Showing papers in "Drug Design Development and Therapy in 2019"
TL;DR: This article aims to review and update current information on the pharmacology, mechanism of action, clinical efficacy, and adverse events of topical minoxidil.
Abstract: Minoxidil was first introduced as an antihypertensive medication and the discovery of its common adverse event, hypertrichosis, led to the development of a topical formulation for promoting hair growth. To date, topical minoxidil is the mainstay treatment for androgenetic alopecia and is used as an off-label treatment for other hair loss conditions. Despite its widespread application, the exact mechanism of action of minoxidil is still not fully understood. In this article, we aim to review and update current information on the pharmacology, mechanism of action, clinical efficacy, and adverse events of topical minoxidil.
159 citations
TL;DR: The level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression, as there is a lack of data concerning ketamine with repeated administration at higher doses.
Abstract: Depression is the third leading cause of disability in the world. Depressive symptoms may be reduced within several weeks after the start of conventional antidepressants, but treatment resistance concerns one-third of patients who fail to achieve recovery. Over the last 20 years, ketamine, an antagonist of the N-methyl-D-aspartate receptor, has been described to have antidepressant properties. A literature review was conducted through an exhaustive electronic search. It was restricted to Cochrane reviews, meta-analyses, and randomized controlled trials (RCTs) of ketamine for major depressive disorder and/or bipolar disorder. This review included two Cochrane reviews, 14 meta-analyses and 15 trials. Ketamine was studied versus placebo, versus other comparators and as an anesthetic adjuvant before electroconvulsive therapy. In 14 publications, ketamine provided a rapid antidepressant effect with a maximum efficacy reached at 24 hrs. Its effect lasted for 1-2 weeks after infusion, but a longer-term effect is little reported. Ketamine does not seem to improve depressive symptoms at the end of electroconvulsive sessions. Safety and tolerability profiles with ketamine at low single dose are generally good in depressed patients. However, there is a lack of data concerning ketamine with repeated administration at higher doses. The clinical use of ketamine is increasing. Intranasal (S)-ketamine has recently been approved for depression by the Food and Drug Administration. It could be a promising treatment in depressed patients with suicidal ideation. Collectively, the level of proof of efficacy remains low and more RCTs are needed to explore efficacy and safety issues of ketamine in depression.
126 citations
TL;DR: Although the complexity of the BBB (dynamic and adaptable barrier) affects approaches of CNS drug delivery and promotes disease progression, understanding the composition and functions of BBB provides a platform for novel innovative approaches towards drug delivery to CNS.
Abstract: The blood-brain barrier (BBB) is comprised of brain microvascular endothelial central nervous system (CNS) cells, which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by responding against pathological environments and modulating disease progression. The BBB plays a crucial role in maintaining homeostasis in the CNS by maintaining restricted transport of toxic or harmful molecules, transport of nutrients, and removal of metabolites from the brain. Neurological disorders, such as NeuroHIV, cerebral stroke, brain tumors, and other neurodegenerative diseases increase the permeability of the BBB. While on the other hand, semipermeable nature of BBB restricts the movement of bigger molecules i.e. drugs or proteins (>500 kDa) across it, leading to minimal bioavailability of drugs in the CNS. This poses the most significant shortcoming in the development of therapeutics for CNS neurodegenerative disorders. Although the complexity of the BBB (dynamic and adaptable barrier) affects approaches of CNS drug delivery and promotes disease progression, understanding the composition and functions of BBB provides a platform for novel innovative approaches towards drug delivery to CNS. The methodical and scientific interests in the physiology and pathology of the BBB led to the development and the advancement of numerous in vitro models of the BBB. This review discusses the fundamentals of BBB structure, permeation mechanisms, an overview of all the different in-vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods towards the critical role in the development of the CNS therapeutics.
115 citations
TL;DR: Emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro, confirming that emodin may provide an alternative treatment for my Cardiomyocytes injury.
Abstract: Background Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes. Materials and methods Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes' ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA. Results The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins. Conclusion This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.
112 citations
TL;DR: The biological barriers that nanoparticles need to overcome, followed by presenting different types of drug delivery systems to improve drug accumulation in tumors, and cancer cell membrane targets that increase cellular drug uptake through active targeting mechanisms are described.
