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ID PMID Title PublicationDate abstract
30005862 Pathogenic role of tissue-resident memory T cells in autoimmune diseases. 2018 Sep The tissue-resident memory T (T(RM)) cells constitute a newly identified subset of memory T cells which are non-circulating and they persist for long-term in epithelial barrier tissues, including skin, lung, gastrointestinal tract and reproductive tract, and in non-barrier tissues, including brain, kidney, pancreas and joint. These cells provide rapid on-site immune protection against previous exposed pathogens in peripheral tissues. There cells are transcriptionally, functionally and phenotypically distinguished from circulating effector memory T cells. In addition to their protective functions, increasing evidence reveals that autoreactive and/or aberrantly activated T(RM) cells may be involved in the pathogenesis of autoimmune disorders such as psoriasis and, as recently reported, may contribute to vitiligo, autoimmune hepatitis and rheumatoid arthritis. Therefore, this review aims to summarize the current progress in the biology of T(RM) cells, such as the newly identified T(RM) markers, upstream regulators, and the functions of T(RM) cells. We also discuss the contributions of T(RM) cells to the development of autoimmunity to broaden our understanding of autoimmune diseases and to provide novel potential therapeutic strategies for these diseases.
29851818 Difficulty in tracheal extubation followed by tracheal collapse after balloon dilatation f 2018 Jun RATIONALE: Tracheobronchomalacia (TBM) refers to the weakening trachea or the trachea loss of structural integrity of airway cartilaginous structures. It causes tracheal stenosis, resulting in significantly high rates of mortality. Bronchoplasty by high-pressure balloon dilation under general anesthesia is a simple but effective and safe method to treat tracheobronchial stenosis. However, recurrent postoperative dyspnea after extubation due to tracheal collapse is still a challenge for anesthetists. PATIENT CONCERNS: A 52-year-old man weighing 72 kg was scheduled for balloon dilatation surgery under general anesthesia because of breathing difficulties caused by tracheal stenosis. His previous medical history included rheumatoid arthritis, obstructive sleep apnea syndrome (OSAS), chronic bronchitis and a history of tracheal intubation. Laryngeal computerized tomography confirmed the stenosis at the level of thyroid gland. DIAGNOSIS: The tracheal collapse after balloon dilatation for tracheal stenosis therapy. INTERVENTIONS: Postoperatively, the patient presented with more serious and repetitive symptoms of dyspnea after extubation when compared to that before treatment. So, we had to re-insert the laryngeal mask airway (LMA), and exclude some anesthesia-associated factors, such as laryngospasm, bronchospasm and so on. After a series of treatments, we ultimately found the cause in time (the airway collapsed), and succeeded in tracheal extubation after the stent was inserted. OUTCOMES: The patient recovered well and reported high satisfaction with anesthesia management. LESSONS: In such an emergency even, the anesthesiologist should take valuable treatments to ensure the patient's effective ventilation. If the anesthesia-related factors can be eliminated, tracheomalacia or airway collapse should be considered whenever dyspnea occurs in the patients who unexpectedly fail to be extubated.
29755460 Proteinase 3 Interferes With C1q-Mediated Clearance of Apoptotic Cells. 2018 Proteinase 3 (PR3) is the autoantigen in granulomatosis with polyangiitis, an autoimmune necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Moreover, PR3 is a serine protease whose membrane expression can potentiate inflammatory diseases such as ANCA-associated vasculitis and rheumatoid arthritis. During apoptosis, PR3 is co-externalized with phosphatidylserine (PS) and is known to modulate the clearance of apoptotic cells through a calreticulin (CRT)-dependent mechanism. The complement protein C1q is one mediator of efferocytosis, the clearance of altered self-cells, particularly apoptotic cells. Since PR3 and C1q are both involved in the clearance of apoptotic cells and immune response modulation and share certain common ligands (i.e., CRT and PS), we examined their possible interaction. We demonstrated that C1q binding was increased on apoptotic rat basophilic leukemia (RBL) cells that expressed PR3, and we demonstrated the direct interaction between purified C1q and PR3 molecules as shown by surface plasmon resonance. To better understand the functional consequence of this partnership, we tested C1q-dependent phagocytosis of the RBL cell line expressing PR3 and showed that PR3 impaired C1q enhancement of apoptotic cell uptake. These findings shed new light on the respective roles of C1q and PR3 in the elimination of apoptotic cells and suggest a novel potential axis to explore in autoimmune diseases characterized by a defect in apoptotic cell clearance and in the resolution of inflammation.
