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ID PMID Title PublicationDate abstract
33328268 Does the presence of cranial contrast spread during a sacroiliac joint injection predict s 2021 Mar BACKGROUND: The innervation of the sacroiliac joint (SIJ) is complex, with a dual innervation originating from the lumbosacral plexus anteriorly as well as the sacral lateral branches posteriorly. Nociceptors are found in intra-articular structures as well as periarticular structures. In patients with SIJ pain, a fluoroscopy-guided SIJ injection is usually performed posteriorly into the bottom one-third of the joint with local anesthetic and corticosteroids, but this does not always reach all intra-articular structures. The correlation between a cranial contrast spread and clinical success is undetermined in patients with SIJ pain. METHODS: In a tertiary referral pain center, electronic medical records of patients who underwent an SIJ injection were retrospectively analyzed. Only patients with at least three positive provocation maneuvers for SIJ pain were selected. Contrast images of the SIJ were classified as with or without cranial spread on fluoroscopy as a marker of intra-articular injection. Clinical success was defined as ≥50% improvement in the patient's global perceived effect after 3-4 weeks. The primary outcome was defined as the correlation between cranial contrast spread and clinical success after an SIJ injection. RESULTS: 128 patients in total were included. In 68 patients (53.1%) fluoroscopy showed cranial contrast spread. Clinical success was higher in patients with cranial spread of contrast (55 of 68, 81%) versus those without (35 of 60, 58%) (p=0.0067). In a multivariable analysis with age, gender, presence of rheumatoid arthritis, side, and number of positive provocation maneuvers, the cranial spread of contrast remained the only independent factor of clinical success (p=0.006; OR 3.2, 95% CI 1.4 to 7.7). CONCLUSION: In patients with SIJ pain, identified by positive pain provocation maneuvers, cranial contrast spread as a marker of intra-articular injection, with subsequent injection of 3 mL of local anesthetic and methylprednisolone 40 mg, was significantly correlated with clinical success up to 4 weeks. Therefore, attempts should be made to reach this final needle position before injecting local anesthetic and corticosteroids. This result needs to be confirmed in a high-quality prospective trial.
32731768 Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 wit 2021 Nov BACKGROUND: Alopecia Areata (AA) is a common inflammatory immune-mediated non-scarring hair loss; however, the exact genetic susceptibility remains to be clarified. Cytotoxic T-lymphocyte Associated Protein 4 (CTLA4) has emerged as a central and critically important modulator of immune responses and is believed to play a crucial rule in AA pathogenesis. OBJECTIVES: To investigate the association of CTLA4 variant (rs231775) within codon 17 with AA risk and outcomes. METHODS: Genetic analyses of the rs231775 SNP of CTLA4 gene were performed in 186 males (93 AA patients and 93 controls). RESULTS: The rs231775 CTLA4 variant was significantly higher in AA patients in comparison with control subjects especially among heterozygous and dominant model. This association varied significantly with disease severity. CONCLUSIONS: Individuals with homozygosity of rs231775 CTLA4 variant represented AA disease risk and increased severity than their counterparts.Abbreviations: AA: Alopecia areata; CTLA4: Cytotoxic T-lymphocyte Associated Protein 4; SNP: Single nucleotide polymorphism; LADA: Latent autoimmune diabetes in adults; SLE: Systemic lupus erythematosus; SCU: Suez Canal University; SALT: Severity of Alopecia Tool; DNA: Deoxyribonucleic acid; RT-PCR: Real-time polymerase chain reaction, HWE: Hardy-Weinberg equation; RA: rheumatoid arthritis.
