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ID PMID Title PublicationDate abstract
34638561 In Silico Identification and Evaluation of Natural Products as Potential Tumor Necrosis Fa 2021 Sep 23 Tumor necrosis factor (TNF) is a regulator of several chronic inflammatory diseases, such as rheumatoid arthritis. Although anti-TNF biologics have been used in clinic, they render several drawbacks, such as patients' progressive immunodeficiency and loss of response, high cost, and intravenous administration. In order to find new potential anti-TNF small molecule inhibitors, we employed an in silico approach, aiming to find natural products, analogs of Ampelopsin H, a compound that blocks the formation of TNF active trimer. Two out of nine commercially available compounds tested, Nepalensinol B and Miyabenol A, efficiently reduced TNF-induced cytotoxicity in L929 cells and production of chemokines in mice joints' synovial fibroblasts, while Nepalensinol B also abolished TNF-TNFR1 binding in non-toxic concentrations. The binding mode of the compounds was further investigated by molecular dynamics and free energy calculation studies, using and advancing the Enalos Asclepios pipeline. Conclusively, we propose that Nepalensinol B, characterized by the lowest free energy of binding and by a higher number of hydrogen bonds with TNF, qualifies as a potential lead compound for TNF inhibitors' drug development. Finally, the upgraded Enalos Asclepios pipeline can be used for improved identification of new therapeutics against TNF-mediated chronic inflammatory diseases, providing state-of-the-art insight on their binding mode.
34629864 Development of an UPLC-MS/MS Method for the Quantitative Analysis of Upadacitinib in Beag 2021 BACKGROUND: Upadacitinib, a novel selective Janus kinase 1 (JAK1) inhibitor, has been recently approved by the US FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative analysis of upadacitinib in beagle dog plasma was developed and validated. METHODS: Upadacitinib and fedratinib (internal standard, IS) were extracted with ethyl acetate under alkaline condition and then separated and detected. The chromatographic column was Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm), the mobile phase was acetonitrile and 0.1% formic acid in water with gradient elution procedure, and the flow rate was 0.40 mL/min. Under the positive ion mode, upadacitinib and IS were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 447.00 → 361.94 for upadacitinib and m/z 529.82 → 141.01 for IS. RESULTS: In the concentration range of 1-500 ng/mL, upadacitinib had good linearity, and the lower limit of quantification (LLOQ) was 1 ng/mL. The RSD of the intra- and inter-day precision was less than 10.03%, and the RE of accuracy was -3.79% to 2.58%. The extraction recovery of upadacitinib was more than 80%, the matrix effect was around 100%, and upadacitinib was found to be stable. CONCLUSION: The novel optimized UPLC-MS/MS assay was an effective tool for the determination of upadacitinib and had been successfully applied to the pharmacokinetic study of upadacitinib in beagle dogs, and this method would also be used to study DDIs.
34368605 Factors Associated With Adherence to Osteoporosis Medications Among Male Veterans. 2021 Aug Risk factors for nonadherence to osteoporosis medication have been well described for cohorts of women with osteoporosis, but little is known about predictors or mediators of nonadherence in men. We conducted a secondary analysis of a national cohort of male veterans to explore factors associated with nonadherence to osteoporosis medications. We included veterans with a prescription for an oral bisphosphonate or calcitonin between 2000 and 2010. We identified demographic, comorbid, and fracture-related risk factors by their International Classification of Diseases-9 (ICD-9) and Current Procedural Terminology (CPT) codes and used multivariable logistic regression to evaluate their association with adherence. Adherence was measured by medication possession ratio (MPR) over 5 years, starting at the time of their first prescription during the study period and censoring at death or end of study period. Of 135,306 men identified with at least one prescription for an osteoporosis medication during the study period, 90,406 (67%) were nonadherent (MPR < 0.80). The median duration of therapy was 3.2 years (interquartile range [IQR] = 1.7-5.0). In the fully adjusted model, the odds of adherence were lower in those aged <65 years (odds ratio [OR] = 0.87; 95% confidence interval [CI] 0.84-0.89), with no copay (OR = 0.78; 95% CI 0.76-0.80), dementia (OR = 0.87; 