29678878 A bispecific antibody that targets IL-6 receptor and IL-17A for the potential therapy of p 2018 Jun 15 Despite the success of current biological therapeutics for rheumatoid arthritis, these therapies, targeting individual cytokines or pathways, produce beneficial responses in only about half of patients. Therefore, better therapeutics are needed. IL-6 and IL-17A are proinflammatory cytokines in many autoimmune and inflammatory diseases, and several therapeutics have been developed to specifically inhibit them. However, targeting both of these cytokines with a bispecific therapeutic agent could account for their nonoverlapping proinflammatory functions and for the fact that IL-6 and IL-17A act in a positive feedback loop. Here, we present the development of MT-6194, a bispecific antibody targeting both IL-6R and IL-17A that was developed with the FynomAb technology. We also present data from mouse inflammatory disease experiments, indicating that simultaneous inhibition of both IL-6 and IL-17A yields enhanced efficacy compared with inhibition of each cytokine alone.
29492747 Biosimilars in the Treatment of Inflammatory Bowel Disease: Supporting Evidence in 2017. 2018 Mar PURPOSE OF REVIEW: Monoclonal antibodies targeting tumor necrosis factor-alpha, integrin molecules, and interleukin-12/23 have become backbone therapies for Crohn's disease and ulcerative colitis. While clinically effective, these biologic therapies come with significant expense, contributing to overall healthcare spending in the USA. Biosimilars have the potential to significantly reduce expenditures secondary to the use of biologic medications such as infliximab and adalimumab, though their complicated manufacturing process results in inherent differences in structure when compared to the originator compounds. In this article, we review the available literature regarding biosimilars in IBD. RECENT FINDINGS: Several biosimilar agents to infliximab and adalimumab are currently FDA-approved, with many more currently in development. Initial clinical trials for approval have been conducted in one of the original indications for each originator biologic. There are growing data demonstrating similar clinical efficacy, immunogenicity, and safety of each of the approved infliximab and adalimumab biosimilars, both through indication extrapolation from other diseases such as rheumatoid arthritis and ankylosing spondylitis, as well observational data in patients with inflammatory bowel disease. Further research is ongoing regarding the efficacy and safety of substitution and interchangeability of biosimilars, as well as therapeutic drug monitoring for biosimilar agents. Research to date supports the utilization of reference biologics and biosimilars for new initiators, while additional data are being accrued regarding the interchangeability between these agents.
29423085 The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma 2018 Jan 9 Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAF(V600E) mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.
29398333 A Rare Manifestation of Primary Bone Lymphoma: Solitary Diffuse Large B-Cell Lymphoma of t 2018 Aug Solitary primary non-Hodgkin bone lymphoma of the hand is a rare entity with only 3 cases reported in the literature. We report the case of a 77-year-old patient with isolated large B-cell bone lymphoma of the proximal phalanx of the little finger without rheumatoid arthritis or methotrexate treatment. The patient was treated with digital amputation and at 6 months' follow-up showed no relapse or dissemination of the disease.