Abstract: Cancer is the second largest cause of death worldwide with the number of new cancer cases predicted to grow significantly in the next decades. Biotechnology and medicine can and should work hand-in-hand to improve cancer diagnosis and treatment efficacy. However, success has been frequently limited, in particular when treating late-stage solid tumors. There still is the need to develop smart and synergistic therapeutic approaches to achieve the synthesis of strong and effective drugs and delivery systems. Much interest has been paid to the development of smart drug delivery systems (drug-loaded particles) that utilize passive targeting, active targeting, and/or stimulus responsiveness strategies. This review will summarize some main ideas about the effect of each strategy and how the combination of some or all of them has shown to be effective. After a brief introduction of current cancer therapies and their limitations, we describe the biological barriers that nanoparticles need to overcome, followed by presenting different types of drug delivery systems to improve drug accumulation in tumors. Then, we describe cancer cell membrane targets that increase cellular drug uptake through active targeting mechanisms. Stimulus-responsive targeting is also discussed by looking at the intra- and extracellular conditions for specific drug release. We include a significant amount of information summarized in tables and figures on nanoparticle-based therapeutics, PEGylated drugs, different ligands for the design of active-targeted systems, and targeting of different organs. We also discuss some still prevailing fundamental limitations of these approaches, eg, by occlusion of targeting ligands.
88 citations
TL;DR: The main objective of this review is to examine the potential of drug-free nanomaterials that do not kill the pathogen but target virulent factors such as adhesins, toxins, or secretory systems in the detection and treatment of antibiotic-resistant pathogenic organisms.
Abstract: The worldwide misuse of antibiotics and the subsequent rise of multidrug-resistant pathogenic bacteria have prompted a paradigm shift in the established view of antibiotic and bacterial-human relations. The clinical failures of conventional antibiotic therapies are associated with lengthy detection methods, poor penetration at infection sites, disruption of indigenous microflora and high potential for mutational resistance. One of the most promising strategies to improve the efficacy of antibiotics is to complex them with micro or nano delivery materials. Such materials/vehicles can shield antibiotics from enzyme deactivation, increasing the therapeutic effectiveness of the drug. Alternatively, drug-free nanomaterials that do not kill the pathogen but target virulent factors such as adhesins, toxins, or secretory systems can be used to minimize resistance and infection severity. The main objective of this review is to examine the potential of the aforementioned materials in the detection and treatment of antibiotic-resistant pathogenic organisms.
87 citations
TL;DR: Salvianolic acid A (SA-A), a traditional Chinese medicine extracted from the plant Danshen, could effectively inhibit the liver fibrosis, which is induced by CCl4 in vivo, and the molecular mechanisms behind it are closely associated with the regulation of PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved casing pathways.
Abstract: Background: Liver fibrosis occurs due to chronic liver disease due to multiple pathophysiological causes. The main causes for this condition are chronic alcohol abuse, nonalcoholic steatohepatitis, and infection due to hepatitis C virus. Currently, there is more and more information available about the molecular as well as cellular mechanisms, which play a role in the advancement of liver fibrosis. However, there is still no effective therapy against it. Purpose: In order to find an effective treatment against liver fibrosis, our study explored whether salvianolic acid A (SA-A), a traditional Chinese medicine extracted from the plant Danshen, could effectively inhibit the liver fibrosis, which is induced by CCl4 in vivo. Methods: The effects of SA-A were evaluated by assessing the parameters related to liver fibrosis such as body weight, histological changes, and biochemical parameters. Thereafter, the related protein or gene levels of P13K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways were determined by western blotting, real-time PCR or immunohistochemistry staining. Results: According to the results of our study, SA-A could reduce liver fibrosis by inhibiting liver function, liver fibrosis index, collagen deposition, and improving the degree of liver fibrosis in rats. Mechanistically, the PI3K/AKT/mTOR signaling cascade was inhibited by SA-A to prevent the stimulation of hepatic stellate cell, as well as the synthesis of extracellular matrix, and regulated Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways to prevent hepatocyte apoptosis. Conclusion: The novel findings of this study suggested that SA-A could reduce liver fibrosis and the molecular mechanisms behind it are closely associated with the regulation of PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways.
83 citations
TL;DR: Kaempferol exhibits beneficial effects on skeleton, thus is potentially effective for the prophylaxis and treatment of osteoporosis.
Abstract: Kaempferol is a dietary bioflavonoid ubiquitously found in various types of plant. It possesses a wide range of medicinal properties suggesting its potential clinical utility that requires further investigation. The present review intends to highlight the efficacy of kaempferol and its molecular mechanisms of action in regulating bone metabolism. Many reports have acknowledged the bone-protecting property of kaempferol and kaempferol-containing plants using in vitro and in vivo experimental models. Kaempferol supplementation showed bone-sparing effects in newborn rats, glucocorticoid-induced and ovariectomy-induced osteoporotic models as well as bone fracture models. It achieves the bone-protective effects by inhibiting adipogenesis, inflammation, oxidative stress, osteoclastic autophagy and osteoblastic apoptosis while activating osteoblastic autophagy. The anti-osteoporotic effects of kaempferol are mediated through regulation of estrogen receptor, bone morphogenetic protein-2 (BMP-2), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways. In summary, kaempferol exhibits beneficial effects on skeleton, thus is potentially effective for the prophylaxis and treatment of osteoporosis.