95% CI 0.83-0.91), anxiety/depression (OR = 0.92; 95% CI 0.90-0.95), tobacco use (OR = 0.91; 95% CI 0.89-0.94), alcohol abuse (OR = 0.91; 95% CI 0.89-0.94), rheumatoid arthritis (OR = 0.92; 95% CI 0.87-0.97), and on androgen deprivation therapy (OR = 0.89; 95% CI 0.83-0.95). The odds of adherence were higher in whites (OR = 1.14; 95% CI 1.11-1.17), with a prior screening colonoscopy (OR = 1.12; 95% CI 1.09-1.14), on alendronate versus other agents (OR = 1.61; 95% CI 1.55-1.67), with a dual-energy X-ray absorptiometry (DXA) (OR = 1.14; 95% CI 1.12-1.17), on glucocorticoids (OR = 1.08; 95% CI 1.02-1.14), and with recent fracture (OR = 1.07; 95% CI 1.04-1.10). In conclusion, adherence to oral bisphosphonates/calcitonin is poor, with particular subgroups at greatest risk. These findings may help tailor approaches for supporting adherence in men prescribed osteoporosis medications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
34342515 TLR3TLR7 as Differentially Expressed Markers Among Viral, Nonviral, and Autoimmune Disease 2021 Nov Toll-like receptors (TLRs) represent the immune link between the innate and the adaptive immune signals against various pathogens. This study aimed to evaluate the TLRs3 and 7 as immune-markers in differentiating between hepatitis C virus (HCV)-infected and -uninfected patients. Also, the use of the TLR3 and TLR7 as immune markers was compared with the prevalent bio and immune markers for autoimmune diseases in HCV-infected or -uninfected patients. The levels of GPT, GOT, B cell activated factors, tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-10 were measured in plasma, while the levels of TLR3 and TLR7 were quantified in lysates of peripheral blood mononuclear cells from healthy donors, HCV-infected patients, nonalcoholic fatty liver (NAFL) patients without autoimmune diseases and with autoimmune diseases (HCV-infected patients with autoimmune diseases [HCV+auto], nonalcoholic fatty liver patients with autoimmune diseases [NAFL+auto]), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) patients. The relative expression of TLR3, TLR7, TNF, and IL-10 in cell lysates was assessed against glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by quantitative real time-polymerase chain reaction (qRT-PCR). Results showed that TLRs 3 and 7 levels were significantly higher in SLE, RA, HCV, HCV+auto, and the NAFL patients compared to the normal control. The cell lysates from SLE patients expressed TLR3 at relatively significantly higher mRNA levels compared to normal subjects or other patient groups. The NAFL+auto patients expressed TLR7 at relatively significantly high mRNA levels compared to normal subjects or other patients. The RA patients expressed TLR7 at relatively significantly higher mRNA levels when compared to HCV, HCV+auto, and NAFL+auto patients. Conclusions: At the protein level, TLR7 can differentiate between HCV and NAFL patients. In addition, both TLRs3 and 7 can serve as potent markers in differentiating between NAFL and NAFL+auto.
34333043 Oral probiotic promotes indoleamine 2,3-dioxygenase- and TGF-β-Producing plasmacytoid den 2021 Nov Colonization factor antigen I (CFA/I) fimbria, an adhesin from enterotoxigenic Escherichia coli, confers protection in murine autoimmune models for type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis. Although CFA/I fimbriae's initial mode of action is in a bystander or in an antigen (Ag)-independent fashion, protection is ultimately dependent upon the induction and/or activation of auto-Ag-specific regulatory T cells (Tregs). However, little is known about how protection transitions from bystander suppression to Ag-specific Tregs. Since dendritic cells (DCs) play an integral role in fate decisions for T cells becoming inflammatory or tolerogenic, the described study tests the hypothesis that Lactococcus lactis expressing CFA/I (LL-CFA/I) stimulates DCs to establish a regulatory microenvironment. To this end, bone marrow-derived dendritic cells (BMDCs) were infected in vitro with LL-CFA/I. Results revealed increased production of IL-10, TGF-β, and indoleamine 2,3-deoxygenase (IDO). Although co-culture of LL-CFA/I infected BMDCs with naïve T cells did not promote Foxp3 expression, TNF-α and IFN-γ production was suppressed. NOD mice orally dosed with LL-CFA/I showed an increase in regulatory plasmacytoid DCs (pDCs) expressing IDO and TGF-β in pancreatic lymph nodes (PaLNs) and spleen three days post-treatment. However, Tregs did not appear in the mucosal inductive sites until much later. These findings show that LL-CFA/I influences specific DC populations to establish tolerance.