29258726 A systematic review of outcome measures utilised to assess self-management in clinical tri 2018 May OBJECTIVES: The aim of this review was to identify, appraise and synthesise the outcome measures used to assess self-management in patients with chronic pain. METHODS: Medline, Embase, CINAHL, PsycINFO, the Cochrane Library and Google Scholar were searched to identify quantitative measures used within randomised or non-randomised clinical trials to assess self-management in adults (≥18 years) with chronic pain. RESULTS: 25 RCTs published between 1998 and 2016 were included in this review. Studies included patients with chronic pain, hip/knee osteoarthritis, rheumatoid arthritis, chronic low back pain, fibromyalgia and chronic fatigue syndrome. Included studies utilised 14 different measures assessing a variety of constructs including self-efficacy (n = 19), coping (n = 4), empowerment (n = 2), pain attitude and management (n = 3), self-care (n = 1), role behaviour (n = 1) and multiple constructs of self-management (n = 1). The Chronic Pain Coping Inventory (CPCI) and Health Education Impact Questionnaire (heiQ) cover different self-management related constructs across the physical, mental and social health domains. CONCLUSION: The review identified 14 measures used as proxy measure to assess self-management in patients with chronic pain. These measures have good content and construct validity, and internal consistency. However additional research is required to develop their reliability, responsiveness and interpretability. PRACTICE IMPLICATIONS: Multi-constructs measures (CPCI, heiQ) are suitable for assessing self-management.
29094181 Cardiovascular disease in patients with autoinflammatory syndromes. 2018 Jan Autoinflammatory syndromes (AIS) are characterized by recurring events of inflammation, leading to a variety of organ manifestations and fever attacks. A subgroup of AIS is commonly referred to as hereditary periodic fever syndromes (HPFS). There is substantial evidence that autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are strongly associated with cardiovascular morbidity and mortality. The link between AIS and cardiovascular disease is not that clear, even if the concept of continuous inflammation as a risk factor for cardiovascular disease is widely accepted. Research on the association of AIS and cardiovascular disease is increasing within the last years. In this review, we will discuss the association of several AIS with cardiovascular disease. Based on the rarity of some entities, lack of data, however, led to exclusion of some rare AIS. Especially, for Behcet's disease (BD), adult-onset Still's disease (AOSD), and Familial Mediterranean fever (FMF), there is an association with a number of cardiovascular abnormalities. BD is the AIS, which is most strongly associated with manifestation in the arterial and venous system. AOSD is strongly associated with cardiac inflammation (peri-/myocarditis). FMF patients are likely to suffer from serositis. Of note, there seems to be a link between variants of AOSD as well as FMF and idiopathic recurrent acute pericarditis.
29998827 Survival and safety of infliximab bio-original and infliximab biosimilar (CT-P13) in usual 2019 Jan OBJECTIVES: Reports to-date indicate similarity between infliximab biosimilar (IB) and infliximab bio-original (IO) in clinical efficacy and safety. This study examines the survival of IB and IO using routinely collected data over a 2-year period. METHODS: Routinely collected clinical data inputted directly in an electronic database at a large rheumatology centre were analysed. Adult patients taking IO or IB for any rheumatological diagnosis were included. Kaplan-Meier survival analyses were used to examine IB and IO survival, with a sub-group analysis among those starting infliximab from 2008 onwards. RESULTS: Out of 395 patients analysed, 53% (n=209) were female; the majority had rheumatoid arthritis (31%) followed by spondyloarthritis (28%). Ninety-nine patients had IB as the first infliximab drug. Patients who started on IB vs. IO as their first infliximab product, had better survival over the first 2 years (log rank=0.001). Discontinuation due to inefficacy was much commoner in IO versus IB users (18 vs. 5%). In patients switching from IO to IB, drug survival was better versus those receiving IB as the first infliximab drug (log rank=0.073). CONCLUSIONS: IB was well-tolerated and comparable to IO, with no additional safety signals identified. The results suggest superior survival of IB over IO over the first 2 years.