32623537 Atlanto-axial rotary instability (Fielding type 1): characteristic clinical and radiologic 2021 Jun Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes, where it typically presents as a rotary subluxation due to incompetence of the alar ligament. This retrospective, IRB-approved study examines 20 subjects with Fielding type 1 rotary subluxation, characterized by anterior subluxation of the facet on one side, with a normal atlanto-dental interval. Subjects diagnosed with a heritable connective tissue disorder, and AAI had failed non-operative treatment and presented with severe headache, neck pain, and characteristic neurological findings. Subjects underwent a modified Goel-Harms posterior C1-C2 screw fixation and fusion without complication. At 15 months, two subjects underwent reoperation following a fall (one) and occipito-atlantal instability (one). Patients reported improvement in the frequency or severity of neck pain (P < 0.001), numbness in the hands and lower extremities (P = 0.001), headaches, pre-syncope, and lightheadedness (all P < 0.01), vertigo and arm weakness (both P = 0.01), and syncope, nausea, joint pain, and exercise tolerance (all P < 0.05). The diagnosis of Fielding type 1 AAI requires directed investigation with dynamic imaging. Alignment and stabilization is associated with improvement of pain, syncopal and near-syncopal episodes, sensorimotor function, and exercise tolerance.
35126098 Synthesis, Characterization, and in vivo Evaluation of a Novel Potent Autotaxin-Inhibitor. 2021 The autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway plays a role in a variety of autoimmune diseases, such as rheumatoid arthritis or neurodegeneration. A link to the pathogenesis of glaucoma is suggested by an overactive ATX-LPA axis in aqueous humor samples of glaucoma patients. Analysis of such samples suggests that the ATX-LPA axis contributes to the fibrogenic activity and resistance to aqueous humor outflow through the trabecular meshwork. In order to inhibit or modulate this pathway, we developed a new series of ATX-inhibitors containing novel bicyclic and spirocyclic structural motifs. A potent lead compound (IC(50) against ATX: 6 nM) with good in vivo PK, favorable in vitro property, and safety profile was generated. This compound leads to lowered LPA levels in vivo after oral administration. Hence, it was suitable for chronic oral treatment in two rodent models of glaucoma, the experimental autoimmune glaucoma (EAG) and the ischemia/reperfusion models. In the EAG model, rats were immunized with an optic nerve antigen homogenate, while controls received sodium chloride. Retinal ischemia/reperfusion (I/R) was induced by elevating the intraocular pressure (IOP) in one eye to 140 mmHg for 60 min, followed by reperfusion, while the other untreated eye served as control. Retinae and optic nerves were evaluated 28 days after EAG or 7 and 14 days after I/R induction. Oral treatment with the optimized ATX-inhibitor lead to reduced retinal ganglion cell (RGC) loss in both glaucoma models. In the optic nerve, the protective effect of ATX inhibition was less effective compared to the retina and only a trend to a weakened neurofilament distortion was detectable. Taken together, these results provide evidence that the dysregulation of the ATX-LPA axis in the aqueous humor of glaucoma patients, in addition to the postulated outflow impairment, might also contribute to RGC loss. The observation that ATX-inhibitor treatment in both glaucoma models did not result in significant IOP increases or decreases after oral treatment indicates that protection from RGC loss due to inhibition of the ATX-LPA axis is independent of an IOP lowering effect.
35008464 Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Pe 2021 Dec 21 Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.
34907694 Analytical evaluation of the Nittobo Medical tartrate resistant acid phosphatase isoform 5 2022 Feb 23 OBJECTIVES: Tartrate-resistant acid phosphatase, isoform 5b (TRACP-5b) is a bone resorption marker not influenced by renal function or food intake. TRACP-5b can be measured with Nittobo Medical enzymatic-immunoassay and IDS-iSYS automated immunoassay. We evaluated the Nittobo assay and established reference ranges for a Western-European population. We compared Nittobo and IDS results in different well-defined clinical populations. METHODS: We established the limits of detection and quantification (LOD-LOQ), linearity, imprecision and the reference ranges in 119 males, 50 women (<45 years) and 120 women (>60 years) for TRACP-5b with the Nittobo assay. We compared both assays in 30 hemodialyzed (HD), and 40 stage 3-5 patients suffering from chronic kidney disease (CKD), 40 patients suffering from rheumatoid arthritis and osteoporosis and 80 post-menopausal women. We measured TRACP-5b, β-crosslaps (β-CTX), bone alkaline phosphatase (B-ALP) and PTH in 20 hemodialyzed (HD) and 40 CKD patients. RESULTS: LOD and LOQ were 0.02 and 0.35 U/L. CV ranged from 8.3 to 4.3% (2/5 samples presenting CV > desirable CV). Method was linear up to of 11.3 U/L. Upper and lower limits of normality were 0.8-7.6 U/L in men, 0.9-4.7 U/L in women <45 and 0.9-7.1 U/L in women >60. The regression equation between the 2 methods was Nittobo = 1.13 (95% CI: 1.09-1.16) × iSYS - 0.4 (95% CI: -0.5; -0.3). TRACP-5b and b-ALP were in their respective reference ranges for most of CKD and HD patients. That was not the case for β-CTX, which increased with decreasing eGFR. CONCLUSIONS: Nittobo TRACP-5b presents interesting analytical features and a good concordance with IDS iSYS. These methods could thus potentially be harmonized.
