Notes

Medicine repurposing for COVID-19: Techniques, challenges and also offering applicants.
The actual RADx Tech Scientific studies Primary: One with regard to Instructional Based Scientific studies.
The function of Dysbiosis throughout Significantly Ill Patients With COVID-19 along with Severe Breathing Distress Affliction.
Heart failure with reduced left ventricular ejection fraction is a progressive disease that claims > 352,000 lives annually in the United States alone. Despite the development of an extensive array of pharmacologic and device therapies, prognosis remains poor. Disruption in autonomic balance in the form of heightened sympathetic nerve activity and reduced vagal tone have been established as major causes of heart failure progression. Interest in chronic neuromodulation mediated by vagus nerve stimulation (VNS) has intensified in recent years. This review focuses on four main goals (1) To review the preclinical evidence that supports the concept of a cardioprotective effect of VNS on autonomic function and cardiac electrical stability along with the underlying putative mechanisms. (2) To present the initial clinical experience with chronic VNS in patients with heart failure and highlight the controversial aspects of the findings. (3) To discuss the latest findings of the multifactorial effects of VNS on autonomic tone, baroreceptor sensitivity, and cardiac electrical stability and the state-of-the-art methods employed to monitor these relationships. (4) To discuss the implications of the current findings and the gaps in knowledge that require attention in future investigations.This review aimed to analyze the scientific literature on pancreatic diseases (especially exocrine pancreatic insufficiency). This review also describes the correlation between the physiological fitness of the pancreas and obesity. The influence of the pancreatic exocrine function on the development of the organism of adults and adolescents was also described. The results of piglet studies available in the literature were cited as an established model used to optimize treatments for pancreatic diseases in humans. The pancreas has an exocrine and hormonal function. Consequently, it is one of the key internal organs in animals and humans. Pancreatic diseases are usually severe and particularly troublesome. A properly composed diet and taken dietary supplements significantly improve the patient's well-being, as well as the course of the disease. Therefore, a diet and a healthy lifestyle positively affect maintaining the optimal physiological efficiency of the pancreas.The relationship between the muscle deoxygenation breakpoint (Deoxy-BP) measured with near-infrared spectroscopy (NIRS), and the respiratory compensation point (RCP) has been well established. This relationship has also been reported using wearable NIRS, however not in locomotor and non-locomotor muscles simultaneously during whole-body cycling exercise. Our aim was to measure muscle oxygen saturation (SmO2) using wearable NIRS sensors, and to compare the Deoxy-BPs at each muscle with RCP during a ramp cycling exercise test. Twenty-two trained female and male cyclists completed a ramp exercise test to task intolerance on a cycling ergometer, at a ramp rate of 1 W every 2 s (30 W/min). SmO2 was recorded at the subjects' right vastus lateralis (VL) and right lateral deltoid. SmO2 and the Deoxy-BPs were assessed using a piecewise double-linear regression model. Ventilation (V̇E) and gas exchange were recorded, and RCP was determined from V̇E and gas exchange using a V-slope method and confirmed by two physiologists. The SmO2 profiles of both muscles and gas exchange responses are reported as V̇O2, power output (W), and time of occurrence (TO). SmO2 profiles at both muscles displayed a near-plateau or breakpoint response near the RCP. No differences were detected between the mean RCP and mean Deoxy-BP from either the locomotor or non-locomotor muscles; however, a high degree of individual variability was observed in the timing and order of occurrence of the specific breakpoints. These findings add insight into the relationships between ventilatory, locomotor, and non-locomotor muscle physiological breakpoints. While identifying a similar relationship between these breakpoints, individual variability was high; hence, caution is advised when using wearable NIRS to estimate RCP in an incremental ramp test.Paroxysmal atrial fibrillation (PAF) may related to the risk of thromboembolism and is the most common cardiac risk factor of cryptogenic stroke (CS). Due to its paroxysmal characteristics, it is usually diagnosed by continuous long-term ECG. Patients with paroxysmal atrial fibrillation usually have premature beats at the same time which is easy to be confused with the rhythm of atrial fibrillation. Therefore, in this article, we designed a screening algorithm for single premature beat, multi premature beats, bigeminy and trigeminy premature beats, according to their rhythm characteristics to reduce false detection caused by premature beats during the PAF detection process. The proposed elimination method was verified on ECG segments with different types of premature beats, and tested on long-term ECG data of PAF patients. ECG segments of different kinds of premature beats were selected from MIT Atrial Fibrillation database (MIT-AFDB), MIT-BIH Arrhythmia database (MIT-AR) and wearable ECG data from the China Physiological Signal Challenge 2021 (CPSC 2021). The proposed method can effectively eliminate single premature beat segments with 99.5% accuracy, and it also can eliminate more than 95% of ECG segments with other types of premature beats. We designed PAF-score as a new index to evaluate the accuracy of detection, and we also calculate the misjudged and missed segments to comprehensively evaluate the PAF detection algorithm. The proposed method get a PAF-score of 0.912 on MIT-AFDB. The proposed method also has the potential to implant low computing power wearable devices for real-time analysis.Astaxanthin (Axn), a feed additive, is becoming increasingly important for modulating the metabolism, growth, development, and reproduction of aquatic organisms in aquaculture. In this study, Exopalaemon carinicauda (E. carinicauda) is an economically important fishery species in China that has been found to exhibit increased body weight following Axn feeding as compared to a standard diet. The antioxidant, transcriptomic, and metabolomic analyses of the response of E. carinicauda after Axn feeding were investigated. Axn could reduce the content of malondialdehyde and increase the activities of various antioxidant enzymes, which also proved that axn can improve the antioxidant capacity Transcriptomic analysis suggested that synthesis and secretion of immune proteins, cytoskeleton structure, and apoptosis signaling were altered after Axn feeding. The metabolic response to axn mainly includes the up regulation of different amino acids and the change of unsaturated fatty acids. Combined transcriptomic and metabolomic data indicated that amino acid metabolic pathways were upregulated in the muscles after Axn feeding. For good measure, energy metabolism pathways were upregulated in the muscles to improve ATP and unsaturated fatty acid production. This study provides key information to increase our understanding of the effects of Axn in shrimp.