34097181 The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therape 2022 Feb The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or more amino acids that inhibits the action of multiple proangiogenic factors. Preclinical and clinical evidence supports the therapeutic potential of vasoinhibin against angiogenesis-related diseases including diabetic retinopathy, peripartum cardiomyopathy, rheumatoid arthritis, and cancer. However, the use of vasoinhibin in the clinic has been limited by difficulties in its production. Here, we removed this barrier to using vasoinhibin as a therapeutic agent by showing that a short linear motif of just three residues (His46-Gly47-Arg48) (HGR) is the functional determinant of vasoinhibin. The HGR motif is conserved throughout evolution, its mutation led to vasoinhibin loss of function, and oligopeptides containing this sequence inhibited angiogenesis and vasopermeability with the same potency as whole vasoinhibin. Furthermore, the oral administration of an optimized cyclic retro-inverse vasoinhibin heptapeptide containing HGR inhibited melanoma tumor growth and vascularization in mice and exhibited equal or higher antiangiogenic potency than other antiangiogenic molecules currently used as anti-cancer drugs in the clinic. Finally, by unveiling the mechanism that obscures the HGR motif in prolactin, we anticipate the development of vasoinhibin-specific antibodies to solve the on-going challenge of measuring endogenous vasoinhibin levels for diagnostic and interventional purposes, the design of vasoinhibin antagonists for managing insufficient angiogenesis, and the identification of putative therapeutic proteins containing HGR.
33798594 Nabumetone induced photogenotoxicity mechanism mediated by ROS generation under environmen 2021 Jun 1 Nabumetone (NB) is a non-steroidal anti-inflammatory drug (NSAID), prescribed for managing pain associated with acute/chronic rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders. Though some incidences of photosensitivity have been reported, there is limited information available on its phototoxicity potential. In this study, NB photodegraded in a time-dependant manner (0-4 h) under UVA (1.5 mW/cm(2)), UVB (0.6 mW/cm(2)) and natural sunlight as observed through UV-vis spectrophotometer and the results were further confirmed with Ultra High-Performance Liquid Chromatography (UHPLC). Photosensitized NB generated reactive oxygen species (ROS) as observed by lipid peroxidation, suggesting oxidative degradation of lipids in cell membrane, thereby resulting in cell damage. MTT and NRU (neutral red uptake) assays revealed that NB induced phototoxicity in concentration-dependent manner (0.5, 1, 5, 10 μg/ml) under UVA, UVB and sunlight exposure (30 min) in human keratinocytes cell line (HaCaT), with significant phototoxicity at the concentration of 5 μg/ml. Photosensitized NB generated intracellular ROS, disrupted mitochondrial and lysosomal membrane integrity, resulting in cell death. UV-induced genotoxicity by NB was confirmed through micronuclei generation, γ-H2AX induction and cyclobutane pyrimidine dimer formation. This is the first study which showed the phototoxicity and photogenotoxicity potential of NB in HaCaT cell line. We also observed that photosensitized NB upregulated inflammatory markers, such as COX-2 and TNFα. This study proposes that sunlight exposure should be avoided by patients using nabumetone and proper guidance should be provided by clinicians regarding photosensitivity of drugs for better safety and efficacy.