29966270 Gut Microbiome and Cardiovascular Diseases. 2018 Jun 29 Recent evidence has suggested that the gut microbiome is involved in human health and diseases, such as inflammatory bowel disease, liver cirrhosis, rheumatoid arthritis, and type 2 diabetes. Cardiovascular diseases, which are associated with high morbidity and mortality across the world, are no exception. Increasing evidence has suggested a strong relationship between the gut microbiome and the progression of cardiovascular diseases. We first reported such a relationship with coronary artery disease two years ago. Next-generation sequencing techniques, together with bioinformatics technology, constantly and dramatically expand our knowledge of the complex human gut bacterial ecosystem and reveal the exact role of this bacterial ecosystem in cardiovascular diseases via the functional analysis of the gut microbiome. Such knowledge may pave the way for the development of further diagnostics and therapeutics for prevention and management of cardiovascular diseases. The aim of the current review is to highlight the relationship between the gut microbiome and their metabolites, and the development of cardiovascular diseases by fostering an understanding of recent studies.
29938195 Novel Therapeutic Targets in Axial Spondyloarthritis. 2018 PURPOSE OF REVIEW: Axial spondyloarthritis remains an area of significant unmet clinical need with only two immune pathways currently targeted by licenced therapies compared to other immune-mediated inflammatory joint disorders such as rheumatoid arthritis where a multitude of therapeutic options are available. This review will look at emerging therapeutic targets in axial spondyloarthritis beyond the neutralisation of IL-17A and TNF by monoclonal antibodies. RECENT FINDINGS: Several promising targets are in various stages of pre-clinical and clinical development in axial spondyloarthritis. These include small molecule approaches to target transcription factors, epigenetic modification and intracellular modulation of cytokine signalling by kinase inhibition. GM-CSF has also emerged as a potential driver of inflammation. SUMMARY: A number of novel and promising therapeutic options are in various stages of development in axial spondyloarthritis. The Janus kinase inhibitors have shown great promise in other immune-mediated inflammatory disorders and will be an exciting addition to the axial spondyloarthritis field as the first oral disease-modifying agents. GM-CSF blockade also shows great promise since antibodies for neutralising this cytokine are safe in patients and have shown efficacy in other immune-mediated inflammatory diseases.
29899295 Impact of Dietary Cholesterol on the Pathophysiology of Infectious and Autoimmune Disease. 2018 Jun 13 Cellular cholesterol metabolism, lipid raft formation, and lipoprotein interactions contribute to the regulation of immune-mediated inflammation and response to pathogens. Lipid pathways have been implicated in the pathogenesis of bacterial and viral infections, whereas altered lipid metabolism may contribute to immune dysfunction in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Interestingly, dietary cholesterol may exert protective or detrimental effects on risk, progression, and treatment of different infectious and autoimmune diseases, although current findings suggest that these effects are variable across populations and different diseases. Research evaluating the effects of dietary cholesterol, often provided by eggs or as a component of Western-style diets, demonstrates that cholesterol-rich dietary patterns affect markers of immune inflammation and cellular cholesterol metabolism, while additionally modulating lipoprotein profiles and functional properties of HDL. Further, cholesterol-rich diets appear to differentially impact immunomodulatory lipid pathways across human populations of variable metabolic status, suggesting that these complex mechanisms may underlie the relationship between dietary cholesterol and immunity. Given the Dietary Guidelines for Americans 2015⁻2020 revision to no longer include limitations on dietary cholesterol, evaluation of dietary cholesterol recommendations beyond the context of cardiovascular disease risk is particularly timely. This review provides a comprehensive and comparative analysis of significant and controversial studies on the role of dietary cholesterol and lipid metabolism in the pathophysiology of infectious disease and autoimmune disorders, highlighting the need for further investigation in this developing area of research.
29891764 Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy? 2018 Jun 11 A new era of metal-based drugs started in the 1960s, heralded by the discovery of potent platinum-based complexes, commencing with cisplatin [(H₃N)₂PtCl₂], which are effective anti-cancer chemotherapeutic drugs. While clinical applications of gold-based drugs largely relate to the treatment of rheumatoid arthritis, attention has turned to the investigation of the efficacy of gold(I) and gold(III) compounds for anti-cancer applications. This review article provides an account of the latest research conducted during the last decade or so on the development of gold compounds and their potential activities against several cancers as well as a summary of possible mechanisms of action/biological targets. The promising activities and increasing knowledge of gold-based drug metabolism ensures that continued efforts will be made to develop gold-based anti-cancer agents.