Cooling by cardiopulmonary bypass (CPB) to deep hypothermic cardiac arrest (HCA) for cardiac surgical interventions, followed by CPB-rewarming is performed on a routine basis with relatively low mortality. In contrast, victims of deep accidental hypothermia rewarmed with CPB generally have a much worse prognosis. Thus, we have developed an intact pig model to compare effects on perfusion pressures and global oxygen delivery (DO
) during immersion cooling versus cooling by CPB. Further, we compared the effects of CPB-rewarming between groups, to restitute cardiovascular function, brain blood flow, and brain metabolism.

Total sixteen healthy, anesthetized juvenile (2-3 months) castrated male pigs were randomized in a prospective, open placebo-controlled experimental study to immersion cooling (IMM
,
= 8), or cooling by CPB (CPB
,
= 8). After 75 minutes of deep HCA in both groups, pigs were rewarmed by CPB. After weaning from CPB surviving animals were observed for 2 h before euthanasia.

Surviischemic damage may have taken place during cooling in the brain of IMM c animals below 25°C. The need for prolonged extracorporeal membrane oxygenation (ECMO) should be considered in all victims of accidental hypothermic arrest that cannot be weaned from CPB immediately after rewarming.Acute Lung Injury (ALI) is characterized by widespread inflammation which in its severe form, Acute Respiratory Distress Syndrome (ARDS), leads to compromise in respiration causing hypoxemia and death in a substantial number of affected individuals. Loss of endothelial barrier integrity, pneumocyte necrosis, and circulating leukocyte recruitment into the injured lung are recognized mechanisms that contribute to the progression of ALI/ARDS. Additionally, damage to the pulmonary microvasculature by Gram-negative and positive bacteria or viruses (e.g., Escherichia coli, SARS-Cov-2) leads to increased protein and fluid permeability and interstitial edema, further impairing lung function. While most of the vascular leakage is attributed to loss of inter-endothelial junctional integrity, studies in animal models suggest that transendothelial transport of protein through caveolar vesicles, known as transcytosis, occurs in the early phase of ALI/ARDS. Here, we discuss the role of transcytosis in healthy and injured endothelium and highlight recent studies that have contributed to our understanding of the process during ALI/ARDS. We also cover potential approaches that utilize caveolar transport to deliver therapeutics to the lungs which may prevent further injury or improve recovery.Cross-sectional studies have reported lower pulmonary and aerobic function during exercise in people with cystic fibrosis-related diabetes (CFRD) compared to non-CFRD counterparts. However, this association has yet to be longitudinally investigated. Therefore, this study examines these differences over time between people with cystic fibrosis (CF) of differing glycaemic status. Annual review data, including cardiopulmonary exercise tests and pulmonary function tests, were retrospectively analysed at baseline (T0, n = 82) and at a one-year follow-up (T1, n = 54). Data was analysed in three groups normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and CFRD. Further analyses were undertaken, with a dichotomous split of NGT and a combined IGT/CFRD group. At baseline, a significant reduction in the majority of variables, including forced expiratory volume in one second (FEV1) and maximal oxygen uptake (VO2max), was observed in the CFRD (n = 19) group compared to NGT (n = 58). At follow-up, no significant differences were observed, and no interaction effect between CFRD status and time was identified. FEV1 and VO2max presented with varying directions and magnitudes of change within patients. In summary, patients with CFRD have a reduced aerobic and pulmonary function compared to non-CFRD counterparts, although such changes disappeared at follow up. Varying responses for FEV1 and VO2max highlight the need to consider both variables as independent markers of function in CF.Connexins are a family of proteins that can form two distinct types of channels hemichannels and gap junction channels. Hemichannels are composed of six connexin subunits and when open allow for exchanges between the cytoplasm and the extracellular milieu. Gap junction channels are formed by head-to-head docking of two hemichannels in series, each one from one of two adjacent cells. These channels allow for exchanges between the cytoplasms of contacting cells. The lens is a transparent structure located in the eye that focuses light on the retina. The transparency of the lens depends on its lack of blood irrigation and the absence of organelles in its cells. To survive such complex metabolic scenario, lens cells express Cx43, Cx46 and Cx50, three connexins isoforms that form hemichannels and gap junction channels that allow for metabolic cooperation between lens cells. This review focuses on the roles of Cx46 hemichannels and gap junction channels in the lens under physiological conditions and in the formation of cataracts, with emphasis on the modulation by posttranslational modifications.Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan-Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro +/+ and Ptpro -/- mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.Epilepsy and depression are both serious and potentially disabling conditions which often coexist-bidirectional relationship between the two disorders has been observed. Comorbidity between depression and epilepsy can be attributed to underlying common pathophysiological mechanisms, psychiatric side effect of antiepileptic medications and psychological response to stress in people with chronic, neurological condition. Despite high prevalence of depressive symptoms in patients with epilepsy, current evidence of the effectiveness of antidepressant therapy in this group of patients is very limited. Vortioxetine is an antidepressant with multimodal activity, very good treatment tolerability, low risk of inducing pharmacokinetic interactions, relative safety of treatment in patients with somatic comorbidities, low risk of causing sedation, sexual dysfunctions and metabolic side effects. Vortioxetine seems to be a promising treatment option for depressed patients with cognitive dysfunctions, anhedonia and anxiety. ervation period during vortioxetine therapy ranged from 2 to 48 months. In conclusion, vortioxetine can be a promising treatment option in patients with epilepsy and comorbid depressive symptoms.Although studies have shown that basic fibroblast growth factor (bFGF) can activate autophagy and promote peripheral nerve repair, the role and the molecular mechanism of action of bFGF in the facial nerve are not clear. In this study, a thermosensitive in situ forming poloxamer hydrogel was used as a vehicle to deliver bFGF for treating facial nerve injury (FNI) in the rat model. Using H&E and Masson's staining, we found that bFGF hydrogel can promote the functional recovery and regeneration of the facial nerve. Furthermore, studies on the mechanism showed that bFGF can promote FNI recovery by promoting autophagy and inhibiting apoptosis. Additionally, this study demonstrated that the role of hydrogel binding bFGF in nerve repair was mediated through the activation of the PAK1 signaling pathway in Schwann cells (SCs). These results indicated that poloxamer thermosensitive hydrogel loaded with bFGF can significantly restore the morphology and function of the injured facial nerve by promoting autophagy and inhibiting apoptosis by activating the PAK1 pathway, which can provide a promising strategy for FNI recovery.In neuropathic pain (NP), injury or diseases of the somatosensory system often result in highly debilitating chronic pain. Currently, there is no effective drug for the complete and definitive treatment of NP. We investigated the therapeutic potential of conditioned medium (CM) derived from stem cells from human exfoliated deciduous teeth (SHED-CM) against NP using a mouse partial sciatic nerve ligation (PSL) model. Abnormal pain sensation, such as tactile allodynia and hyperalgesia, can be caused by PSL. In the behavioral test, intravenous administration of SHED-CM greatly improved the PSL-induced hypersensitivity. We found that treatment with SHED-CM resulted in the recruitment of M2 macrophages in the injured sciatic nerve and ipsilateral L4/L5 dorsal root ganglion and suppressed microglial activation in the spinal cord. Notably, specific depletion of the anti-inflammatory M2 macrophages by mannosylated-Clodrosome markedly reduced the antinociceptive effect of SHED-CM. Intravenous administration of CM from M2 induced by SHED-CM (M2-CM) ameliorated the PSL-induced hypersensitivity. We found that M2-CM directly suppressed the expression of nociceptive receptors as well as proinflammatory mediators in Schwann cells. Taken together, our data suggest that SHED-CM ameliorates NP through the induction of the analgesic anti-inflammatory M2 macrophages. Thus, SHED-CM may be a novel therapeutic candidate for NP.Background There is no effective medication for treatment or prevention of hepatic ischemia-reperfusion (HIR) injury caused by liver transplantation and hepatectomy. This study aimed to investigate the therapeutic effects of metformin on HIR injury and related myocardial injury in rats. Methods Wistar male rats were randomly divided into four groups sham group, ischemia-reperfusion group, and IR group treated with metformin 150 mg/kg and 100 mg/kg. Wistar male rats were administered metformin 150 mg/kg, 100 mg/kg or saline 30 min pre-operative and underwent 15 min ischemia and 6 h reperfusion (n = 4). Results Metformin significantly alleviates the injury caused by HIR. Administration of metformin resulted in a significant reduction in the serum levels of alanine transaminase and aspartate transaminase and the activity of malondialdehyde, creatine kinase-MB, and lactate dehydrogenase but maintained high catalase and superoxide dismutase activity. Metformin significantly inhibited the IR-induced elevation of tumor necrosis factor-α in liver and heart tissue. Conclusion Metformin can alleviate hepatic and myocardial injury induced by IR by inhibiting oxidative stress.Objective Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors. Methods This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated. Results Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3-4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3-4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths. Conclusion For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.Cardiometabolic disorders (CMD) have become a global emergency and increasing burden on health and economic problems. Due to the increasing need for new drugs for cardiometabolic diseases, many alternative medicines from plants have been considered and studied. Moringa oleifera Lam. (MO), one of the native plants from several Asian countries, has been used empirically by people for various kinds of illnesses. In the present systematic review, we aimed to investigate the recent studies of MO in CMD and its possible mechanism of action. Selleckchem Panobinostat We systematically searched from three databases and summarized the data. This review includes a total of 108 papers in nonclinical studies and clinical trials of MO in cardiometabolic-related disorders. Moringa oleifera, extracts or isolated compound, exerts its effect on CMD through its antioxidative, anti-inflammatory actions resulting in the modulation in glucose and lipid metabolism and the preservation of target organ damage. Several studies supported the beneficial effect of MO in regulating the gut microbiome, which generates the diversity of gut microbiota and reduces the number of harmful bacteria in the caecum. Molecular actions that have been studied include the suppression of NF-kB translocation, upregulation of the Nrf2/Keap1 pathway, stimulation of total antioxidant capacity by reducing PKCζ activation, and inhibiting the Nox4 protein expression and several other proposed mechanisms. The present review found substantial evidence supporting the potential benefits of Moringa oleifera in cardiovascular or metabolic disorders.Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the prognosis of non-small cell lung cancer (NSCLC) with EGFR mutation-positive. Although third-generation EGFR-TKI osimertinib is demonstrated with superior efficacy compared with first-generation EGFR-TKIs, acquired resistance to EGFR-TKIs remains the bottleneck. The Chinese herbal medicine (CHM) Yiqi-Yangyin-Jiedu decoction (YYJD) has been shown to delay acquired resistance to first-generation EGFR-TKIs in the CATLA study, but there is no high-level evidence for its effect when combined with osimertinib. This trial aims to evaluate the efficacy and safety of YYJD combined with osimertinib as first-line treatment in EGFR mutation-positive advanced NSCLC. Methods This is a double-blind, multi-center, randomized controlled trial conducted in eight hospitals in China. A total of 314 participants will be randomly assigned to the osimertinib plus YYJD group (O+YYJD) or the osimertinib plus placebo group (O+placebo). Selleckchem Panobinostat Treatment will last until disease progression or death. Patients diagnosed with advanced NSCLC harboring EGFR Ex19del or L858R will be enrolled if they are ready to take osimertinib as first-line treatment, aged 18-74 years old, and provide signed informed consent. The primary outcome is progression-free survival (PFS). The secondary outcomes include a comparison of overall survival (OS), objective response rate (ORR), disease control rate (DCR), and quality of life (QoL). The analysis will be based on intention-to-treat and per-protocol subject analysis principles. Discussion The goal of this trial is to evaluate the efficacy and safety of YYJD when added to osimertinib as first-line treatment in EGFR mutation-positive advanced NSCLC.Objectives To determine the prevalence and load of Ureaplasma spp. DNA in the cervical fluid of women with singleton pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to intra-amniotic infection, sterile intra-amniotic inflammation, and colonization of the amniotic fluid. Methods A total of 217 women with PPROM between gestational ages 24 + 0 and 33 + 6 weeks were included in this study. Paired amniotic and cervical fluid samples were collected at the time of admission via transabdominal amniocentesis and using a Dacron polyester swab, respectively. Microbial invasion of the amniotic cavity was diagnosed using a combination of culture and molecular biology methods. Intra-amniotic inflammation was determined based on the concentration of interleukin-6 in the amniotic fluid. Based on the presence or absence of these conditions, the women were stratified into the following subgroups intra-amniotic infection (with both), sterile intra-amniotic inflammation (with inflammation onf the amniotic fluid was associated with a higher prevalence and/or load of Ureaplasma spp. DNA in the cervical fluid than the absence of intra-amniotic complications.Pulmonary fibrosis (PF) is a progressive disease characterized by extracellular matrix (ECM) deposition that destroys the normal structure of the lung parenchyma, which is classified into two successive inflammatory and fibrotic phases. To investigate the anti-inflammatory and anti-fibrotic roles of miR-130a-3p in mice with bleomycin (BLM)-induced PF and the underlying mechanism, we performed single-cell RNA-sequencing analysis, which demonstrated that BLM increased/decreased the percentage of macrophages and fibroblasts/epithelial cells in PF lungs, respectively. The differentially expressed genes were enriched in PPAR signaling pathway and lysosome, ECM-receptor interaction and ribosome, and metabolism reaction. Time-course studies demonstrated that the inflammation-related factors increased significantly at day 7 (inflammatory phase), whereas the fibrosis-related factors increased at day 28 (fibrotic phase) after BLM exposure. Meanwhile, miR-130a-3p could ameliorate pulmonary lesions by downregulating the secretion of inflammatory cytokines (IL-1β, IL-6, TNF-α, and TGF-β1) and the deposition of ECM (α-SMA, FN, HYP, and collagen) in the inflammatory and fibrotic phase, respectively. In the LPS-induced inflammatory cell model, the upregulation of miR-130a-3p was mainly achieved by the activation of the NF-κB signaling pathway, which suppressed the proinflammatory factor TNF-α. Comparatively, the TGF-β/Smad signaling pathway was inhibited by miR-130a-3p targeting TGF-βRII in the TGF-β1-deduced fibrotic cell model. The evidence supports that miR-130a-3p exerts an anti-inflammatory and anti-fibrotic effect in BLM-induced PF, implying a potential pharmacological agent in the therapy of PF patients.Acute appendicitis is the most common surgical emergency in children. Despite the high incidence rate of appendicitis, it is sometimes misdiagnosed or missed. Complex appendicitis (CA) in children is characterized by a critical condition, several complications, and high mortality. Precision distinguishing between simple appendicitis and CA correctly is key to choosing appropriate treatment. A safe, cheap, rapid, extensive and accurate diagnostic marker of appendicitis will be of great significance for emergency general surgeons to treat suspected CA. Many studies have investigated possible diagnostic markers for the diagnosis of CA in children. In this