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ID PMID Title PublicationDate abstract
31057000 Rapid isolation and purification of functional platelet mitochondria using a discontinuous 2020 The isolation of mitochondria is gaining importance in experimental and clinical laboratory settings. The mitochondrion is known as the powerhouse of the cell as it produces the energy to power most cellular functions but is also involved in many cellular processes. Of interest, mitochondria and mitochondrial components (i.e. circular DNA, N-formylated peptides, cardiolipin) have been involved in several human inflammatory pathologies, such as cancer, Alzheimer's disease, Parkinson's disease, and rheumatoid arthritis. Therefore, stringent methods of isolation and purification of mitochondria are of the utmost importance in assessing mitochondrial-related diseases. While several mitochondrial isolation methods have been previously published, these techniques are aimed at yielding mitochondria from cells types other than platelets. In addition, little information is known on the number of platelet-derived microparticles that can contaminate the mitochondrial preparation or even the overall quality and integrity of the mitochondria. In this project, we provide an alternate purification method yielding mitochondria of high purity and integrity from human platelets. Using human platelets, flow cytometry and transmission electron microscopy experiments were performed to demonstrate that the Percoll gradient method yielded significantly purified mitochondria by removing platelet membrane debris. Mitochondrial respiration following the substrate-uncoupler-inhibitor-titration (SUIT) protocol was similar in both the purified and crude mitochondrial extraction methods. Finally, the cytochrome c effect and JC-1 staining did not exhibit a significant difference between the two methods, suggesting that the mitochondrial integrity was not affected. Our study suggests that the Percoll discontinuous gradient purifies viable platelet-derived mitochondria by removing platelet-derived debris, including microparticles, therefore confirming that this isolation method is ideal for studying the downstream effects of intact mitochondria in mitochondrial-related diseases.
33425947 What Role Does Trabecular Bone Score Play in Chronic Inflammatory Rheumatic Diseases? 2020 Patients suffering from rheumatic inflammatory diseases, e.g., systemic sclerosis, rheumatoid arthritis, and ankylosing spondylitis, are at risk of low bone mass. Dual-energy X-ray Absorptiometry (DXA) is the traditional radiological measurement technique for bone mineral density (BMD). The recently developed trabecular bone score (TBS) enhances the skeletal information provided by standard BMD. It re-analyzes the spatial dynamics of pixel intensity changes in lumbar spine DXA images, defining a quantitative index, characterizing trabecular bone microarchitecture. It has been demonstrated that low TBS values are associated with an increased incidence of fractures in patients with rheumatic diseases. These methods used together for bone damage evaluation can be of value to identify individuals who will potentially fracture. The main scientific literature on the clinical aspects of osteoporosis, including the use of TBS in evaluating this pathology, are herein reported aimed at shedding light on the role trabecular bone score plays in chronic inflammatory rheumatic diseases.
32357816 Computational Approaches for the Design of (Mutant-)Selective Tyrosine Kinase Inhibitors: 2020 Kinases remain one of the major attractive therapeutic targets for a large number of indications such as cancer, rheumatoid arthritis, cardiac failure and many others. Design and development of kinase inhibitors (ATP-competitive, allosteric or covalent) is a clinically validated and successful strategy in the pharmaceutical industry. The perks come with limitations, particularly the development of resistance to highly potent and selective inhibitors. When this happens, the cycle needs to be repeated, i.e., the design and development of kinase inhibitors active against the mutated forms. The complexity of tumor milieu makes it awfully difficult for these molecularly-targeted therapies to work. Every year newer and better versions of these agents are introduced in the clinic. Several computational approaches such as structure-, ligand-based or hybrid ones continue to live up to their potential in discovering novel kinase inhibitors. New schools of thought in this area continue to emerge, e.g., development of dual-target kinase inhibitors. But there are fundamental issues with this approach. It is indeed difficult to selectively optimize binding at two entirely different or related kinases. In addition to the conventional strategies, modern technologies (machine learning, deep learning, artificial intelligence, etc.) started yielding the results and building success stories. Computational tools invariably played a critical role in catalysing the phenomenal progress in kinase drug discovery field. The present review summarized the progress in utilizing computational methods and tools for discovering (mutant-)selective tyrosine kinase inhibitor drugs in the last three years (2017-2019). Representative investigations have been discussed, while others are merely listed. The author believes that the enthusiastic reader will be inspired to dig out the cited literature extensively to appreciate the progress made so far and the future prospects of the field.