80 citations
TL;DR: Hesperidin regulates lipid metabolism and glucose metabolism by mediating AMPK and PPAR signaling pathways, directly regulates antioxidant index and anti-apoptosis, and indirectly mediates NF-κB signaling pathway to regulate inflammation to play a role in the treatment of obesity.
Abstract: Obesity is a chronic metabolic disease caused by multiple factors and is considered to be a risk factor for type 2 diabetes, cardiovascular disease, hypertension, stroke and various cancers. Hesperidin, a flavanone glycoside, is a natural phenolic compound with a wide range of biological effects. Mounting evidence has demonstrated that hesperidin possesses inhibitory effect against obesity diseases. Our review discusses mechanisms of hesperidin in the treatment of obesity. Hesperidin regulates lipid metabolism and glucose metabolism by mediating AMPK and PPAR signaling pathways, directly regulates antioxidant index and anti-apoptosis, and indirectly mediates NF-κB signaling pathway to regulate inflammation to play a role in the treatment of obesity. In addition, hesperidin-enriched dietary supplements can significantly improve symptoms such as postprandial hyperglycemia and hyperlipidemia. Further clinical trials are also required for confirming lipid-lowering efficacy of this natural flavonoid and evaluating its safety profile.
79 citations
TL;DR: Esketamine administration as a single dose of 0.5 mg/kg was generally safe and tolerated in patients undergoing painless gastroscopy and in terms of anesthesia, a relatively small dose of esketamine can be used instead of racemate ketamine for routine treatment without consideration of gender differences.
Abstract: Purpose To assess the pharmacokinetics and safety of pure S-ketamine (esketamine) in Chinese patients undergoing painless gastroscopy and evaluate the potential advantage of esketamine in clinical treatment compared with racemate ketamine hydrochloride injection. Patients and methods A randomized, open-label, parallel-controlled, Phase I study was performed with 32 patients undergoing painless gastroscopy. Patients received a single dose of esketamine (0.5 mg/kg) or racemic ketamine (1 mg/kg, esketamine:R-ketamine=1:1), injected in 10 s. Blood samples were collected for pharmacokinetic analysis. The concentrations of esketamine, R-ketamine, S-norketamine, and R-norketamine were measured with a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Results After administering a single dose of esketamine and racemate ketamine, the pharmacokinetics parameters of esketamine and S-norketamine are both similar in treatment groups. The clearance of esketamine in two groups was 18.1±3.2 and 18.4±3.4 mL/min•kg, respectively. However, in the ketamine group, esketamine has a larger clearance than R-ketamine (18.4±3.4 mL/min·kg vs 15.8±3.1 mL/min·kg, P<0.001). Further analysis showed that gender did not affect the pharmacokinetics of esketamine and racemate ketamine. Regarding the safety of esketamine and racemate ketamine, no serious adverse events were observed during treatment, and the incidences of adverse events were 75.0% (esketamine) and 87.5% (racemate ketamine). The main adverse reactions were dizziness, agitation, nausea, vomiting, headache, and fatigue. However, compared with racemic ketamine, esketamine offers a shorter recovery time (9 mins vs. 13 mins, P<0.05) and orientation recovery time (11.5 mins vs. 17 mins, P<0.05) after short anesthesia. Conclusion Esketamine administration as a single dose of 0.5 mg/kg was generally safe and tolerated in patients undergoing painless gastroscopy. In terms of anesthesia, a relatively small dose of esketamine can be used instead of racemate ketamine for routine treatment without consideration of gender differences.
78 citations
TL;DR: It is suggested that aucubin has a protective effect on articular cartilage and slowing progression of OA in a mouse model and can significantly inhibit mediators of apoptosis in rat primary chondrocytes.