34780984 A comprehensive review of research progress on the genus Arisaema: Botany, uses, phytochem 2022 Mar 1 ETHNOPHARMACOLOGICAL RELEVANCE: The genus Arisaema belongs to the family Araceae, which includes Chinese herbal medicines with wide-ranging pharmacological functions, including those useful for the treatment of stubborn phlegm, cough, epilepsy, tetanus, snakebite, rheumatoid arthritis, and other ailments. AIM OF THE STUDY: The current study aimed to comprehensively review the botany, uses, phytochemistry, pharmacology, toxicity, quality control and pharmacokinetics of plants in the genus Arisaema and to provide novel insights to develop future research in this field. MATERIALS AND METHODS: Relevant information on the genus Arisaema was obtained from published scientific materials (including materials from PubMed, Elsevier, Web of Science, Google Scholar, Baidu Scholar, CNKI, and Wiley) and other literature sources (e.g., the Chinese Pharmacopoeia, 2020 edition; Chinese herbal books and PhD and MSc thesis). RESULTS: The application information complied with this review and included processing techniques, traditional uses, clinical applications and classic prescriptions. Approximately 260 compounds, including flavonoids, alkaloids, saccharides, steroids, fatty acids, amino acids and volatile oils, have been separated and identified from the genus Arisaema. The isolated compounds exhibit wide-ranging pharmacological activities such as antitumor activity, analgesic and sedative activity, antioxidant activity and anti-inflammatory activity. The toxicity and irritant impacts, quality control, and pharmacokinetics are also discussed in this review. CONCLUSIONS: Plants in the genus Arisaema are valuable resources with therapeutic potential for a broad spectrum of ailments. Based on the limited literature, this review comprehensively and systematically summarizes current knowledge regarding the genus Arisaema for the first time. However, there have been insufficient studies on the active ingredients and germplasm and insufficient in-depth mechanistic studies. Therefore, isolation and identification of additional effective components and through research on the germplasm, pharmacodynamic mechanisms, and toxicology should be conducted to assess effectiveness and safety and to ensure the quality of the related drugs.
34593286 Predictors of preoperative deep vein thrombosis in hip fractures: A systematic review and 2021 Sep 27 BACKGROUND: The predictors of preoperative deep vein thrombosis (DVT) in patients with hip fractures remain unclear. Therefore, this study describes the results of a systematic review and meta-analysis of relevant peer-reviewed literature on this topic. METHODS: We searched PubMed, Google Scholar, Cochrane Library, Web of Science, and MEDLINE for articles published in English on the predictors of preoperative DVT in hip fractures. We calculated pooled odds ratios (OR) or mean differences (MD) for the DVT groups as compared with the non-DVT groups for each variable, including gender, age, body mass index, injury side, current smoking status, time from injury to admission, time from injury to surgery, fracture type, hypertension, arrhythmia, coronary artery disease, diabetes, stroke, kidney disease, liver disease, lung disease, malignancy, rheumatoid arthritis, D-dimer, fibrinogen, activated partial thromboplastin time, prothrombin time, thrombin time, hemoglobin, albumin, total cholesterol, and triglycerides. RESULTS: We included 9 studies involving 3,123 Asian patients with hip fractures (DVT, n = 570; non-DVT, n = 2,553). Being female (OR = 1.27; 95% confidence interval [CI] 1.04-1.56; p = 0.02), being of advanced age (MD = 1.63; 95% CI 0.80-2.47; p = 0.0001), having a longer time from injury to admission (MD = 0.80; 95% CI 0.48-1.12; p < 0.00001), having a longer time from injury to surgery (MD = 2.20; 95% CI 1.53-2.88; p < 0.00001), and the presence of kidney disease (OR = 1.76; 95% CI 1.04-2.96; p = 0.03) were correlated with a high risk of DVT. However, we found no significant differences between the two groups in the other predictors. CONCLUSIONS: Evidence indicates that being female, being of advanced age, having a longer time from injury to admission, having a longer time from injury to surgery, and having kidney disease are significantly correlated with a high risk of preoperative DVT in Asian patients with hip fracture. Further investigations with patients of other ethnicities are required.