33513356 Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update. 2021 Mar Owing to the dysregulation of protein kinase activity in many diseases including cancer, the protein kinase enzyme family has become one of the most important drug targets in the 21st century. There are 62 FDA-approved therapeutic agents that target about two dozen different protein kinases and eight of these were approved in 2020. All of the FDA-approved drugs are orally effective with the exception of netarsudil (a ROCK1/2 non-receptor protein-serine/threonine kinase antagonist given as an eye drop for the treatment of glaucoma) and temsirolimus (an indirect mTOR inhibitor given intravenously for the treatment of renal cell carcinoma). Of the approved drugs, ten target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block non-receptor protein-tyrosine kinases, and 35 target receptor protein-tyrosine kinases. The data indicate that 55 of these drugs are prescribed for the treatment of neoplasms (52 against solid tumors including breast, lung, and colon, nine against non-solid tumors such as leukemias, and four against both solid and non-solid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). A total of three drugs (baricitinib, tofacitinib, upadacitinib) is used for the treatment of inflammatory diseases including rheumatoid arthritis. Seven of the approved drugs form covalent bonds with their target enzymes and are classified as TCIs (targeted covalent inhibitors). Of the 62 approved drugs, eighteen are used in the treatment of multiple diseases. Imatinib, for example, is approved for the treatment of eight different disorders. The most common drug targets of the approved pharmaceuticals include BCR-Abl, B-Raf, vascular endothelial growth factor receptors (VEGFR), epidermal growth factor receptors (EGFR), and ALK. The following eight drugs received FDA approval in 2020 for the treatment of the specified diseases: avapritinib and ripretinib (gastrointestinal stromal tumors), capmatinib (non-small cell lung cancer), pemigatinib (cholangiocarcinoma), pralsetinib and selpercatinib (non-small cell lung cancer, medullary thyroid cancer, differentiated thyroid cancer), selumetinib (neurofibromatosis type I), and tucatinib (HER2-positive breast cancer). All of the eight drugs approved in 2020 fulfill Lipinski's rule of five criteria for an orally effective medicine (MW of 500 Da or less, five or fewer hydrogen bond donors, 10 or fewer hydrogen bond acceptors, calculated log(10) of the partition coefficient of five or less) with the exception of three drugs with a molecular weight greater that 500 Da: pralsetinib (534), selpercatinib (526) and ripretinib (510). This review summarizes the physicochemical properties of all 62 FDA-approved small molecule protein kinase inhibitors.
33171272 A review of the phytochemistry and pharmacology of Kadsura heteroclita, an important plant 2021 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Kadsura heteroclita (Roxb.) Craib (traditionally known as "Xue Tong") is an important member of the economically and medicinally important plant family Schisandraceae. "Xue Tong" is an imperative ingredient of the Tujia ethnomedicine, traditionally used for the treatment of rheumatoid arthritis (RA), hepatitis, and muscles and joint spasm. The plant is known to be a rich source of lignans and triterpenoids. These classes of natural products have been known to possess various pharmacological activities. AIM OF REVIEW: This review was motivated by the importance of K. heteroclita in traditional Chinese medicine (TCM). It aims to compile the available information on its botanical distribution and description, traditional uses, phytochemistry, pharmacological activities, toxicity, and quality control to provide a solid base for further research and development. MATERIALS AND METHODS: Relevant literature was collected by several scientific databases including PubMed, CNKI, Scifinder, The Plant List, Google Scholar, Baidu Scholar, Books (Tujia pharmaceutical records, Guangxi Chinese herbal medicine, Hunan pharmaceutical records and Field identification manual of Chinese herbal medicine) and other literature sources (Flora of China, Pharmacopoeia of the People's Republic of China) which helped in collecting maximum data about the studied species. RESULTS: Traditional uses of K. heteroclita have proven its medicinal importance, providing a rationale for scientific research. Phytochemical studies on the stem of K. heteroclita resulted in the identification of 187 chemical constituents, among which lignans and triterpenoids are the predominant groups. The isolates and crude extracts have been found to exhibit a wide spectrum of in vivo and in vitro pharmacological activities such as anti-RA, anti-inflammatory and analgesic, hepatoprotection, anti-HIV, anti-cancer and anti-HBV. Schisanlactone E (xuetongsu), a triterpenoid, is one of the major components of K. heteroclita exhibiting anti-cancer, neuroprotective and anti-neuroinflammation activities. Interestingly and luckily, this plant has been found to be safe and non-toxic within the therapeutic dose range. CONCLUSION: Pharmacological investigations have validated the use of K. heteroclita in traditional Chinese medicine (TCM). Literature review has demonstrated that lignans and triterpenoids are possibly responsible for most of the biological activities exhibited by this plant. To conclude, this plant shows immense potential for the discovery of more potent bioactive secondary metabolites and therefore further phytochemical and biological studies on other parts of K. heteroclita need to be conducted and more compounds need to be tested regarding their biological activities to completely explore its value as a tremendously important medicinal plant species.