32247672 Knee or Spine Surgery First? A Survey of Treatment Order for Patients With Concurrent Dege 2020 Aug BACKGROUND: Total knee arthroplasty (TKA) and lumbar spine surgery have been reported to affect the outcomes of each other. There is insufficient evidence to guide the choice of treatment order for patients with both disorders that are equally symptomatic. METHODS: Five clinical scenarios of concurrent, advanced, degenerative knee and lumbar spinal disorders were designed to survey surgeons' choices of treatment order and rationale. The spinal disorder was consistently degenerative lumbar spinal stenosis, but the knee conditions varied to include (1) osteoarthritis (OA) with varus deformity, (2) OA with valgus deformity, (3) rheumatoid arthritis with a severe flexion contracture, (4) OA without deformity, and (5) bilateral OA with windswept deformities. The survey was distributed to selected clinical members of the Knee Society and Scoliosis Research Society in North America. The surgeons' choices were compared among the 5 scenarios, and their comments were analyzed using text-mining. RESULTS: Responses were received from 42 of 74 (57%) knee arthroplasty surgeons and 55 of 100 (55%) spine surgeons. The percentages of knee arthroplasty surgeons recommending "TKA first" differed significantly among scenarios: 29%, 79%, 55%, 7%, and 81% for scenarios 1 through 5, respectively (P < .001). A similar pattern was noted for the spine surgeons. CONCLUSION: For patients with concurrent degenerative knee and lumbar spinal disorders, the severity and type of knee deformity influenced the preference of treatment order in both specialties. Severe valgus deformity and windswept deformities of the knee would drive the decision toward "TKA first."
32219644 Noninfectious Autoimmune Scleritis: Recognition, Systemic Associations, and Therapy. 2020 Mar 26 PURPOSE OF REVIEW: The aim of this review is to provide the information necessary for recognizing scleritis in rheumatology patients, recognize associated systemic diseases in scleritis patients referred to rheumatology, and choose the best conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic therapy, based on the most recent data. RECENT FINDINGS: Scleritis is most often associated with systemic conditions, particularly autoimmune conditions. Rheumatologists should be most vigilant about rheumatoid arthritis and ANCA-associated vasculitis. A recent systemic association has been found with IgG4-related disease as well. Most of the therapeutic decisions are based on observational data. Most recently, there is increasing evidence of the role of rituximab for refractory disease. Scleritis is a severe inflammatory ocular condition that leads to complications including vision loss. It can precede a systemic autoimmune disease diagnosis, especially in the case of vasculitis. Prompt recognition and adequate therapy are needed in order to avoid serious ocular complications. There is an unmet need for (1) head-to-heat trials on csDMARDs and biologic drugs for the treatment of idiopathic scleritis and (2) randomized controlled trials on the treatment of refractory cases.
32033287 Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Au 2020 Feb 5 Bacille Calmette-Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli's ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn's disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto's thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson's disease. Epidemiologic evidence points to BCG providing a "heterologous" protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer's disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection-this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.
33300326 Chronic cancer and non-cancer pain and opioid-induced hyperalgesia share common mechanisms 2021 Feb Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in peripheral and central nervous system (CNS), consists in altered vascular permeability followed by leukocyte recruitment and activation in the inflamed tissue, release of inflammatory mediators including cytokines and chemokines, and finally in the activation of microglia and astrocytes in the spinal cord and CNS. This phenomenon mediates and even worsen the inflammatory pain in many painful states and is responsible for central sensitization leading to pain chronicity. We describe the major neuroinflammatory mechanisms shared by cancer and non-cancer pain. Particular attention is given to two different chronic inflammatory painful diseases such as the complex regional pain syndrome and the rheumatoid arthritis as prototypes of neuroinflammatory diseases (gliopathies). In addition, we describe the complexity of tumor microenvironment, their main cellular components (tumor cells, tumor infiltrating leukocytes and sensory neurons) and their reciprocal interactions that characterize different forms and intensity of cancer pain. We also hypothesize that one type of cancer pain, the breakthrough pain, can be attributable to receptor-mediated interaction of opioids with tumor cells and intratumoral leukocytes. Surprisingly, long-term opioid treatment shares the same neuroinflammatory potential responsible for the chronicity of both cancer and non-cancer pain; thus, resulting in paradoxical worsening rather than relieving pain. This paradox has upset the world of pain therapy, with neuroinflammation now being a main target of emerging therapies.