34268037 Ropinirole-Associated Orthostatic Hypotension as Cause of a Prescribing Cascade in an Elde 2021 Jun Ropinirole is an overall well-tolerated antiparkinsonian medication that is also used to treat restless leg syndrome (RLS). The incidence of side effects is low, with orthostatic hypotension (OH) only anecdotally reported. Additionally, it is known that the elderly population is very susceptible to adverse drug effects and the prevalence of prescribing cascades that these can trigger is unknown. A 71-year-old male with history of atrial fibrillation, well-controlled diabetes on oral agents, hyperlipidemia, hypertension, ischemic heart failure status post (s/p) implantable cardioverter-defibrillator (ICD) placement with improved ejection fraction (EF), transient ischemic attack (TIA), rheumatoid arthritis, RLS, aortic stenosis s/p mechanical aortic valve replacement on anticoagulation, deep venous thrombosis (DVT), and right knee replacement, presented to the ED with generalized weakness, with difficulty standing from seated position, followed by a fall without head trauma. Over the eight months prior to this presentation, the patient had had similar symptoms that resulted in four falls, two hospital admissions, and new prescriptions of midodrine and compression stockings. On admission, vital signs were remarkable for positive orthostatics with blood pressure (BP) 110/74 mmHg, heart rate (HR) of 86 bpm in supine position and BP 87/51 mmHg, HR of 70 bpm while in standing position. Physical exam was unremarkable except for a known ejection murmur and dry oral mucous membranes. Labs included a creatinine 3.6 mg/dl, blood urea nitrogen (BUN) 66 mg/dl, international normalized ration (INR) of 4.1, B-natriuretic peptide (BNP) of 313 pg/mL, troponin <0.03 ng/mL. A kidney ultrasound was normal, and a transthoracic echocardiogram showed left ventricle ejection fraction (LVEF) of 55-65%, improved compared to a prior study. Furosemide, carvedilol and canagliflozin were discontinued and IV fluids were administered. In the subsequent days, his creatinine improved, and so did the patient's volume status, but he continued to be orthostatic despite midodrine and stockings. On further interview, the patient disclosed starting ropinirole 0.25 mg three times daily approximately 10 months prior to this admission, due to asymptomatic RLS that was reported in a sleep study. Decision was made to discontinue this medication, which resulted in improvement of symptoms. We were able to discontinue IV fluids, midodrine and stockings, and reintroduce carvedilol, furosemide and canagliflozin in a stepwise manner. In a follow-up visit one month after discharge, the patient was symptom-free. This case illustrates two major points. First, this prescribing cascade potentially induced by ropinirole, as well as the increase in health care costs associated to iatrogenic admissions, is major preventable problem faced mostly by the geriatric population. Second, although OH associated with ropinirole has only been reported in patients treated for Parkinson's disease, this side effect should be considered when prescribing ropinirole for other indications, with cautious assessment of risks and benefits. Further studies need to be conducted to establish the frequency of OH related to ropinirole.