33169195 Nodal EBV-positive polymorphic B cell lymphoproliferative disorder with plasma cell differ 2021 May Plasma cell differentiation (PCD) is frequently observed in some entities of non-Hodgkin B cell lymphoma, including both low-grade and high-grade lymphomas. However, except for plasmablastic lymphoma and primary effusion lymphoma, EBV(+) B cell lymphoproliferative disorder (LPD) with PCD has not been well addressed due to its rarity. We clinicopathologically examined five cases of nodal EBV(+) polymorphic B cell LPD with PCD (PBLPD-PCD) initially diagnosed as polymorphic EBV(+) diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) with PCD (n = 3) and methotrexate-associated B cell LPD (MTX-associated B-LPD) (n = 2). One case had a concomitant brain lesion which was clinically diagnosed as EBV-related encephalitis. This patient received therapy with vidarabine, and both the brain lesion and the nodal EBV(+) PBLPD-PCD lesions disappeared. Another case was characterized by Mott cell differentiation. This case was the first reported case of EBV(+) B cell lymphoma or LPD with Mott cell differentiation. The two cases of MTX-associated B cell LPD which arose in patients with rheumatoid arthritis spontaneously regressed after MTX cessation. TCRγ and IGH PCR analysis was performed in four cases. Two cases had TCRγ rearrangements, but no IGH rearrangements. The other two cases had no rearrangements in these genes. We concluded that nodal EBV(+) PBLPD-PCD is rare, with heterogeneous characteristics. PCR analysis revealed that nodal EBV(+) PBLPD-PCD may have only TCR clonality and no IGH clonality. Considering the partial or complete loss of CD20 expression on the tumor cells, this result may be confusing for accurate diagnosis of EBV(+) PBLPD-PCD, and pathologists need to be aware of this phenomenon to avoid misdiagnosis.
33152433 Kirenol, darutoside and hesperidin contribute to the anti-inflammatory and analgesic activ 2021 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese traditional medicine of Siegesbeckia pubescens Makino (SM), which has the effect of healing rheumatism and promoting joint health, is often used to treat rheumatoid arthritis and ischemic stroke. AIM OF THE STUDY: To clarify the mechanisms underlying the anti-inflammatory and analgesic influence of active components in the ethanol extract of Siegesbeckia pubescens Makino (ESM). MATERIALS AND METHODS: The active ingredients in the ESM were identified practicing high-performance liquid chromatography-diode array detection (HPLC-DAD). Four models including xylene-induced ear oedema, complete Freund's adjuvant (CFA)-induced hind paw oedema, acetic acid-induced pain writhing and lipopolysaccharide (LPS)-induced RAW264.7 cell migration, were used to clarify the anti-inflammatory and analgesic mechanisms of the active ingredients in the ESM. RESULTS: (1) Three active ingredients of kirenol, darutoside and hesperidin were identified in the ESM, with relative proportion of 0.6%, 0.2% and 0.01%, respectively; hesperidin was reported for the first time in the ESM. (2) Both the ESM and its active ingredients could effectively alleviate the degree of swelling of the auricle and toes, increase the threshold of heat pain, decrease the overexpression of inflammatory protein cyclooxygenase-2 (COX-2) in the skin tissue of the tested parts of the toes, and reduce the number of writhes induced by acetic acid in mice. (3) ESM and its active ingredients also dose-dependently inhibited the migration of RAW264.7 cells. CONCLUSIONS: ESM and its active ingredients can effectively attenuate the expression of inflammatory factors induced by chemical inflammation, prevent the infiltration of inflammatory cells, and exert good anti-inflammatory and antinociceptive activities.