33271551 Immunomodulation in Autoimmune Interstitial Lung Disease. 2020 Interstitial lung diseases (ILDs) associated with autoimmune or systemic disease are increasingly recognized and our pathophysiological understanding rapidly expanding. Treatment modalities, however, are still mainly driven by established disease-modifying antirheumatic drugs (DMARDs) where, despite decades of experience of their use in the underlying diseases such as rheumatoid arthritis, mostly ret-rospective data exist informing their effect on the course of interstitial lung disease (ILD). In recent years, randomized trials investigating the effects of biological DMARDs (bDMARDs) have been completed or are currently running, generating new treatment options for often relentlessly progressive diseases. Herein, we summarize the evidence and current use of both synthetic DMARDs and bDMARDs in the context of ILDs associated with autoimmune/systemic disease.
33151338 The cholinergic anti-inflammatory pathway in chronic kidney disease-review and vagus nerve 2020 Nov 1 Inflammation and autonomic dysfunction are common findings in chronic and end-stage kidney disease and contribute to a markedly increased risk of mortality in this patient population. The cholinergic anti-inflammatory pathway (CAP) is a vagal neuro-immune circuit that upholds the homoeostatic balance of inflammatory activity in response to cell injury and pathogens. CAP models have been examined in preclinical studies to investigate its significance in a range of clinical inflammatory conditions and diseases. More recently, cervical vagus nerve stimulation (VNS) implants have been shown to be of potential benefit for patients with chronic autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. We have previously shown that dialysis patients have a functional CAP ex vivo. Here we review the field and the potential role of the CAP in acute kidney injury and chronic kidney disease (CKD) as well as in hypertension. We also present a VNS pilot study in haemodialysis patients. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for improved treatment, outcome, prognosis and quality of life for patients with CKD.
32957384 Efficacy and safety of tripterygium glycosides in the treatment of hyperthyroidism: A syst 2020 Sep 18 BACKGROUND: Hyperthyroidism is a condition in which the thyroid gland is overreactive and produces excess amounts of thyroid hormone. Tripterygium glycosides, traditional Chinese medicine has been widely used in the treatment of rheumatoid arthritis, nephrotic syndrome, hyperthyroidism and other diseases due to its anti-inflammatory and immunosuppressive effects. Evidence-based research is becoming popular especially with the application of Chinese traditional medicine. This paper systematically reviews and evaluates existing clinical data on the efficacy and safety of Tripterygium glycosides in the treatment of hyperthyroidism. MATERIALS AND METHODS: PubMed, Cochrane library and EMBase, Chinese biomedical literature database (CBM), Chinese journal full-text database (CNKI), Wan fang digital periodical full-text database and China Science and Technology Journal Database (VIP) were searched based on the defined inclusion and exclusion criteria. Data extraction, research quality assessment and meta-analysis were conducted with RevMan5.3 software. Trial sequential analysis (TSA) was used to evaluate information size and treatment benefits. RESULTS: Seventeen randomized controlled clinical trials with 1536 participants were included in the systematic review. In the meta-analysis, there were two subgroups: Tripterygium glycosides combined with thiamazole and prednisone group; Tripterygium glycosides combined with thiamazole group. The study results revealed that the degree of exophthalmos, FT3, FT4, BGP, and AKP decreased while TSH, SOD, GSH-PX increased after the addition of Tripterygium glycosides. This study results suggested that Tripterygium glycosides combined with western medicine are an effective therapy for hyperthyroidism. CONCLUSION: This study indicates that Tripterygium glycosides enhances the effect of thiamazole and prednisone in the treatment of hyperthyroidism and without increasing the risk of adverse events.