study, studies related to CA in children in recent years are summarized, and the related markers and scoring system for the diagnosis of CA in children are summarized.Background Diabetes is among the top ten most prevalent diseases in Pakistan, and the availability of medicines to treat the disease is vital for a great percentage of the country's population. Insulin was discovered a century ago; however, its access in several parts of the globe remains an issue. This study aims to evaluate prices, availability, and affordability (access components) of insulin and five comparator medicine access in Pakistan. Methods A nationwide cross-sectional survey was conducted to evaluate the access to insulin and some comparator medicines in eight cities of Pakistan, using a modified WHO/HAI methodology. The survey included 80 medicine outlets, i.e., 40 private pharmacies and 40 public hospitals. Data for every unique insulin product available in the Pakistani market were obtained, including five comparator medicines. Percentage availability, median unit prices (MUPs), and affordability (the number of days' wages (NDWs) required for a month's course by the lowest-paid unskilled governman and analog insulin were 1.38 and 5.06. Conclusion In Pakistan, the insulin availability falls short of the WHO's benchmark of 80%. Insulin continues to be unaffordable in both private and government sectors. To increase insulin access, the government should optimize insulin procurement at all levels, promote local production, enforce biosimilar prescribing, and provide financial subsidies for these products.Background Reynoutria multiflora (Thunb.) Moldenke (PM) is a widely-used medicinal plant in China, whose root and stem are included in the Chinese Pharmacopoeia as Polygoni Multiflori Radix (RPM), Polygoni Multiflori Radix Preparata (PMP), and Polygoni Multiflori Caulis (PMC). The hepatotoxicity of RPM and PMP is concerned by the public, while the risk of PMC is ignored. Purpose Here, we investigate the potential risks for PMC-induced liver injury from clinical, chemical, and animal features. Study design First, we analyzed the 12-month usage of RPM, PMP, and PMC in Longhua Hospital. Second, we determined the contents of gallic acid, cis-2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (cis-SG), trans-2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (trans-SG), emodin-8-O-β-D-glucoside (EG), physcion-8-O-β-D-glucoside (PG), emodin, and physcion in the water extracts from 15 batches of RPM, PMP, and PMC. Third, we probed the hepatotoxic effect of RPM, PMP, and PMC in mice and explored the mechanism of cis-SG and trans-SG causing the liver injury at the dosages based on our results from the first and second parts. Results PMC had nearly five times the amount of usage in both outpatient prescriptions and inpatient orders than RPM and PMP. Overall, 68% dosage of PMC was 30 g. The contents of cis-SG, trans-SG, and emodin in PMC water extracts were significantly lower than those in RPM and PMP water extracts. PMC induced milder idiosyncratic liver injury for its lower content of cis-SG and trans-SG than its root counterparts. Conclusion The potential risks for PMC-induced liver injury should be fully aware of.Background Tinnitus is a common problem worldwide. There is still no effective method to cure it. Traditional Chinese medicine (TCM) may be a potentially effective treatment approach for tinnitus. However, there is still no clinical trial with scientifically rigorous methodology to evaluate the treatment effect of TCM for tinnitus. Therefore, we propose a pilot study to inform the feasibility of a future full-scale RCT to establish the efficacy of TCM formula for tinnitus. link= Selleckchem Panobinostat Objectives The aim of this study is to determine the feasibility of a full-scale RCT and explore whether a TCM formula (BHT) has an additional effect on improving tinnitus when compared to informative counseling alone. link2 Design An assessor-blinded, randomized, controlled clinical trial is used. Participants Twenty-four patients with chronic subjective tinnitus will be enrolled. Interventions The patients will be allocated randomly to receive a TCM formula (BHT, Bushen Huoxue Tongluo) and informative counseling or informative counseling alone. The oral BHT herbal granules will be taken twice per day continuously for 8 weeks. Main outcome measures The primary outcomes include recruitment rate, intervention completion rate, and data completion rate to evaluate the feasibility. The secondary outcomes include Tinnitus Handicap Inventory, tinnitus functional index, tinnitus sensation level, self-rated visual analogue scale on tinnitus loudness and annoyance, Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and adverse event. The outcome measures will be collected at baseline, end of treatment, and 4-week follow-up. Discussion This trial is currently ongoing and is recruiting patients. The expected study results will find some preliminary evidence about the clinical effectiveness of BHT on chronic tinnitus and will also determine if it is feasible to conduct a full-scale RCT of BHT and identify the necessary changes to the protocol if possible.Long non-coding RNA (lncRNA) is involved in the regulation of rheumatoid arthritis (RA) and many other diseases. In this study, a new lncRNA, NR-133666, was identified to be highly expressed in the adjuvant-induced arthritis rat model using the Agilent lncRNA microarray assay. qRT-PCR verified that NR-133666 was upregulated in fibroblast-like synoviocyte of a collagen-induced arthritis (CIA) rat model. Fluorescence in situ hybridization analysis showed that NR-133666 is mainly expressed in the cytoplasm of collagen-induced arthritis FLS. MTT assay and EdU staining results showed that the proliferation of CIA FLS was inhibited after NR-133666 was