34165690 Complex Regional Pain Syndrome: A Comprehensive Review. 2021 Dec Complex regional pain syndrome (CRPS) is a chronic pain condition often involving hyperalgesia and allodynia of the extremities. CRPS is divided into CRPS-I and CRPS-II. Type I occurs when there is no confirmed nerve injury. Type II is when there is known associated nerve injury. Female gender is a risk factor for developing CRPS. Other risk factors include fibromyalgia and rheumatoid arthritis. Unfortunately, the pathogenesis of CRPS is not yet clarified. Some studies have demonstrated different potential pathways. Neuropathic inflammation, specifically activation of peripheral nociceptors of C-fibers, has been shown to play a critical role in developing CRPS. The autonomic nervous system (ANS) is involved. Depending on whether it is acute or chronic CRPS, norepinephrine levels are either decreased or increased, respectively. Some studies have suggested the importance of genetics in developing CRPS. More consideration is being given to the role of psychological factors. Some association between a history of depression and/or post-traumatic stress disorder (PTSD) and the diagnosis of CRPS has been demonstrated. Treatment modalities available range from physical therapy, pharmacotherapy, and interventional techniques. Physical and occupational therapies include mirror therapy and graded motor imagery. Medical management with non-steroidal anti-inflammatory drugs (NSAIDs) has not shown significant improvement. There have been supporting findings in the use of short-course steroids, bisphosphonates, gabapentin, and ketamine. Antioxidant treatment has also shown some promise. Other pharmacotherapies include low-dose naltrexone and Botulinum toxin A (BTX-A). Sympathetic blocks are routinely used, even if their short- and long-term effects are not clear. Finally, spinal cord stimulation (SCS) has been used for decades. In conclusion, CRPS is a multifactorial condition that still requires further studying to better understand its pathogenesis, epidemiology, genetic involvement, psychological implications, and treatment options. Future studies are warranted to better understand this syndrome. This will provide an opportunity for better prevention, diagnosis, and treatment of CRPS.
34090139 Key role for hypothalamic interleukin-6 in food-motivated behavior and body weight regulat 2021 Sep The pro-inflammatory role of interleukin-6 (IL-6) is well-characterized. Blockade of IL-6, by Tocilizumab, is used in patients with rheumatoid arthritis and those diagnosed with cytokine storm. However, brain-produced IL-6 has recently emerged as a critical mediator of gut/adipose communication with the brain. Central nervous system (CNS) IL-6 is engaged by peripheral and central signals regulating energy homeostasis. IL-6 is critical for mediating hypophagia and weight loss effects of a GLP-1 analog, exendin-4, a clinically utilized drug. However, neuroanatomical substrates and behavioral mechanisms of brain IL-6 energy balance control remain poorly understood. We propose that the lateral hypothalamus (LH) is an IL-6-harboring brain region, key to food intake and food reward control. Microinjections of IL-6 into the LH reduced chow and palatable food intake in male rats. In contrast, female rats responded with reduced motivated behavior for sucrose, measured by the progressive ratio operant conditioning test, a behavioral mechanism previously not linked to IL-6. To test whether IL-6, produced in the LH, is necessary for ingestive and motivated behaviors, and body weight homeostasis, virogenetic knockdown by infusion of AAV-siRNA-IL6 into the LH was utilized. Attenuation of LH IL-6 resulted in a potent increase in sucrose-motivated behavior, without any effect on ingestive behavior or body weight in female rats. In contrast, the treatment did not affect any parameters measured (chow intake, sucrose-motivated behavior, locomotion, and body weight) in chow-fed males. However, when challenged with a high-fat/high-sugar diet, the male LH IL-6 knockdown rats displayed rapid weight gain and hyperphagia. Together, our data suggest that LH-produced IL-6 is necessary and sufficient for ingestive behavior and weight homeostasis in male rats. In females, IL-6 in the LH plays a critical role in food-motivated, but not ingestive behavior control or weight regulation. Thus, collectively these data support the idea that brain-produced IL-6 engages the hypothalamus to control feeding behavior.