Abstract: Objective Chondrocyte apoptosis has also been strongly correlated with the severity of cartilage damage and matrix depletion in an osteoarthritis (OA) joint. Therefore, pharmacological inhibitors of apoptosis may provide a novel treatment option for patients with OA. Aucubin, a natural compound isolated from Eucommia ulmoides, has been proved to possess antioxidative and anti-apoptotic properties. However, anti-osteoarthritis effect of aucubin in animal model and anti-apoptotic response of aucubin in OA chondrocytes remain unclear. This study aimed to determine whether aucubin could slow progression of OA in a mouse model and inhibit the IL-1β-induced chondrocyte apoptosis. Methods OA severity and articular cartilage degradation were evaluated by Safranin-O staining, Hematoxylin-eosin (HE the apoptotic rate of chondrocytes was evaluated by flow cytometry (FCM) with Annexin V-FITC/PI kit. Mediators of apoptosis were tested by Western blot of Bax, caspase-3, caspase-9, and Bcl-2 expression. The intracellular levels of Reactive oxygen species (ROS) were assessed by the probe of 2,7-Dichlorofluorescin diacetate (DCFH-DA). Results The articular cartilage in the limb with destabilization of the medial meniscus (DMM) exhibited early OA-like manifestations characterized by proteoglycan loss, cartilage fibrillation, and erosion, with lower OARSI score. Oral administration of aucubin remarkably attenuated the loss of proteoglycan and the articular cartilage erosion and decreased the OARSI scores underwent DMM surgery. Aucubin treatment significantly reverses IL-1β-induced cytotoxicity and attenuated the IL-1β-induced chondrocyte apoptosis. In addition, aucubin can significantly inhibit mediators of apoptosis in rat primary chondrocytes. Furthermore, aucubin remarkably attenuated the IL-1β-induced intracellular ROS production. Conclusion Our findings suggest that aucubin has a protective effect on articular cartilage and slowing progression of OA in a mouse model. This protective effect may result from inhibiting chondrocyte apoptosis and excessive ROS production.
TL;DR: This review starts with an overview of complement pathways involved in AMD and their therapies correspondingly, and discusses the development of the therapeutics existed now.
Abstract: Age-related macular degeneration (AMD) is directly attributable to vision loss, posing significant pressure on public health. AMD is recognized to be a multi-factorial disease and among them, complement system is under heated discussion in recent years. In this review, we start with an overview of complement pathways involved in AMD and their therapies correspondingly. Finally, we discuss the development of the therapeutics existed now. Also, we enclose a list of drugs undergoing clinical trials.
TL;DR: UC-MSC cells plus DMARDs therapy can be a safe, effective and feasible therapeutic option for RA patients.
Abstract: Background The traditional anti-inflammation disease-modifying anti-rheumatic drugs (DMARDs) have limited therapeutic effects in rheumatoid arthritis (RA) patients. We previously reported the safety and efficacy of umbilical cord mesenchymal stem cell (UC-MSC) treatment in RA patients that were observed for up to 8 months after UC-MSC infusion. The aim of this study is to assess the long-term efficacy and safety of UC-MSC along with DMARDs for the treatment of RA. Methods 64 RA patients aged 18-64 years were recruited in the study. During the treatment, patients were treated with 40 mL UC-MSC suspension product (2 × 107 cells/20 mL) via intravenous injection immediately after the infusion of 100 mL saline. The serological markers tests were used to assess safety and the 28-joint disease activity score (DAS28) and the Health Assessment Questionnaire (HAQ) to assess efficacy. Results 1 year and 3 years after UC-MSC cells treatment, the blood routine, liver and kidney function and immunoglobulin examination showed no abnormalities, which were all in the normal range. The ESR, CRP, RF of 1 year and 3 years after treatment and anti-CCP of 3 years after treatment were detected to be lower than that of pretreatment, which showed significant change (P < 0.05). Health index (HAQ) and joint function index (DAS28) decreased 1 year and 3 years after treatment than before treatment (P < 0.05). Conclusion UC-MSC cells plus DMARDs therapy can be a safe, effective and feasible therapeutic option for RA patients.
TL;DR: Dexmedetomidine 0.5 μg/kg reduced the incidence of ED after sevoflurane anesthesia and might be used to prevent NPOBCs and observe postoperative behavioral changes through long-term follow-up.
Abstract: Objectives Emergence delirium (ED) is a common neurologic complication that can not only distress children and their families in the early postanesthetic period, but can also have adverse effects on children in the long-term. This study aimed to investigate the effects of single-dose dexmedetomidine on ED in children with sevoflurane anesthesia and to observe postoperative behavioral changes through long-term follow-up. Methods Patients aged 2-7 years, American Society of Anesthesiologists class (ASA) I or II, scheduled for tonsillectomy with and without adenoidectomy were randomized to receive dexmedetomidine 0.5 μg/kg (Group D) or volume-matched normal saline (Group C) over 10 minutes after induction of anesthesia. The primary outcome was the incidence of ED within 30 minutes after extubation. Other outcomes were the incidence of pain, extubation time, post-anesthesia care unit (PACU) length of stay after extubation, adverse events, and the incidence of negative postoperative behavioral changes (NPOBCs). Results Ninety children completed the study. Compared with the control group (Group C), dexmedetomidine decreased the incidence of ED (31.1% vs 53.3%; P=0.033) and pain (28.9% vs 57.8%; P=0.006), but it prolonged extubation time (P⩽0.001). PACU length of stay after extubation and the percentage of adverse events were similar between groups. The incidence of NPOBCs in Group D was significantly lower at 1 and 7 days after discharge (33.3% vs 60.0%; P=0.011% and 24.4% vs 46.7%; P=0.028, respectively) than it was in Group C, but no significant difference was found at the 30th day. Conclusion Dexmedetomidine 0.5 μg/kg reduced the incidence of ED after sevoflurane anesthesia and might be used to prevent NPOBCs. Clinical trials registration ChiCTR1800016828.