29874690 A Disintegrin and Metalloproteases (ADAMs) in Cardiovascular, Metabolic and Inflammatory D 2018 Jul A disintegrin and metalloproteases (ADAMs) are membrane-bound enzymes responsible for the shedding or cleavage of various cell surface molecules, such as adhesion molecules, cytokines/chemokines and growth factors. This shedding can result in the release of soluble proteins that can exert agonistic or antagonistic functions. Additionally, ADAM-mediated cleavage can render these membrane proteins inactive. This review will describe the role and association of ADAMs in various pathologies with a main focus on ADAM10 and ADAM17 in atherosclerosis, including a brief overview of atherosclerosis-related ADAM substrates. Furthermore, ADAMs involvement in other metabolic and inflammatory diseases like diabetes, sepsis, Alzheimer's disease and rheumatoid arthritis will be highlighted. Subsequently, we will briefly discuss an interesting emerging field of research, i.e. the potential implications of ADAM expression in extracellular vesicles. Finally, several ADAM-based therapeutic and diagnostic (theranostic) opportunities will be discussed, while focusing on key questions about the required specificity and selectivity.
29107339 Comorbidities in rosacea: A systematic review and update. 2018 Apr BACKGROUND: Rosacea is linked to abnormalities of cutaneous vasculature and dysregulation of the inflammatory response. Recent reports on rosacea have shown a significant association with cardiovascular, gastrointestinal, and psychiatric diseases, all of which may affect morbidity and mortality among these patients. OBJECTIVE: To review available data regarding comorbidities associated with rosacea, discuss their pathogenesis, and highlight the evaluation of affected patients. METHODS: We performed a complete and systematic literature review in PubMed/Medline, Embase, and the Cochrane Collaboration databases, searching for all articles on possible associated diseases that have been reported with rosacea, with no limits on publication date, participant age, sex, or nationality. RESULTS: A total of 29 studies were included in this systematic review, including 14 case-control, 8 cross-sectional, and 7 cohort studies. Statistically significant association with rosacea has been mostly demonstrated with depression (n = 117,848 patients), hypertension (n = 18,176), cardiovascular diseases (n = 9739), anxiety disorder (n = 9079), dyslipidemia (n = 7004), diabetes mellitus (n = 6306), migraine (n = 6136), rheumatoid arthritis (n = 4192), Helicobacter pylori infection (n = 1722), ulcerative colitis (n = 1424), and dementia (n = 1194). LIMITATIONS: Limitations included the accuracy of the published data, potential patient selection, and possible confounding factors. The true nature of the drawn correlations is uncertain, and causality cannot be established. CONCLUSIONS: Rosacea is associated with a number of systemic disorders. Recognition of these conditions is critical to providing appropriate screening and management of affected patients.
30713550 Conserved Disease Modules Extracted From Multilayer Heterogeneous Disease and Gene Network 2018 Disease relationship studies for understanding the pathogenesis of complex diseases, diagnosis, prognosis, and drug development are important. Traditional approaches consider one type of disease data or aggregating multiple types of disease data into a single network, which results in important temporal- or context-related information loss and may distort the actual organization. Therefore, it is necessary to apply multilayer network model to consider multiple types of relationships between diseases and the important interplays between different relationships. Further, modules extracted from multilayer networks are smaller and have more overlap that better capture the actual organization. Here, we constructed a weighted four-layer disease-disease similarity network to characterize the associations at different levels between diseases. Then, a tensor-based computational framework was used to extract Conserved Disease Modules (CDMs) from the four-layer disease network. After filtering, nine significant CDMs were reserved. The statistical significance test proved the significance of the nine CDMs. Comparing with modules got from four single layer networks, CMDs are smaller, better represent the actual relationships, and contain potential disease-disease relationships. KEGG pathways enrichment analysis and literature mining further contributed to confirm that these CDMs are highly reliable. Furthermore, the CDMs can be applied to predict potential drugs for diseases. The molecular docking techniques were used to provide the direct evidence for drugs to treat related disease. Taking Rheumatoid Arthritis (RA) as a case, we found its three potential drugs Carvedilol, Metoprolol, and Ramipril. And many studies have pointed out that Carvedilol and Ramipril have an effect on RA. Overall, the CMDs extracted from multilayer networks provide us with an impressive understanding disease mechanisms from the perspective of multi-layer network and also provide an effective way to predict potential drugs for diseases based on its neighbors in a same CDM.