34044348 Bio-inspired Ag nanovilli-based sandwich-type SERS aptasensor for ultrasensitive and selec 2021 Sep 15 Vitamin D has been identified as an essential biomarker for various diseases such as rheumatoid arthritis, cancer, and cardiovascular diseases. Recently, many reports have demonstrated a potential link between vitamin D and systemic infections, including coronavirus disease 2019. The villi of the small intestine increase the surface area of the intestinal walls, demonstrating exceptionally efficient absorption of nutrients in the lumen and adding digestive secretions. In this study, based on the villi structure, we developed a bio-inspired silver nanovilli-based sandwich-type surface enhanced Raman scattering aptasensor for the ultrasensitive and selective detection of 25-hydroxy vitamin D(3). The densely packed nanovilli structure enhanced the Raman signal, forming hotspots owing to its large surface area. Using experiments and electromagnetic simulations, we optimized the nanovilli structure as a SERS sensor. The sandwich-type aptasensor was designed using an aptamer and 4-Phenyl-1,2,4-triazoline-3,5-dione-methylene blue complex. The nanovilli-based aptasensor could sensitively detect various concentrations of 25-hydroxy vitamin D(3), ranging from those found in deficient to excess conditions. The detection limit of the nanovilli-based sandwich-type aptasensor for 25-hydroxy vitamin D(3) was 0.001 ng/mL, which is much lower than the deficiency concentration, and was detectable even in the human serum. In addition, our proposed sensor exhibited good repeatability (17.76%) and reproducibility (7.47%). Moreover, the nanovilli-based sandwich-type SERS aptasensor could selectively distinguish 25-hydroxy vitamin D(3) from other vitamins. The silver nanovilli-based sandwich-type surface enhanced Raman scattering aptasensor opens a new avenue for the development of a bio-inspired vitamin-sensing platform.
33958874 Intermanual Transfer Effects on Performance Gain Following Dominant Hand Training in Commu 2021 PURPOSE: This study aimed to evaluate the intermanual transfer effects of dominant hand training on the functional task of the untrained hand. METHODS: Fifty community-dwelling healthy adults (mean age, 23.4 ± 2.5 Y; females, 60%) were participated. Participants in the experimental group received 15 minutes of right-hand training on a pegboard apparatus twice a week for four weeks. The control group received no training. The Jebsen Taylor test (JTT) and a 16-hole pegboard test were used for the assessment of hand function and dexterity. RESULTS: Most of the JTT subtests except the writing and simulated feeding subtests and the performance of pegboard task by untrained hand were significantly improved in the experimental group after 4 weeks of training. However, no changes in the untrained hand function after 4 weeks in the control group. There were no significant differences in the pegboard task and JTT subtests found at baseline between the two groups. There were significant differences in the pegboard task between the two groups after dominant hand training. The experimental group took 4.3- and 2.5-second lesser time to complete the pegboard task using the dominant and non-dominant hand, respectively. Similarly, most of the JTT subtests except the writing and simulated feeding subtests were significantly better in the training group than the control group. CONCLUSION: This study indicates that the function of the untrained non-dominant hand may be improved after functional training of the dominant hand. Since this study included only healthy young adults, results of this study cannot be generalized to other groups of people such as the elderly. While this study suggests that intermanual transfer could have a therapeutic value in many clinical situations, more longitudinal studies are warranted to examine the intermanual transfer effects of functional gain in different clinical conditions, such as stroke, parkinsonism, rheumatoid arthritis, and so on.
33916057 Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Da 2021 Apr 1 Janus kinase inhibitors (JAKis) represent a new strategy in rheumatoid arthritis (RA) therapy. Still, data directly comparing different JAKis are rare. In the present in vitro study, we investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib, upadacitinib, and filgotinib) currently approved for RA treatment by the European Medicines Agency. Increasing concentrations of JAKi or methotrexate, conventionally used in RA therapy, were either added to freshly mitogen-stimulated or preactivated peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers. A comparable, dose-dependent inhibition of lymphocyte proliferation was observed in samples treated with tofacitinib, baricitinib, and upadacitinib, while dosage of filgotinib had to be two orders of magnitude higher. In contrast, antiproliferative effects were strongly attenuated when JAKi were added to preactivated PBMCs. High dosage of upadacitinib and filgotinib also affected cell viability. Further, analyses of DNA double-strand break markers γH2AX and 53BP1 indicated an enhanced level of DNA damage in cells incubated with high concentrations of filgotinib and a dose-dependent reduction in clearance of radiation-induced γH2AX foci in the presence of tofacitinib or baricitinib. Thereby, our study demonstrated a broad comparability of immunomodulatory effects induced by different JAKi and provided first indications, that (pan)JAKi may impair DNA damage repair in irradiated PBMCs.