34447382 Mycobacterium tuberculosis Immune Response in Patients With Immune-Mediated Inflammatory D 2021 Subjects with immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis (RA), have an intrinsic higher probability to develop active-tuberculosis (TB) compared to the general population. The risk ranges from 2.0 to 8.9 in RA patients not receiving therapies. According to the WHO, the RA prevalence varies between 0.3% and 1% and is more common in women and in developed countries. Therefore, the identification and treatment of TB infection (TBI) in this fragile population is important to propose the TB preventive therapy. We aimed to study the M. tuberculosis (Mtb) specific T-cell response to find immune biomarkers of Mtb burden or Mtb clearance in patients with different TB status and different risk to develop active-TB disease. We enrolled TBI subjects as example of Mtb-containment, the active-TB as example of a replicating Mtb status, and the TBI-IMID as fragile population. To study the Mtb-specific response in a condition of possible Mtb sterilization, we longitudinally enrolled TBI subjects and active-TB patients before and after TB therapy. Peripheral blood mononuclear cells were stimulated overnight with Mtb peptides contained in TB1- and TB2-tubes of the Quantiferon-Plus kit. Then, we characterized by cytometry the Mtb-specific CD4 and CD8 T cells. In TBI-IMID, the TB therapy did not affect the ability of CD4 T cells to produce interferon-γ, tumor necrosis factor-α, and interleukin-2, their functional status, and their phenotype. The TB therapy determined a contraction of the triple functional CD4 T cells of the TBI subjects and active-TB patients. The CD45RA(-) CD27(+) T cells stood out as a main subset of the Mtb-specific response in all groups. Before the TB-preventive therapy, the TBI subjects had higher proportion of Mtb-specific CD45RA(-)CD27(+)CD4(+) T cells and the active-TB subjects had higher proportion of Mtb-specific CD45RA(-)CD27(-)CD4(+) T cells compared to other groups. The TBI-IMID patients showed a phenotype similar to TBI, suggesting that the type of IMID and the IMID therapy did not affect the activation status of Mtb-specific CD4 T cells. Future studies on a larger and better-stratified TBI-IMID population will help to understand the change of the Mtb-specific immune response over time and to identify possible immune biomarkers of Mtb-containment or active replication.
34381024 Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30. 2021 Aug 11 Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.
34380536 Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as 2021 Aug 11 BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. METHODS/DESIGN: This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. DISCUSSION: Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20-35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02936375 . Registered on October 18, 2016.
34194898 Protein-protein interaction and in silico mutagenesis studies on IL17A and its peptide inh 2021 Jun Protein-protein interactions of Interleukin-17 (IL17) play vital role in the autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and psoriasis. Potent therapeutics for these diseases could be developed by blocking or modulating these interactions through biologics, peptide inhibitors and small molecule inhibitors. Unlike biologics, peptide inhibitors are cost effective and can be orally available. Peptide inhibitors do not require a binding groove as that of small molecules either. Therefore, crystal structure of IL17A in complex with a high affinity peptide inhibitor (HAP) (1-IHVTIPADLWDWIN-14) is investigated with an aim to find hot spots that could improve its potency. An in silico mutagenesis strategy was implemented using FoldX PSSM to scan for positions tolerant to amino acid substitution. Three positions T4, A7, and N14 showed improved stability when mutated with 'F/M/Y', 'P' and 'F/M/Y', respectively. A set of 31 mutant peptides are designed through combinations of these tolerant mutations using Build Model application of FoldX. Binding affinity and interactions of 31 peptides are assessed through protein-peptide docking and binding free energy calculations. Two peptides namely, P1 ("1-IHVTIPPDLWDWIY-14") and P2 ("1-IHVMIPPDLWDWIF-14") showed better binding affinity to IL17A dimerization site compared to HAP. Interactions of P1, P2 and HAP are also analyzed through 100 ns molecular dynamics simulations using GROMACS v5.0. The results revealed that the P2 peptide likely to offer better potency compared to HAP and P1. Therefore, the P2 peptide can be synthesized to develop oral therapies for autoimmune and inflammatory diseases with further experimental evaluations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-02856-y.