30514664 Regulatory and effector B cells: Friends or foes? 2019 Jan B cells have moved to the center stage in many autoimmune diseases including autoantibody-mediated diseases and T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. B cells play an important role for immune response beyond antibody production through mechanisms like antigen presentation and cytokine production. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by production of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β. Regulatory B cells have been found to be decreased and/or functionally impaired in various autoimmune diseases. In contrast, B cells also produce pro-inflammatory cytokines, such as IL-6, IFN-γ and GM - CSF. These effector B cells contribute to the pathogenesis of autoimmune diseases. Regulatory and effector B cell balance regulates immune response through the release of cytokines. Furthermore, a protocol that selectively depletes effector B cells while sparing regulatory B cells would represent a potent therapy for autoimmune diseases rather than pan-B cell depletion using anti-CD20 mAb.
30319765 Clinical utility of ozone therapy for musculoskeletal disorders. 2018 Jul Oxygen-ozone (O(3)) therapy serves as an alternative medical technique that increases the oxygen in the body along with the introduction of O(3). O(3) therapy has finally reached a level where the biological mechanisms of action have been understood, showing that they are in the domain of physiology, biochemistry, and pharmacology. Few clinical applications have been reviewed here as well as exemplifying that O(3) therapy is particularly useful in musculoskeletal disorders. In the therapeutic range, O(3) can be used as a more effective and safe substitute of standard medications. O(3) therapy has been used for many years for its ability to inactivate various viruses, cancer, and acquired immune deficiency syndrome but is now making strides in the treatment of musculoskeletal disorders such as rheumatoid arthritis, lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, osteoarthritis, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder.
30245627 Raging the War Against Inflammation With Natural Products. 2018 Over the last few decade Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the drugs of choice for treating numerous inflammatory diseases including rheumatoid arthritis. The NSAIDs produces anti-inflammatory activity via inhibiting cyclooxygenase enzyme, responsible for the conversation of arachidonic acid to prostaglandins. Likewise, cyclooxegenase-2 inhibitors (COX-2) selectively inhibit the COX-2 enzyme and produces significant anti-inflammatory, analgesic, and anti-pyretic activity without producing COX-1 associated gastrointestinal and renal side effects. In last two decades numerous selective COX-2 inhibitors (COXIBs) have been developed and approved for various inflammatory conditions. However, data from clinical trials have suggested that the prolong use of COX-2 inhibitors are also associated with life threatening cardiovascular side effects including ischemic heart failure and myocardial infection. In these scenario secondary metabolites from natural product offers a great hope for the development of novel anti-inflammatory compounds. Although majority of the natural product based compounds exhibit more selectively toward COX-1. However, the data suggest that slight structural modification can be helpful in developing COX-2 selective secondary metabolites with comparative efficacy and limited side effects. This review is an effort to highlight the secondary metabolites from terrestrial and marine source with significant COX-2 and COX-2 mediated PGE(2) inhibitory activity, since it is anticipated that isolates with ability to inhibit COX-2 mediated PGE(2) production would be useful in suppressing the inflammation and its classical sign and symptoms. Moreover, this review has highlighted the potential lead compounds including berberine, kaurenoic acid, α-cyperone, curcumin, and zedoarondiol for further development with the help of structure-activity relationship (SAR) studies and their current status.