33824270 Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) ago 2021 Apr 6 In the early 1990s, it has been described that LTα and LTβ form LTα(2)β and LTαβ(2) heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ(2)-LTβR system has been intensively studied while the LTα(2)β-TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα(2)β-TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα(2)β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα(2)β (memLTα(2)β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα(2)β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.
33808822 Health Potential of Clery Strawberries: Enzymatic Inhibition and Anti-Candida Activity Eva 2021 Mar 19 Strawberries, belonging to cultivar Clery (Fragaria × ananassa Duchesne ex Weston) and to a graft obtained by crossing Clery and Fragaria vesca L., were chosen for a study on their health potential, with regard to the prevention of chronic and degenerative diseases. Selected samples, coming from fresh and defrosted berries, submitted to different homogenization techniques combined with thermal and microwave treatments, had been previously analyzed in their polyphenolic content and antioxidant capacity. In the present work, these homogenates were evaluated in relation to their enzymatic inhibition activity towards acetylcholinesterase and butyrylcholinesterase, α-amylase, α-glucosidase and tyrosinase. All these enzymes, involved in the onset of diabetes, and neurodegenerative and other chronic diseases, were modulated by the tested samples. The inhibitory effect on tyrosinase and cholinesterase was the most valuable. Antifungal activity against Candida albicans, recently shown to play a crucial role in human gut diseases as well as diabetes, rheumatoid arthritis and Alzheimer's disease, was also shown in vitro and confirmed by the in vivo text on Galleria mellonella. Overall, the obtained results confirm once again the health potential of strawberries; however, the efficacy is dependent on high quality products submitted to correct processing flow charts.
33727095 Lapatinib ditosylate rescues memory impairment in D-galactose/ovariectomized rats: Potenti 2021 Jul Epidermal growth factor receptor (EGFR) signaling plays a substantial role in learning and memory. The upregulation of EGFR has been embroiled in the pathophysiology of Alzheimer's disease (AD). Nevertheless, most of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been extensively studied for non-CNS diseases such as cancer and rheumatoid arthritis. TKIs targeting-based research in neurodegenerative disorders sounds to be lagging behind those of other diseases. Hence, this study aims to explore the molecular signaling pathways and the efficacy of treatment with lapatinib ditosylate (LAP), as one of EGFR-TKIs that has not yet been investigated in AD, on cognitive decline induced by ovariectomy (OVX) with chronic administration of D-galactose (D-gal) in female Wistar albino rats. OVX rats were injected with 150 mg/kg/day D-gal ip for 8 weeks to induce AD. Administration of 100 mg/kg/day LAP p.o. for 3 weeks starting after the 8(th) week of D-gal administration improved memory and debilitated histopathological alterations. LAP decreased the expression of GFAP, p-tau, and Aβ 1-42. Besides, it reduced EGFR, HER-2, TNF-α, NOX-1, GluR-II, p38 MAPK, and p-mTOR. LAP increased nitrite, and neuronal pro-survival transduction proteins; p-PI3K, p-AKT, and p-GSK-3β levels. Taken together, these findings suggest the role of LAP in ameliorating D-gal-induced AD in OVX rats via activating the pro-survival pathway; PI3K-Akt-GSK-3β, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways. Moreover, this research offered a significant opportunity to advance awareness of the repositioning of TKI anti-cancer drugs for the treatment of AD.
33686135 Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates d 2021 Mar 8 Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABA(A)-receptors (GABA(A)-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABA(A)-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.
33679757 Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases? 2021 Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56(hi) NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.
33627323 Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macr 2021 Sep Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.