34136195 Antioxidant vitamins promote anticancer effects on low-concentration methotrexate-treated 2021 Jun Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.
30000400 Methotrexate. 2006 Most sources consider breastfeeding to be contraindicated during maternal high-dose antineoplastic drug therapy with methotrexate. An abstinence period of at least 1 week after chemotherapy doses of methotrexate has been suggested.[1] Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[2] Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant.[3] Maternal doses of methotrexate up to 92 mg (1.12 mg/kg) produce low levels in milk, leading some authors to state that low single or weekly doses, such as those used for ectopic pregnancy or rheumatoid arthritis, are of low risk to the breastfed infant,[4-8] although some expert opinion warns against this use.[9-13] Withholding breastfeeding for 24 hours after a weekly low dose of methotrexate may decrease the infant's dose by 40%.[14-16] If breastfeeding during long-term, low-dose methotrexate use is undertaken, monitoring of the infant's complete blood count and differential could be considered.
33563259 Association between body mass index and fragility fracture in postmenopausal women: a cros 2021 Feb 9 BACKGROUND: The present study examined the relationship between body mass index (BMI) and the risk for fragility fractures in postmenopausal Korean women. METHODS: Among subjects who participated in the 4th Korea National Health and Nutrition Examination Survey (2008-2009), 2114 women ≥ 40 years of age were included. BMI was based on standards set by the Korean Society for the Study of Obesity, as follows: < 18.5 kg/m(2), underweight; 18.5 ≤ to < 25 kg/m(2), normal weight; and ≥ 25 kg/m(2), obese. Subjects were also divided into three groups according to the location of fragility fracture: spine, hip, or wrist. RESULTS: The mean (± SD) rate of fragility fracture was significantly different among the three groups: 5.9 ± 2.9% (underweight), 1.1 ± 0.3% (normal weight), and 3.0 ± 0.7% (obese) (p = 0.001). After correcting for age, family history, and treatment history of osteoporosis and rheumatoid arthritis, smoking and drinking status, and level of exercise, multivariable regression analysis revealed that the odds ratio for fragility fracture in the underweight group was 5.48 [95% confidence interval (CI) 1.80-16.73] and 3.33 (95% CI 1.61-6.87) in the obese group. After subdividing fragility fractures into vertebral and non-vertebral, the odds ratio for vertebral fracture in the underweight group was 5.49 (95% CI 1.31-23.09) times higher than that in the normal weight group; in the obese group, the non-vertebral fracture odds ratio was 3.87 (95% CI 1.45-10.33) times higher. Analysis of non-vertebral fractures in the obese group revealed an odds ratio for fracture 22.05 (95% CI 1.33-365.31) times higher for hip fracture and 3.85 (95% CI 1.35-10.93) times higher for wrist fracture. CONCLUSIONS: Obesity and underweight increased the risk for fragility fractures in postmenopausal Korean women.
33550262 Medication adherence in multiple sclerosis as a potential model for other chronic diseases 2021 Feb 5 OBJECTIVE: To determine whether better medication adherence in multiple sclerosis (MS) might be due to specialised disease-modifying drug (DMD) support programmes by: (1) establishing higher adherence in MS than in other chronic diseases and (2) determining if higher adherence is associated with patient-specific or treatment-specific factors. DESIGN: Retrospective cohort study with data from 1 January 1996 to 31 December 2015. SETTING: Population-based health administrative data from three Canadian provinces. PARTICIPANTS: Individual cohorts were created using validated case definitions for MS, epilepsy, Parkinson's disease (PD) and rheumatoid arthritis (RA). Subjects were included if they received ≥1 dispensation for a disease-related drug between 1 January 1997 and 31 December 2014. MAIN OUTCOME MEASURES: Proportion of subjects with optimal adherence (≥80%) measured by the medication possession ratio 1 year after the index date (first dispensation of disease-related drug). RESULTS: 126 478 subjects were included in the primary analysis (MS, n=6271; epilepsy, n=55 739; PD, n=21 304; RA, n=43 164). Subjects with epilepsy (adjusted OR, aOR 0.29; 95% CI 0.19 to 0.45), PD (aOR 0.42; 95% CI 0.29 to 0.63) or RA (aOR 0.26; 95% CI 0.19 to 0.35) were less likely to have optimal 1-year adherence compared with subjects with MS. Within the MS cohort, adherence was higher for DMD than for chronic-use non-MS medications, and no consistent patient-related predictors of adherence were observed across all four non-MS medication classes, including having optimal adherence to DMD. CONCLUSIONS: Subjects with MS were significantly more likely to have optimal 1-year adherence than subjects with epilepsy, RA and PD, and optimal adherence appears related to treatment-specific factors rather than patient-related factors. This supports the hypothesis that higher adherence to the MS DMDs could be due to the specialised support programmes; these programmes may serve as a model for use in other chronic conditions.