TL;DR: Results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.
Abstract: Purpose It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. Materials and methods The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. Results Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. Conclusion Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.
TL;DR: The ability of escin to prevent hypoxia-induced disruption to the normal expression and distribution of platelet endothelial cell-adhesion molecule-1 may help explain its protective effect on blood vessel permeability.
Abstract: This review discusses historical and recent pharmacological and clinical data on the anti-edematous, anti-inflammatory, and venotonic properties of escin (Reparil®). Escin, the active component of Aesculus hippocastanum, or horse chestnut, is available as orally absorbable dragees and as a transdermal gel. The anti-inflammatory and anti-edematous effects of escin have been studied over many years in pre-clinical models. More recent data confirm the anti-inflammatory properties of escin in reducing vascular permeability in inflamed tissues, thereby inhibiting edema formation. The venotonic effects of escin have been demonstrated primarily by in vitro studies of isolated human saphenous veins. The ability of escin to prevent hypoxia-induced disruption to the normal expression and distribution of platelet endothelial cell-adhesion molecule-1 may help explain its protective effect on blood vessel permeability. Escin oral dragees and transdermal gel have both demonstrated efficacy in blunt trauma injuries and in chronic venous insufficiency. Both oral escin and the transdermal gel are well tolerated.
TL;DR: It is found that bone marrow mesenchymal stem cell-derived exosomes attenuated hepatocyte apoptosis by promoting autophagy, and for the first time that BMSC-Exos had the potential to reduce hepatocytes apoptosis after acute liver failure.
Abstract: Background Acute liver failure is an inflammation-mediated hepatocyte injury. Mesenchymal stem cell (MSC) transplantation is currently considered to be an effective treatment strategy for acute liver failure. Exosomes are an important paracrine factor that can be used as a direct therapeutic agent. However, the use of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in the treatment of acute liver failure has not been reported. Purpose Here, we established a model of hepatocyte injury and apoptosis induced by D-galactosamine and lipopolysaccharide (D-GalN/LPS) to study the protective effect of BMSC-Exos on hepatocyte apoptosis, and further explored its protective mechanism. Methods BMSC-Exos was identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. Laser confocal microscopy was used to observe the uptake of Dil-Exos by hepatocytes. D-GalN/LPS-induced primary hepatocytes were pretreated with BMSC-Exos in vitro, and then the cells were harvested. The apoptosis of hepatocytes was observed by TUNEL staining, flow cytometry and Western blot. Electron microscopy and mRFP-GFP-LC3 and Western blot was used to observe autophagy. Results BMSC-Exos increased the expression of autophagy marker proteins LC3 and Beclin-1 and promoted the formation of autophagosomes. After BMSC-Exos treatment, the expression levels of the proapoptotic proteins Bax and cleaved caspase-3 were significantly decreased, while the expression level of the anti-apoptotic protein Bcl-2 was upregulated. However, when the autophagy inhibitor 3MA was present, the effect of BMSC-Exos on inhibiting apoptosis was significantly reversed. Conclusions Our results showed for the first time that BMSC-Exos had the potential to reduce hepatocyte apoptosis after acute liver failure. In particular, we found that BMSC-Exos attenuated hepatocyte apoptosis by promoting autophagy.
TL;DR: BMSCs-Exo play a protective role in spinal cord injury by inhibiting complement mRNA synthesis and release and by inhibition of SCI-activated NF-κB by binding to microglia.