knocked down, and the wound healing assay showed that the migration of CIA FLS was also suppressed. Dual luciferase detection was used to confirm the relationship among NR-133666, miR-133c and MAPK1. MAPK1 is the target gene of miR-133c, where NR-133666 acts as a sponge of miR-133c to reduce the inhibitory effect of miR-133c on MAPK1. Overexpression of NR-133666 and MAPK1 can promote the proliferation and migration of CIA FLS, and overexpression of miR-133c can reverse this phenomenon. Western blot indicated that it may be related to the ERK/MAPK signaling pathway. Collectively, we identified that lncRNA NR-133666 acted as a miR-133c sponge that can promote the proliferation and migration of CIA FLS through regulating the miR-133c/MAPK1 axis.Objective The purpose of this study was to establish an N6-methylandenosine (m6A)-related long non-coding RNA (lncRNA) signature to predict the prognosis of hepatocellular carcinoma (HCC). Methods Pearson correlation analysis was used to identify m6A-related lncRNAs. We then performed univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct an m6A-related lncRNA signature. Based on the cutoff value of the risk score determined by the X-title software, we divided the HCC patients into high -and low-risk groups. A time-dependent ROC curve was used to evaluate the predictive value of the model. Finally, we constructed a nomogram based on the m6A-related lncRNA signature. Results ZEB1-AS1, MIR210HG, BACE1-AS, and SNHG3 were identified to comprise an m6A-related lncRNA signature. These four lncRNAs were upregulated in HCC tissues compared to normal tissues. The prognosis of patients with HCC in the low-risk group was significantly longer than that in the high-risk group. The M6A-related lncRNA signature was significantly associated with clinicopathological features and was established as a risk factor for the prognosis of patients with HCC. The nomogram based on the m6A-related lncRNA signature had a good distinguishing ability and consistency. Conclusion We identified an m6A-related lncRNA signature and constructed a nomogram model to evaluate the prognosis of patients with HCC.Objective For meropenem 40%T > MIC is associated with optimal killing of P. aeruginosa and E. coli. However, it is unknown how the distribution of %T > MIC through a treatment day impacts the antimicrobial effect in vitro. Therefore, we investigated the in vitro antibiotic activity of meropenem, precisely if 40%T > MIC is achieved in one single long period (single dose), 2 × 20% periods (dosing-bid), or 3 × 13.3% (dosing t.i.d.) thereby keeping the overall period of T > MIC constant. Material/Methods Time kill curves (TKC) with P. aeruginosa-ATCC-27853 and E. coli-ATCC-25922 and five clinical isolates each were implemented over 24 h in CAMHB with concentrations from 0.25×MIC-32×MIC. Periods over and under MIC were simulated by centrifugation steps (discarding supernatant and refilling with fresh CAMHB). Double and triple dosing involved further addition and removal of antibiotic. Complementary growth controls (GC) with and without centrifugation steps were done and the emergence of phenotypical resistance wasion in vitro, but also the distribution of the selected %T > MIC. Thus, dividing the 40%T > MIC in three short periods requested lowers antibiotic concentrations to achieve efficient bacterial killing and reduces the emergence of resistance in P. aeruginosa isolates. link2 The distribution of the %T > MIC did impact the bacterial eradication of susceptible pathogens in vitro and might play an even bigger role in infections with intermediate or resistant pathogens.C-kit/CD117, expressed in a series of tissue-specific progenitor cells, plays an important role in tissue regeneration and tissue homeostasis. We previously demonstrated that organoid-derived c-kit+ retinal progenitor cells can facilitate the restoration of degenerated retina. Meanwhile, we have identified a population of endogenous c-kit+ cells in retinas of adult mouse. However, the exact role of these cells in retinal degeneration remains unclear. Here, we demonstrated that stimulation of endogenous c-kit+ cells by stem cell factor (SCF) conferred protection against retinal degeneration. Retinal degeneration was induced by intravitreal injection of N-methyl-D-aspartate (NMDA). NMDA challenge increased the total number of c-kit+ cells in the retinal ganglion cell layer (GCL), while deregulated the protein level of SCF, which was mainly expressed in Müller cells. Both flash electroretinogram (fERG) and light/dark transition tests showed that intravitreal injection of SCF effectively improved the visual function of NMDA-treated mice. Mechanistically, SCF administration not only prevented the loss of retinal ganglion cells (RGCs), but also maintained the function of RGCs as quantified by fERG. Further, we performed transcriptome sequencing analysis of the retinal cells isolated from SCF-treated mice and the parallel control. Gene Ontology analysis showed that SCF-induced transcriptome changes were closely correlated with eye development-related pathways. Crystallins and several protective factors such as Pitx3 were significantly upregulated by SCF treatment. Our results revealed the role of SCF stimulated c-kit+ cells in the protection of RGCs in NMDA-treated mice, via inhibiting the loss of RGCs. Administration of SCF can act as a potent strategy for treating retinal degeneration-related diseases.