous influence on physical and mental health. Subjective well-being of medical students who undergo a rigorous and stressful academic activity in India, is important issue of research. The study was aimed to assess the SWB of medical students in the eastern part of India and its correlates. Methods: A cross-sectional study was conducted among 166 students of a medical college of Eastern India during December, 2019 to March, 2020. SWB was assessed using WHO-5 well-being index. The respondents were enquired about their individual characteristics, perceptions and certain behaviors. Bivariate analysis was used to examine association between SWB and its correlates. Results: Nearly 60% of the participants were male (99, 59.6%); mean age of the participants were 19.8 (SD: 1.2) years. Almost four out of ten respondents had poor subjective well-being. SWB was positively associated with perceived SES and perceived family support. Mean standardized well-being score was significantly higher among participants who underwent regular physical exercise; who had higher frequency of exposure to humor; had been appreciated for any accomplishment; had felt real emotions like love and shared fondness/love through hugging or shaking hands in last 2 weeks. Conclusions: A considerable proportion of students had poor subjective well-being and physical exercise, appreciation and inculcating positive emotion might improve the situation.