The accumulation of ginsenosides (triterpenic saponins) was determined in Panax quinquefolium hairy root cultures subjected to an elicitation process using carvacrol at 5, 10, 25, 50, 100, 250, and 500 μM concentrations during 24 and 72 h exposure. This study was the first one in which carvacrol was applied as an elicitor. The content of eight ginsenosides, Rb1, Rb2, Rb3, Rc, Rd, Rg1, Rg2, and Re, was determined using HPLC analysis. Moreover, the quantitative RT-PCR method was applied to assess the relative expression level of farnesyl diphosphate synthase, squalene synthase, and dammarenediol synthase genes in the studied cultures. The addition of carvacrol (100 μM) was an effective approach to increase the production of ginsenosides. The highest content and productivity of all detected saponins were, respectively, 20.01 mg∙g-1 d.w. and 5.74 mg∙L-1∙day-1 after 72 h elicitation. The production profile of individual metabolites in P. quinquefolium cultures changed under the influence of carvacrol. The biosynthesis of most examined protopanaxadiol derivatives was reduced under carvacrol treatment. In contrast, the levels of ginsenosides belonging to the Rg group increased. The strongest effect of carvacrol was noticed for Re metabolites, achieving a 7.72-fold increase in comparison to the control. Saponin Rg2, not detected in untreated samples, was accumulated after carvacrol stimulation, reaching its maximum concentration after 72 h exposure to 10 μM elicitor.

Background Post-acute COVID-19 syndrome (PACS) is a syndrome characterized by a wide spectrum of symptoms emerging after clearance of coronavirus 2019 (COVID-19) infection. These symptoms include fatigue, myalgia, arthralgia, cognitive dysfunction, and many other psychiatric symptoms. Given that fibromyalgia patients have similar symptoms, we conducted a web-based cross-sectional study to investigate the prevalence and predictors of fibromyalgia patients who recovered from COVID-19. Methods Data were collected between the 9th and 19th of March 2022 using a web-based survey. The questionnaire consisted of 25 questions gathering sociodemographic information, comorbid diseases and features of acute COVID-19 infection. Lastly, the American College of Rheumatology (ACR) survey criteria completed the questionnaire. Results A final sample of 404 individuals (75% women) filled out the form. Of these, 80 (19.8%) satisfied the ACR survey criteria for fibromyalgia (93.8% women). A multivariate logistic regression model including demographic and clinical factors showed that female gender (OR: 6.557, 95% CI: 2.376 - 18.093, p = 0.001) and dyspnea (OR: 1.980, 95% CI: 1.146 - 3.420, p = 0.014) were the strongest predictors of being classified as having post-COVID-19 fibromyalgia. Bivariate correlation revealed that age (r = 0.200, p = 0.001) and duration of COVID-19 infection (r = 0.121, p = 0.015) were directly correlated with fibromyalgia symptom (FS) score. Conclusion Our data suggest that clinical features of fibromyalgia are common in patients who recovered from COVID-19 and that dyspnea and female gender increase the risk of developing post-COVID-19 fibromyalgia.

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To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes.
Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database.
We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated.
This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.

Sjögren syndrome (SS) is a multisystem autoimmune disease, primarily targeting salivary and lacrimal glands; skin, nasal and vaginal dryness, along with musculoskeletal pain and fatigue are the most commonly reported symptoms. Hearing loss is hypothesized to be frequent as well. The purpose of this systematic review was to estimate the prevalence of Hearing loss and its different subtypes in patients with Sjögren syndrome. PRISMA guidelines were followed to ensure highest quality for our systematic review. A random effects model meta-analysis and meta-regression was conducted using I2 as heterogeneity indicator. Eleven observational studies were included in this systematic review. Ten of them were cross-sectional, while one study was case-control. Studies were assessed for risk of bias: all were rated to a moderate level, except for two rated to a low level. Pooled prevalence of any type of hearing loss was 52.2%. After excluding studies rated to moderate bias, the pooled prevalence of hearing loss was 36.7%. We also conducted a subgroup analysis depending on type of hearing loss. Pooled prevalence of sensorineural hearing loss was 42.6%., while pooled prevalence of conductive hearing loss and mixed hearing loss were 5% and 2.3%, respectively. Meta-regression was conducted in an effort to identify possible variables capable to explain high heterogeneity between studies. Sample size and year of study were separately found to account for a portion of heterogeneity between studies of sensorineural hearing loss. Year of study was also found to account for a portion of heterogeneity between studies of conductive hearing loss. In conclusion, sensorineural hearing loss, is highly prevalent in patients with Sjögren syndrome. On this basis, early screening and follow-up of patients with Sjögren syndrome by pure tone audiometry is important.