[This corrects the article DOI 10.3389/fphar.2019.00079.].Peripheral nerve injury (PNI) results in loss of neural control and severe disabilities in patients. Promoting functional nerve recovery by accelerating angiogenesis is a promising neuroprotective treatment strategy. Here, we identified a bioactive Radix Astragalus polysaccharide (RAP) extracted from traditional Chinese medicine (TCM) as a potent enhancer of axonal regeneration and remyelination. Notably, RAP promoted functional recovery and delayed gastrocnemius muscle atrophy in a rat model of sciatic nerve crush injury. Further, RAP treatment may induce angiogenesis in vivo. Moreover, our in vitro results showed that RAP promotes endothelial cell (EC) migration and tube formation. Altogether, our results show that RAP can enhance functional recovery by accelerating angiogenesis, which was probably related to the activation of AKT/eNOS signaling pathway, thereby providing a polysaccharide-based therapeutic strategy for PNI.ACT-1004-1239 is a potent, selective, first-in-class CXCR7 antagonist, which shows a favorable preclinical and clinical profile. Here we report the metabolites and the metabolic pathways of ACT-1004-1239 identified using results from in vitro and in vivo studies. Two complementary in vitro studies (incubation with human liver microsomes in the absence/presence of cytochrome P450- [CYP] specific chemical inhibitors and incubation with recombinant CYPs) were conducted to identify CYPs involved in ACT-1004-1239 metabolism. For the in vivo investigations, a microtracer approach was integrated in the first-in-human study to assess mass balance and absorption, distribution, metabolism, and excretion (ADME) characteristics of ACT-1004-1239. Six healthy male subjects received orally 100 mg non-radioactive ACT-1004-1239 together with 1 μCi 14C-ACT-1004-1239. Plasma, urine, and feces samples were collected up to 240 h post-dose and 14C-drug-related material was measured with accelerator mass spectrometry. This techniqulite A1 was identified as an analog of M1 after oxidative defluorination, whereas both, A2 and A3, were identified as a reduced analog of M1 and parent, respectively, after addition of two hydrogen atoms at the isoxazole ring. In conclusion, CYP3A4 contributes to a relevant extent to ACT-1004-1239 disposition and two major circulating metabolites were observed in humans. Clinical Trial Registration (https//clinicaltrials.gov/ct2/show/NCT03869320) ClinicalTrials.gov Identifier NCT03869320.Background Hypercoagulability and thromboembolic events are associated with poor prognosis in coronavirus disease 2019 (COVID-19) patients. Whether chronic oral anticoagulation (OAC) improve the prognosis is yet controversial. The present study aimed to investigate the association between the chronic OAC and clinical outcomes in COVID-19 patients. Methods PubMed, Embase, Web of Science, and the Cochrane Library were comprehensively searched to identify studies that evaluated OAC for COVID-19 until 24 July 2021. Random-effects model meta-analyses were performed to pool the relative risk (RR) and 95% confidence interval (CI) of all-cause mortality and intensive care unit (ICU) admission as primary and secondary outcomes, respectively. According to the type of oral anticoagulants [direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs)], subgroup and interaction analyses were performed to compare DOACs and VKAs. Meta-regression was performed to explore the potential confounders on all-cause mortality. Results A total of 12 studies involving 30,646 patients met the inclusion criteria. The results confirmed that chronic OAC did not reduce the risk of all-cause mortality (RR 0.92; 95% CI 0.82-1.03; p = 0.165) or ICU admission (RR 0.65; 95% CI 0.40-1.04; p = 0.073) in patients with COVID-19 compared to those without OAC. The chronic use of DOACs did not reduce the risk of all-cause mortality compared to VKAs (P interaction = 0.497) in subgroup and interaction analyses. The meta-regression failed to detect any potential confounding on all-cause mortality. Conclusion COVID-19 patients with chronic OAC were not associated with a lower risk of all-cause mortality and ICU admission compared to those without OAC, and the results were consistent across DOACs and VKA subgroups. Systematic Review Registration clinicaltrials.gov, identifier CRD42021269764.Allergic asthma is a common respiratory inflammation disease. The crude Radix Paeoniae Alba (RPA) and its processed products have been used frequently as antipyretic and anti-inflammatory agents in traditional medicine. To evaluate the effect of honey and bran processing, different fractions of RPA were used for treating anti-allergic asthma in the ovalbumin (OVA)-induced mice model, and then, the most effective fraction of RPA and stir-frying Radix Paeoniae Alba with honey and bran (FRPA) for treating anti-allergic asthma were compared mutually for pharmacological effects. The results showed that the treatment of the dichloromethane fraction of RPA significantly improved the pathological condition of lung tissues, decreased the number of eosinophils and other cells in bronchoalveolar lavage fluid (BALF), and the increased the expression of various inflammatory factors. Furthermore, the study discovered that the lung pathological conditions, compared with the high dose of dichloromethane RPA fraction, could be ameliorated by high dose of dichloromethane FRPA fraction treatment. Moreover, the expression of inflammatory factors and the phosphorylation of the PI3K/AKT signaling pathway could be diminished by FRPA. Finally, the contents of compounds with a significant difference in the FRPA dichloromethane fraction were paeoniflorin, ethyl gallate, pentagalloylglucose, galloylpaeoniflorin, and others by UPLC/Q-TOF-MS analysis. These findings suggest that the dichloromethane fraction of FRPA has an enhancement effect on anti-allergic asthma and provide the experimental basis for exploring the processed mechanism of RPA.Cutaneous lupus erythematosus (CLE) is a group of autoimmune connective tissue disorders that significantly impact quality of life. Current treatment approaches typically use antimalarial medications, though patients may become recalcitrant. Other treatment