32821152 Evaluating the Role of CXCR3 in Pain Modulation: A Literature Review. 2020 CXCR3 is a well-known receptor involved in immune cell recruitment and inflammation. Pathological inflammation leads to pain stimulation and hence nociception. Therefore, we decided to review the recent research on CXCR3 to identify its precise role in the modulation of pain in a variety of clinical conditions targeting various regions of the body. Studies were selected from PubMed Medline, which relate CXCR3 to the progression of diseases with either bone cancer pain, neuropathic pain, cystitis pain, osteoarthritis and rheumatoid arthritis pain, dental pain, in particular, periodontitis and pulpitis. In all the diseases studied, a high prevalence of CXCR3 and/or its ligand were identified where CXCR3 is a key player in the pathophysiological process of many inflammatory conditions. CXCR3 and its ligands, particularly CXCL10, modulate nociception via actions in the dorsal root ganglia and dorsal horn of the spinal cord, in cases of bone cancer pain, neuropathic, and joint pain. However, with the other studied disease, no direct link to pain has been made, although it contributes to the pathological progression of the diseases and hence would be a causal factor for the pain. Furthermore, CXCR3 appears to play a role in desensitizing the opioid receptor in the descending modulatory pathway within the brain stem as well as modulating opioid-induced hyperalgesia in the dorsal horn of the spinal cord. Further research is required for understanding the exact mechanisms of CXCR3 in pain modulation centrally and peripherally. A greater understanding of the immunological activities and pharmacological consequence of CXCR3 and its ligands could help in the discovery of newer drugs for modulating pain arising from pathogenic or inflammatory sources. Given the significance of the CXCR3 for nociception, its utilization may prove to be beneficial as a target for analgesia.
32674342 Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases. 2020 Jul 14 Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body's immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases-systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.
32590518 Increased Rate of Complications following Trigger Finger Release in Diabetic Patients. 2020 Oct BACKGROUND: The purpose of this study was to investigate the impact of diabetes on complications after open trigger finger release compared with a cohort matched for age, sex, race, and body mass index class. METHODS: A retrospective chart review was performed of diabetic patients who underwent trigger finger release at an academic institution within the past 10 years. Exclusion criteria included rheumatoid arthritis, malignancy, human immunodeficiency virus/acquired immunodeficiency syndrome, connective tissue disorders, or systemic steroid use. These patients were then matched by age, sex, race, and body mass index class to nondiabetic patients who underwent trigger finger release during the same period. One hundred thirty-seven patients met inclusion criteria and were matched with controls. Complications included superficial or deep infection, delayed wound healing, limited range of motion at 6 weeks, pain requiring medication at 6 weeks, and return to the operating room. RESULTS: In adjusted analyses, diabetic patients had a significantly higher rate of all-cause complication following trigger finger release compared with matched nondiabetic controls at an odds ratio of 2.1. Diabetic patients also had a significantly higher rate of limitation in postoperative range of motion compared to the controls with an odds ratio of 2.4. CONCLUSION: This retrospective case-control study identified that diabetic patients undergoing trigger finger release are at increased risk of all-cause postoperative complications and, specifically, range of motion limitation when compared with similar patients without diabetes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.
32526588 Role of IL-6 signalling in Polycystic Ovarian Syndrome associated inflammation. 2020 Sep Polycystic ovarian syndrome is a major factor contributing to the increasing incidence of infertility around the world. The metabolic effects of prolonged exposure to PCOS have been well determined from previous studies and seem to be detrimental in the long run. Studies have shown a multitude of conditions like insulin resistance, obesity and cardiovascular disorders to be associated with PCOS. This makes PCOS a syndrome requiring utmost attention in terms of women's health and reproduction. Interleukin-6 is one of the many cytokines released by adipocytes from fat deposits in the body. This review focuses on the Interleukin 6 signaling pathway and the data available on inflammatory modulators due to its significance PCOS mediated inflammation. There is noteworthy evidence of elevated IL-6 concentration in PCOS subjects that has been discussed in detail. The regulation of IL-6 levels in the body is in turn, maintained by a close relation with other cytokines, especially by a key regulator, NF-κB. Being involved in a multitude of other pathological conditions like rheumatoid arthritis, cardiovascular disorders, asthma, colon cancer and many more, the role of IL-6 is also investigated in PCOS in search of a probable reason for underlying inflammatory condition. On summarizing the IL-6 signaling pathway and therapeutic exploitation of the same, we see that IL-6 targeted drugs may be an efficient way of treating PCOS associated inflammation.