Abstract: Purpose Spinal cord injury (SCI) is a relatively common, devastating traumatic condition resulting in permanent disability. In this study, the use of exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) as a cell-free therapy for the treatment of SCI in rats was investigated to gain insights into their mechanisms of action. Methods Rats were randomly divided into three groups, Sham (treated with PBS), SCI (SCI injury + PBS) and SCI + Exo (SCI injury + BMSCs-Exo). Changes in the complement system between the three groups were assessed with the use of proteomics. The proteomic data were verified using reverse transcription-polymerase chain reaction (RT-PCR). In addition, the distributions of BMSCs-Exo in rats with SCI were detected by immunofluorescence. Moreover, SCI-activated NF-κB levels were determined using Western blot. Results SCI insult increased complement levels, including C4, C5, C6, C4 binding protein alpha and complement factor H. In contrast, the SCI + BMSCs-Exo group exhibited attenuated SCI-induced complement levels. Immunofluorescence assay results revealed that BMSCs-Exo mainly accumulated at the spinal cord injury site and were bound to microglia cells. Western blot analysis of tissue lysates showed that BMSCs-Exo treatment also inhibited SCI-activated nuclear factor kappa-B (NF-κB). Conclusion BMSCs-Exo play a protective role in spinal cord injury by inhibiting complement mRNA synthesis and release and by inhibiting SCI-activated NF-κB by binding to microglia.
TL;DR: Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.
Abstract: Objective: To investigate the exact role of GRP78 in artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Methods: Artesunate-induced KRAS mutant human pancreatic cancer cells (AsPC-1 and PaTU8988) ferroptosis was confirmed by fluorescent staining experiments and CCK8. Western blot and short-hairpin RNA-based knockdown assays were conducted to detect GRP78 activity and its role in artesunate-induced ferroptosis. Results: Artesunate induced AsPC-1 and PaTU8988 cell death in ferroptosis manner, rather than necrosis or apoptosis. In addition, artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 enhanced artesunate-induced ferroptosis of pancreatic cancer cells in vitro and in vivo. Conclusion: Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.
TL;DR: Inotersen, a 2′-O-methyoxyethyl-modified antisense oligonucleotide, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.
Abstract: Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.
TL;DR: Developing a doxorubicin and β-elemene co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs) that would have great potential to inhibit lung tumor cells and tumor growth.
Abstract: Purpose: Co-delivery of drugs to achieve the synergistic anticancer effect is a promising strategy for lung cancer therapy. The purpose of this research is to develop a doxorubicin (DOX) and β-elemene (ELE) co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs). Methods: In this study, DOX/ELE Hyd NLCs were produced by a hot homogenization and ultrasonication method and used for lung cancer treatment. In vitro and in vivo efficiency as well as toxicity of the system was evaluated on lung cancer cell lines and lung tumor-bearing mice. Results: DOX/ELE Hyd NLCs had a particle size of 190 nm, with a PDI lower than 0.2. DOX/ELE Hyd NLCs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 7.86 μg/mL), synergy antitumor effect (combination index lower than 1), and profound tumor inhibition ability (tumor inhibition ratio of 82.9%) compared with the non pH-responsive NLCs and single-drug-loaded NLCs. Conclusion: Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and tumor growth.
TL;DR: Treatment with NAC at the two selected doses significantly attenuated CDDP-induced changes in the brain cholinergic function, improved the brain oxidant/antioxidant status, and also reversed the overproduction of pro-inflammatory cytokines in brain and serum.
Abstract: Background Neurotoxicity is a major obstacle to the effectiveness of cisplatin (CDDP) in cancer chemotherapy. Oxidative stress and inflammation are considered to be the major mechanisms involved in CDDP-induced neurotoxicity. The rationale of our study was to investigate the efficacy of N-acetylcysteine (NAC) at two different doses in the management of CDDP-induced toxicity in rat brain by monitoring its antioxidant and anti-inflammatory effects. Methods Thirty-five male rats were divided into five groups (n=7) as follows: control group (0.5 mL saline), NAC100 group (100 mg/kg), CDDP group (8 mg/kg), NAC50-CDDP group (50 mg/kg NAC and 8 mg/kg CDDP), and NAC100-CDDP group (100 mg/kg NAC and 8 mg/kg CDDP). NAC was administered for 20 consecutive days, while CDDP was injected once on day 15 of the treatment protocol. Results The neurotoxicity of CDDP was evidenced by a marked increase in acetylcholinesterase and monoamine oxidase activities. It also induced oxidative stress as indicated by increased levels of lipid peroxidation, nitric oxide, and protein carbonyl with a concomitant decline in reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase, and catalase in the brain. Moreover, CDDP enhanced the synthesis of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. Treatment with NAC at the two selected doses significantly attenuated CDDP-induced changes in the brain cholinergic function, improved the brain oxidant/antioxidant status, and also reversed the overproduction of pro-inflammatory cytokines in brain and serum. Conclusion NAC could serve as an appropriate and safe complementary therapeutic agent to attenuate the toxicity of CDDP in the brain and therefore improve its outcomes in chemotherapy.
TL;DR: This research presents a novel probabilistic approach to estimating the response of the immune system to laser-spot assisted, 3D image analysis.