Low blood fluid shear stress (SS) promotes vascular remodeling and atherosclerosis; however, the effects of high (H)SS on vascular remodeling and atherogenesis is not fully clarified. The major goal of this study was to investigate the role of HSS in atherosclerotic plaque formation. A perivascular SS modifier was implanted in the right carotid artery of apolipoprotein E (ApoE)‑/‑ mice to induce HSS, whereas the left carotid artery represented undisturbed (U)SS as a control in vivo. In vitro modeling used human umbilical vein endothelial cells and vascular smooth muscle cells exposed to HSS (2.5 Pa) using a parallel‑plate flow system. The results demonstrated that there were no plaque formations or endothelial cells in the HSS regions of the carotid artery in ApoE‑/‑ mice. The number of umbilical vein endothelial cells was markedly decreased in a time‑dependent manner in HSS. HSS significantly decreased α‑smooth muscle actin and increased osteopontin protein expression levels compared with USS in vascular smooth muscle cells (P<0.05). In addition, HSS significantly increased the protein expression levels of collagen α1(XVIII) chain/endostatin and matrix metalloproteinase‑8 in vascular smooth muscle cells. These data indicated that HSS may prevent atherosclerotic plaque formation through endothelium denudation and contractile‑to‑synthetic phenotypic conversion of smooth muscle cells.

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin\'s lymphoma, characterized by malignant T cells infiltrating the skin. CTCL exhibits vast heterogeneity which complicates diagnosis and therapeutic strategies. Current CTCL treatment includes skin-directed therapies (such as topical corticosteroid, topical mechlorethamine, topical bexarotene, ultraviolet phototherapy and localized radiotherapy), total skin electron beam therapy and systemic therapies. Elucidation of molecular and signaling pathways underlying CTCL pathogenesis leads to identification of innovative and personalized treatment schemes.Areas covered: The authors reviewed the molecular and immunological aspects of CTCL with special focus on Mycosis Fungoides (MF), Sézary Syndrome (SS) and associated systemic treatment. A literature search was conducted in PubMed and Web of Science for peer-reviewed articles published until November 2020. Novel treatment approaches including retinoids, targeted therapies, immune checkpoint and JAK/STAT inhibitors, histones deacetylase (HDAC) and mTOR inhibitors as well as proteasome inhibitors, are discussed as potential therapeutic tools for the treatment of CTCL.Expert opinion: Novel therapeutic agents exhibit potential beneficial effects in CTCL patients of high need for therapy such as refractory early stage cutaneous and advanced stage disease. Therapeutic schemes employing a combination of novel agents with current treatment options may prove valuable for the future management of CTCL patients.