32458537 Elastosis perforans serpiginosa induced by d-penicillamine treated with cyclosporine and a 2020 Jul Elastosis perforans serpiginosa (EPS) is a rare condition within the group of perforating dermatoses. It is characterized by the synthesis of anomalous elastic fibers that are eliminated through perforating channels (transepidermal elimination). It is classified into three subtypes. One of them is drug-induced by prolonged treatment with d-penicillamine. This drug is a heavy metal chelator used to treat diseases such as rheumatoid arthritis, cystinuria, and Wilson's disease. Years of treatment with d-penicillamine at high doses are required for developing EPS, with occasional slow regression after drug withdrawal. There is no established treatment for EPS, with described cases using various treatment options such as corticoids, retinoids, tazarotene, cryotherapy, imiquimod, photodynamic therapy, electrosurgery, and CO2 laser among others with inconsistent results. We present a case of EPS induced by d-penicillamine with favorable response to cyclosporine and allopurinol in a patient with a history of Wilson's disease since childhood. They maybe considered as possible therapeutic options not described so far for an entity with variable response to current treatments. We highlight the extensive involvement of the case with progression, despite the suspension of d-penicillamine and failure to previous treatments with photodynamic therapy and retinoids.
32101812 Cardiac Arrhythmias in Autoimmune Diseases. 2020 Apr 24 Autoimmune diseases (ADs) affect approximately 10% of the world's population. Because ADs are frequently systemic disorders, cardiac involvement is common. In this review we focus on typical arrhythmias and their pathogenesis, arrhythmia-associated mortality, and possible treatment options among selected ADs (sarcoidosis, systemic lupus erythematosus, scleroderma, type 1 diabetes, Graves' disease, rheumatoid arthritis, ankylosing spondylitis [AS], psoriasis, celiac disease [CD], and inflammatory bowel disease [IBD]). Rhythm disorders have different underlying pathophysiologies; myocardial inflammation and fibrosis seem to be the most important factors. Inflammatory processes and oxidative stress lead to cardiomyocyte necrosis, with subsequent electrical and structural remodeling. Furthermore, chronic inflammation is the pathophysiological basis linking AD to autonomic dysfunction, including sympathetic overactivation and a decline in parasympathetic function. Autoantibody-mediated inhibitory effects of cellular events (i.e., potassium or L-type calcium currents, M(2)muscarinic cholinergic or β(1)-adrenergic receptor signaling) can also lead to cardiac arrhythmia. Drug-induced arrhythmias, caused, for example, by corticosteroids, methotrexate, chloroquine, are also observed among AD patients. The most common arrhythmia in most AD presentations is atrial arrhythmia (primarily atrial fibrillation), expect for sarcoidosis and scleroderma, which are characterized by a higher burden of ventricular arrhythmia. Arrhythmia-associated mortality is highest among patients with sarcoidosis and lowest among those with AS; there are scant data related to mortality in patients with psoriasis, CD, and IBD.
32099688 Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Si 2020 BACKGROUND: Cutis laxa is a rare dermatosis that is inherited or acquired and clinically features loose, wrinkled, and redundant skin with decreased elasticity. This heterogeneous connective tissue disorder may be localized or generalized, with or without internal manifestations. Generalized cutis laxa often has a cephalocaudal progression and is attributed to inflammatory cutaneous eruptions, medications, and infections. Cutis laxa is also associated with several other conditions including rheumatoid arthritis, systemic lupus erythematosus, and plasma-cell dyscrasias. Case Presentation. We report an unusual case of a 35-year-old male with progression of generalized acquired cutis laxa and vasculitis that occurred over a period of one year. No cutaneous inflammatory eruption preceded or accompanied his decreased skin elasticity, and a biopsy of the skin showed elastolysis. His cutaneous manifestation led to systemic evaluation and an eventual diagnosis of smoldering multiple myeloma accompanied by aortitis and anemia. His myeloma and vasculitis were successfully treated with cyclophosphamide, bortezomib, and dexamethasone and high-dose prednisone, respectively, with no improvement to his cutis laxa. CONCLUSIONS: The presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa. We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of certain dermatologic conditions, including scleromyxedema and amyloidosis. We present a case of a newly acquired cutis laxa secondary to plasma-cell dyscrasias that exemplifies MGODS, alongside a brief literature review, and underscore the clinical relevance of monoclonal gammopathies of dermatological significance.