Abstract: Background Traditional Chinese medicine (TCM) formulations have proven to be advantageous in clinical treatment and prevention of disease. LiuWei DiHuang Pill (LWDH Pill) is a TCM that was employed to treat type 2 diabetes mellitus (T2DM). However, a holistic network pharmacology approach to understanding the active ingredients and the therapeutic mechanisms underlying T2DM has not been pursued. Methods A network pharmacology approach including drug-likeness evaluation, oral bioavailability prediction, virtual docking, and network analysis has been used to predict the active ingredients and potential targets of LWDH Pill in the treatment of type 2 diabetes. Results The comprehensive network pharmacology approach was successfully to identify 45 active ingredients in LWDH Pill. 45 active ingredients hit by 163 potential targets related to T2DM. Ten of the more highly predictive components (such as :quercetin, Kaempferol, Stigmasterol, beta-sitosterol, Kadsurenone, Diosgenin, hancinone C, Hederagenin, Garcinone B, Isofucosterol) are involved in anti-inflammatory, anti-oxidative stress, and the reduction of beta cell damage. LWDH Pill may play a role in the treatment of T2DM and its complications (atherosclerosis and nephropathy) through the AGE-RAGE signaling pathway, TNF signaling pathway, and NF-kappa B signaling pathway. Conclusion Based on a systematic network pharmacology approach, our works successfully predict the active ingredients and potential targets of LWDH Pill for application to T2DM and helps to illustrate mechanism of action on a comprehensive level. This study provides identify key genes and pathway associated with the prognosis and pathogenesis of T2DM from new insights, which also demonstrates a feasible method for the research of chemical basis and pharmacology in LWDH Pill.
TL;DR: It is demonstrated that Tanshinone I might be regarded as a promising therapeutic agent for the treatment of OA after it alleviated cartilage destruction and synovitis and reduced OARSI scores and subchondral bone thickness in a mouse model of Oa.
Abstract: Background
Osteoarthritis (OA) is a prevalent degenerative joint disease, which was characterized by inflammation and cartilage degradation. Accumulating evidence has demonstrated that Tanshinone I has an anti-inflammatory effect in various diseases. However, the efficacy of Tanshinone I as an anti-inflammatory agent in OA remains unclear. This study aimed to explore the role of Tanshinone I on OA both in vitro and in vivo.
TL;DR: MaR1 protects against renal IRI by inhibiting the TLR4/MAPK/NF-κB pathways, which mediate anti-inflammation, and by activating the Nrf2 pathway, which mediates antioxidation.
Abstract: Background Inflammation and oxidative stress play a crucial role in the pathogenesis of renal ischemia/reperfusion injury (IRI). Maresin 1 (MaR1), which has shown strong anti-inflammatory and antioxidant effects, was recently reported to have protective properties in several different animal models. Aim The objectives of our study were to determine whether MaR1 alleviates renal IRI and to identify the underlying mechanisms. Materials and methods The mouse model in this study was induced by ischemia of the left kidney for 45 minutes and by nephrectomy of the right kidney. All mice were intravenously injected with a vehicle or MaR1. Renal histopathologic changes, function, proinflammatory cytokines, and oxidative stress were assessed. The expression of proteins was measured by Western blot. Results The results indicated that MaR1 markedly protected against renal IRI. The protective effects were accompanied by the reduction of histologic changes and reduction of renal dysfunction. Meanwhile, MaR1 remarkably mitigated renal IRI-induced inflammation and oxidative stress. In addition, our results showed that MaR1 significantly inhibited the expression of TLR4 and the expression of phosphorylated Erk, JNK, and P38. Furthermore, MaR1 decreased the nuclear translocation of NF-κB and increased the nuclear translocation of Nrf2. Conclusion MaR1 protects against renal IRI by inhibiting the TLR4/MAPK/NF-κB pathways, which mediate anti-inflammation, and by activating the Nrf2 pathway, which mediates antioxidation.
TL;DR: It is suggested that Dex might exert anti-inflammatory effects in LPS-stimulated BV2 cells via upregulation of miR-340, and might serve as a potential agent for the treatment of neuroinflammation.