options include general immunosuppressants, highlighting the need for more and more targeted treatment options. The purpose of this systematic review was to identify potential compounds that could be repurposed for CLE from natural products since many rheumatologic drugs are derived from natural products, including antimalarials. link3 This study was registered with PROSPERO, the international prospective register of systematic reviews (registration number CRD42021251048). We comprehensively searched Ovid Medline, Cochrane Library, and Scopus databases from inception to April 27th, 2021. These terms included cutaneous lupus erythematosus; general plant, fungus, bacteria terminology; selected plants and plant-derived products; selected antimalarials; and JAK inhibitors. Our search yielded 13,970 studies, of which 1,362 were duplicates. We screened 12,608 abstracts, found 12,043 to be irrelevant, and assessed 565 full-text studies for eligibility. Of these, 506 were excluded, and 59 studies were included in the data extraction. The ROBINS-I risk of bias assessment tool was used to assess studies that met our inclusion criteria. According to our findings, several natural compounds do reduce inflammation in lupus and other autoimmune skin diseases in studies using in vitro methods, mouse models, and clinical observational studies, along with a few randomized clinical trials. Our study has cataloged evidence in support of potential natural compounds and plant extracts that could serve as novel sources of active ingredients for the treatment of CLE. It is imperative that further studies in mice and humans are conducted to validate these findings. Systematic Review Registration https//www.crd.york.ac.uk/prospero/display_record.php?RecordID=251048.Energy metabolism reprogramming is the characteristic feature of tumors. The tumorigenesis, metastasis, and drug resistance of ovarian cancer (OC) is dependent on energy metabolism. Even under adequate oxygen conditions, OC cells tend to convert glucose to lactate, and glycolysis can rapidly produce ATP to meet their metabolic energy needs. Non-coding RNAs (ncRNAs) interact directly with DNA, RNA, and proteins to function as an essential regulatory in gene expression and tumor pathology. Studies have shown that ncRNAs regulate the process of glycolysis by interacting with the predominant glycolysis enzyme and cellular signaling pathway, participating in tumorigenesis and progression. This review summarizes the mechanism of ncRNAs regulation in glycolysis in OC and investigates potential therapeutic targets.Objective To explore the molecular mechanism of lung injury caused by paraquat (PQ) poisoning by investigating miR-199-mediated SET. Methods A paraquat poisoning model was established in C57BL/6 male mice via intraperitoneal injection of paraquat. The mice were transfected with miR-199 siRNA and or mimic. After 14 days of treatment, pathophysiological changes of the lung were observed and lung tissue was analyzed via Hematoxylin-Eosin staining. The levels of miR-199, SETs, surfactant protein SP-A and SP-B, and inflammatory and oxidative factors were analyzed by qPCR, Western Blot, and ELISA kits. link3 Results A acute lung-injury (ALI) model was established using PQ treatment and confirmed with edema of pulmonary endothelium with low electronic density of endothelial cytoplasm, presence of protein-rich fluid, and numerous erythrocytes in alveolar space, concentric figures of damaged tubular myelin, alveolar destruction, and increase in inflammatory cell numbers. Compared with the control group, miR-199 and SET levels were reduced in the PQ-treated group. miR-199 siRNA increased the SET level, inflammatory and oxidative levels, and reduced the levels of SP-A and SP-B, and miR-199 mimic reduced the SET level, inflammatory and oxidative levels, and increased the levels of SP-A and SP-B. PQ treatment reduced miR-199 level. Conclusion Paraquat induces ALI by affecting miR-199-mediated SET.The regulatory peptide galanin is broadly distributed in the central nervous systems and peripheral tissues where it modulates numerous physiological and pathological processes through binding to its three G-protein-coupled receptors, GalR1-3. However, the function and identity of the galaninergic system in the heart remain unclear. Therefore, we investigated the expression of the galanin receptors in cardiac cells and tissues and found that GalR2 is the dominant receptor subtype in adult mouse hearts, cardiomyocytes and H9C2 cardiomyoblasts. In vivo, genetic suppression of GalR2 promotes cardiac hypertrophy, fibrosis and mitochondrial oxidative stress in the heart. In vitro, GalR2 silencing by siRNA abolished the beneficial effects of galanin on cell hypertrophy and mitochondrial reactive oxygen species (ROS) production. These findings unravel new insights into the role of galaninergic system in the heart and suggest novel therapeutic strategies in heart disease.Metformin is a first-line anti-diabetic agent with a powerful hypoglycemic effect. Several studies have reported that metformin can improve the prognosis of stroke patients and that this effect is independent of its hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of metformin in cerebral ischemia-reperfusion (I/R) injury by constructing a transient middle cerebral artery occlusion model in vivo and a glucose and oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo experiments showed that acute treatment with low-dose metformin (10 mg/kg) ameliorated cerebral edema, reduced the cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover, metformin up-regulated the brain-derived neurotrophic factor (BDNF) expression and increased phosphorylation levels of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB) in the ischemia penumbra.
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