33516071 Tea polyphenols and Levofloxacin alleviate the lung injury of hepatopulmonary syndrome in 2021 May BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterized by pulmonary vasodilation and arterial blood oxygen desaturation in patients with chronic liver disease. Generally, common bile duct ligation (CBDL) rats are a suitable experimental model for studying hepatopulmonary syndrome. Our previous study demonstrated that endotoxin surges markedly, followed by bacterial translocation and the loss of liver immune function in all the stages of CBDL, thereby contributing to the pathogenesis of HPS. However, the mechanisms behind the increase of the endotoxin and how to alleviate it have not yet been elucidated. Pulmonary injury induced by increased bilirubin, endotoxin, and inflammatory mediators occurs in the early and later stages of CBDL. This study assessed the effects of Tea polyphenols (TP) and Levofloxacin on endotoxin reduction and suppression of lung injury in HPS rats in the long and short term, respectively. METHODS: Morphological change of pulmonary injury, HPS relative index, endotoxin concentration, and the activation extent of Malondialdehyde (MDA) and Myeloperoxidase (MPO) were evaluated in CBDL rats with or without TP and Levofloxacin for three weeks or six weeks. The inflammation factors of serum, lung tissue, and BALF were then compared at the same condition for the two time periods. This was followed by adoption of the network pharmacology approach, which was mainly composed of active component gathering, target prediction, HPS gene collection, network analysis, and gene enrichment analysis. Finally, the mRNA and protein levels of the inflammatory factors were studied and relative signaling expression was assessed using RT-PCR and Western blot analysis. RESULTS: The obtained results indicated that the pulmonary injury manifestation was perceived and endotoxin, MDA, and MPO activation were markedly increased in the early and later stages of CBDL. TP and Levofloxacin treatment alleviated endotoxin infection and inflammation factor expression three weeks and six weeks after CBDL. In addition, Levofloxacin displayed a short time anti-bacterial effect, while TP exerted a long period function. TP and Levofloxacin also reduced TNF-α, TGF-β, IL-1β, PDGF-BB, NO, ICAM-1, and ET-1 expression on the mRNA or protein expression. With regard to the pharmacological mechanism, the network analysis indicated that 12 targets might be the therapeutic targets of TP and Levofloxacin on HPS, namely ET-1, NOs3, VEGFa, CCl2, TNF, Ptgs2, Hmox1, Alb, Ace, Cav1, and Mmp9. The gene enrichment analysis implied that TP and Levofloxacin probably benefited patients with HPS by modulating pathways associated with the AGE-RAGE signaling pathway, the TNF signaling pathway, the HIF-1 signaling pathway, the VEGF signaling pathway, and the IL-17 signaling pathway, Rheumatoid arthritis, Fluid shear stress, and atherosclerosis. Finally, the TNF-α level was mainly diminished on the protein level following CBDL. CONCLUSIONS: TP and Levofloxacin could alleviate pulmonary injury for short and long period, respectively, while at the same time preventing endotoxin and the development of HPS in CBDL rats. These effects are possibly associated with the regulation of the Endotoxin -TNF-α pathways.