Abstract: Background Dexmedetomidine (Dex) was reported to exhibit anti-inflammatory effect in the nervous system. However, the mechanism by which Dex exhibits anti-inflammation effects on LPS-stimulated BV2 microglia cells remains unclear. Thus, this study aimed to investigate the role of Dex in LPS-stimulated BV2 cells. Methods The BV2 cells were stimulated by lipopolysaccharides (LPS). BV2 cells were infected with short-hairpin RNAs targeting NF-κB (NF-κB-shRNAs) and NF-κB overexpression lentivirus, respectively. In addition, miR-340 mimics or miR-340 inhibitor was transfected into BV2 cells, respectively. Meanwhile, the dual-luciferase reporter system assay was used to explore the interaction of miR-340 and NF-κB in BV2 cells. CCK-8 was used to detect the viability of BV2 cells. In addition, Western blotting was used to detect the level of NF-κB in LPS-stimulated BV2 cells. The levels of TNF-α, IL-6, IL-1β, IL-2, IL-12, IL-10 and MCP-1 in LPS-stimulated BV2 cells were measured with ELISA. Results The level of miR-340 was significantly upregulated in Dex-treated BV2 cells. Meanwhile, the level of NF-κB was significantly increased in BV2 cells following infection with lenti-NF-κB, which was markedly reversed by Dex. LPS markedly increased the expression of NF-κB and proinflammatory cytokines in BV2 cells, which were reversed in the presence of Dex. Moreover, miR-340 mimics enhanced the anti-inflammatory effects of Dex in LPS-stimulated BV2 cells via inhibiting NF-κB and proinflammatory cytokines. Furthermore, Dex obviously inhibited LPS-induced phagocytosis in BV2 cells. Conclusion Taken together, our results suggested that Dex might exert anti-inflammatory effects in LPS-stimulated BV2 cells via upregulation of miR-340. Therefore, Dex might serve as a potential agent for the treatment of neuroinflammation.
TL;DR: This review discusses the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development, and discusses the current knowledge on the molecular basis of CML and new potential therapeutic targets.
Abstract: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR-ABL gene fusion. Instead of progress in the understanding of the molecular etiology of CML and the development of novel therapeutic strategies, clinicians still face many challenges in the effective treatment of patients. In this review, we discuss the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development. We also briefly refer to several aspects regarding the current knowledge on the molecular basis of CML and new potential therapeutic targets.
TL;DR: The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed, in order to highlight the potential roles of EGCG in the treatment of HCC.
Abstract: Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the deadliest cancers worldwide. Despite orthotopic liver transplantation and hepatic resection representing the principal lines of treatment for this pathology, only a minority of patients can be resected owing to cirrhosis or late diagnosis. Keeping in mind the end goal of conquering these challenges, new alternative approaches have been proposed. Accumulating evidence has demonstrated that epigallocatechin-3-gallate (EGCG), the principal catechin of green tea with multiple biological properties, is able to modulate different molecular mechanisms underlying HCC, mainly through its antioxidant activity. In this article, we revise these findings reported in the literature, in order to highlight the potential roles of EGCG in the treatment of HCC. The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed. New bits of information available for translational perspectives into clinical practice are addressed.
TL;DR: Emodin exhibited cytotoxicity in the L02 human hepatic cell line by promoting apoptosis, and it also induced autophagy through the suppression of the PI3K/AKT/mTOR signalling pathway.
Abstract: Background Emodin, a major component of Polygonum multiflorum (PM), has been reported to exert both protective and toxic effects in several cell types. However, the effects and underlying mechanisms of action of emodin in hepatic cells are still obscure. Methods The present study used the normal human liver cell line L02 to investigate the effects and mechanisms of emodin in hepatic cells. After treatment with emodin, L02 cells were examined for viability, apoptosis and autophagy with the Cell Counting Kit-8 (CCK-8), annexin V/PerCP staining and GFP-LC3 plasmid transfection. The expression of proteins including cleaved caspase-3, LC3B-I/II, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, mTOR and actin was examined by using Western blot. Results Emodin significantly inhibited the viability of and induced apoptosis in L02 cells in a dose- and time-dependent manner. In addition, emodin increased the number of GFP-LC3 puncta in L02 cells and upregulated the expression of LC3B-II compared to those in control cells. Furthermore, emodin significantly decreased the expression of p-PI3K, p-AKT and p-mTOR in a dose-dependent manner compared to that in control cells without altering the expression of PI3K, AKT and mTOR. Notably, cotreatment with emodin and 3-methyladenine (3-MA) or rapamycin significantly increased and decreased the apoptosis rate of L02 cells, respectively, compared to that of cells treated with emodin alone. Conclusion In conclusion, emodin exhibited cytotoxicity in the L02 human hepatic cell line by promoting apoptosis, and it also induced autophagy through the suppression of the PI3K/AKT/mTOR signalling pathway. The autophagy could play a protective role following emodin treatment.
TL;DR: A panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide, and these findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etOPoside.
Abstract: Purpose Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small-cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. Methods The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). The data regarding sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. Results ROC analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve =0.804 (95% confidence interval: 0.679-0.930,P Conclusion This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.