The glutamic acid decarboxylase 65 antibody (GAD65-Ab) is an autoimmune marker in some diseases such as diabetes or autoimmune disorders of the central nervous system such as stiff-man syndrome. It can appear with other pancreatic autoantibodies, such as insulin autoantibodies (IAA), presenting as early signs of pancreatic islet β-cells impairing, and play roles in the pathogenesis of type1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). Positive GAD65-Ab is rarely observed in insulin-dependent diabetic patients with other acquired autoimmune diseases, such as Sjogren\'s syndrome (SS). Besides, LADA revealed by islet autoantibodies such as GAD65-Ab can also be complicated with Hashimoto\'s thyroiditis (HT), another autoimmune thyroid disease. To date, whether GAD65-Ab positive in patients with autoimmune diseases predicts the onset or progression to T1D or LADA remains unknown. Herein, two unique cases of middle-aged Chinese Han women free from diabetes for three years are described despite their blood tests persistently testing positive for GAD65-Ab or IAA. Both patients suffered from HT and SS. Follow-up OGTTs (oral glucose tolerance test) for three years revealed that the patients had a well-controlled glycemic level and normal pancreatic function. However, one of the patients had a temporary increase of postprandial glucose after a short-term loss of diet control. The presence of auto-immune antibodies in these patients had little impact on glucose tolerance or insulin secretion in 3 years. The study postulate that both the primary immune injury caused by serum GAD65-Ab positive, an autoimmune marker, and increased body weight contribute to the progression of LADA.

Background: Setleis syndrome (SS) is a focal facial dermal dysplasia presenting with bilateral temporal skin lesions, eyelash abnormalities and absent meibomian glands. SS is a rare autosomal recessive disorder caused by mutations in the TWIST2 gene, which codes for a transcription factor of the bHLH family known to be involved in skin and facial development. Methods: We obtained gene expression profiles by microarray analyses from control and SS patient primary skin fibroblast and lymphoblastoid cell lines. Results: Out of 983 differentially regulated genes in fibroblasts (fold change ≥ 2.0), 479 were down-regulated and 509 were up-regulated, while in lymphoblasts, 1248 genes were down-regulated and 73 up-regulated. RT-PCR reactions confirmed altered expression of selected genes. Conclusions: TWIST2 is described as a repressor, but expression profiling suggests an important role in gene activation as well, as evidenced by the number of genes that are down-regulated, with a much higher proportion of down-regulated genes found in lymphoblastoid cells from an SS patient. As expected, both types of cell types showed dysregulation of cytokine genes. These results identify potential TWIST2 target genes in two important cell types relevant to rare disorders caused by mutations in this bHLH gene.

UNASSIGNED: To introduce a novel technique of encircling laser prophylaxis (ora secunda cerclage Stickler syndrome, OSC/SS) to prevent rhegmatogenous retinal detachment (RRD) in Stickler syndrome eyes.
UNASSIGNED: After first eye RRD at age 50 and at age 18, respectively, a 53-year-old father and his 22-year-old son with type 2 SS (STL2) gave informed consent and underwent OSC/SS prophylaxis, performed in each fellow eye. A 26-year-old STL2 daughter then suffered first eye retinal detachment and similarly chose fellow eye OSC/SS prophylaxis. A second son, 28 years of age with STL2, chose OSC/SS prophylaxis in both eyes.
UNASSIGNED: The three OSC/SS treated fellow eyes have gone 12 years, 11 years, and 8 years without RRD. STL1 and less common STL2 eyes are known to have a similar rate of RRD, and 80% of STL1 fellow eyes develop RRD at a median of 4 years in the absence of prophylaxis. Moreover, five of six (83%) known STL2 family members suffered RRD, only the STL2 son with bilateral OSC/SS remaining bilaterally attached. All five OSC/SS treated eyes (average 8.7 years post-prophylaxis) retained preoperative visual acuity of 20/20 to 20/30, with an average, asymptomatic reduction of meridional field in each eye to 50 degrees. In contrast, in the three eyes having suffered RRD prior to presentation, visual acuity ranged from 20/125 to 8/200 and average meridional field was 29 degrees.
UNASSIGNED: Encircling grid laser (OSC) modified in Stickler eyes to encompass the ora serrata and extend posteriorly to and between the vortex vein ampullae (OSC/SS) is a reasonable RRD prophylaxis option to offer STL1 and STL2 patients as an alternative to no treatment or less effective prophylaxis. Because of rarity and severity, the ultimate proof of safety and efficacy will likely come not from randomized trials, but from a non-randomized, prospective, cohort comparison study of such individual efforts.