32062853 Tramadol/Diclofenac Fixed-Dose Combination: A Review of Its Use in Severe Acute Pain. 2020 Jun Pain is a health issue affecting all populations, regardless of age, gender, economic status, race, or geography. Acute pain is the most common type of pain, with a complex aetiology. Inadequately managed acute pain adversely affects quality of life and imposes significant economic burden. The majority of the available pain-relieving drugs have monomodal mechanisms of analgesia, which necessitates combining drugs with non-redundant mechanisms of action in order to provide adequate pain relief and reduce the side effects from higher doses of individual drugs. In this regard, combining an oral opioid (such as codeine or tramadol) and a non-opioid (such as paracetamol or non-steroidal anti-inflammatory drug) offers a plausible option. Tramadol/diclofenac fixed-dose combination (FDC) is one such analgesic combination which has demonstrated promising clinical activity via its multimodal mechanisms of action. This review seeks to provide an up-to-date narrative on the current scientific literature regarding the pharmacological properties, clinical efficacy, and tolerability of tramadol/diclofenac FDC in the treatment of acute severe pain. A comprehensive, qualitative review of the literature was conducted using a structured search strategy in Medline/PubMed and additional Internet-based sources to identify relevant studies. Based on the available scientific literature, evidence of the efficacy and safety of tramadol/diclofenac FDC for treatment of patients with acute severe pain, including musculoskeletal pain, postoperative pain, and acute flare-up of osteoarthritis or rheumatoid arthritis, appears to be substantial. Although additional comparative studies would be required to definitively position tramadol/diclofenac FDC with respect to other analgesic combinations, the available data suggest that tramadol/diclofenac FDC is a valuable treatment option for patients with acute severe pain.
32023919 TLR4-Targeting Therapeutics: Structural Basis and Computer-Aided Drug Discovery Approaches 2020 Jan 31 The integration of computational techniques into drug development has led to a substantial increase in the knowledge of structural, chemical, and biological data. These techniques are useful for handling the big data generated by empirical and clinical studies. Over the last few years, computer-aided drug discovery methods such as virtual screening, pharmacophore modeling, quantitative structure-activity relationship analysis, and molecular docking have been employed by pharmaceutical companies and academic researchers for the development of pharmacologically active drugs. Toll-like receptors (TLRs) play a vital role in various inflammatory, autoimmune, and neurodegenerative disorders such as sepsis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, multiple sclerosis, cancer, and systemic lupus erythematosus. TLRs, particularly TLR4, have been identified as potential drug targets for the treatment of these diseases, and several relevant compounds are under preclinical and clinical evaluation. This review covers the reported computational studies and techniques that have provided insights into TLR4-targeting therapeutics. Furthermore, this article provides an overview of the computational methods that can benefit a broad audience in this field and help with the development of novel drugs for TLR-related disorders.
32014499 Angiotensin II inhibits osteogenic differentiation of isolated synoviocytes by increasing 2020 Apr The renin-angiotensin system contributes to the pathogenesis of rheumatoid arthritis, but that the mechanism is unclear. This study aims to investigate the effect of angiotensin II (Ang II) on osteogenic differentiation of synoviocytes and the underlying mechanism. Ang II was showed to inhibite osteogenic differentiation of synoviocytes, which was mitigated by a Dickkopf-1 (DKK-1) inhibitor. DKK-1 was upregulated by Ang II, which was weakened by the Ang II type 1 receptor (AT1R) blocker, reactive oxygen species (ROS) scavenger, and p38 inhibitor. Ang II increased the levels of AT1R, ROS, and NADPH oxidase (NOX), and the upregulations were mitigated by the AT1R blocker or NOX inhibitor. Furthermore, Ang II activated the p38 pathway, which was blocked by the AT1R blocker, ROS scavenger, or siRNA-MKK3. In brief, these results indicate that Ang II upregulates NOX expression and ROS production via AT1R, activates the MKK3/p38 signaling, and in turn upregulates DKK-1 expression, participating in the inhibition of osteogenic differentiation of synoviocytes.