Inflammatory bowel disease (IBD) is a spectrum of immune-mediated inflammatory disorders with a complex multifactorial pathogenesis, where different pathways may predominate in different individuals. ...This complexity will most likely require a panoply of drugs targeting different pathways if one wants to treat to steroid-free sustained remission and mucosal healing. Presently, the mainstay of medical management of IBD is based on 5-aminosalicylates, corticosteroids, thiopurines, methotrexate, antitumor necrosis factor, anti-alpha4 beta7 (α4β7) integrin and anti-interleukin (IL)-12/IL-23 therapies. The discovery of new pathways involved in the pathogenesis of IBD resulted in new drugs targeting Janus kinase/signal transducers and activators of transcription, IL-6, spingosine-1-phosphate, and phosphodiesterase 4, among others. These new therapies might result in more advantageous safety profiles. Several of these new drugs have already been successfully tested in other inflammatory disorders, such as psoriasis or rheumatoid arthritis. In this review, evidence from phase II and phase III randomized controlled clinical trials in patients with IBD involving new biologicals and small molecules are summarized.
Endometriosis-associated chronic pelvic pain (EACPP) presents with an intense inflammatory reaction. Melatonin has emerged as an important analgesic, antioxidant, and antiinflammatory agent. This ...trial investigates the effects of melatonin compared with a placebo on EACPP, brain-derived neurotrophic factor (BDNF) level, and sleep quality. Forty females, aged 18 to 45 years, were randomized into the placebo (n = 20) or melatonin (10 mg) (n = 20) treatment groups for a period of 8 weeks. There was a significant interaction (time vs group) regarding the main outcomes of the pain scores as indexed by the visual analogue scale on daily pain, dysmenorrhea, dysuria, and dyschezia (analysis of variance, P < 0.01 for all analyses). Post hoc analysis showed that compared with placebo, the treatment reduced daily pain scores by 39.80% (95% confidence interval CI 12.88-43.01%) and dysmenorrhea by 38.01% (95% CI 15.96-49.15%). Melatonin improved sleep quality, reduced the risk of using an analgesic by 80%, and reduced BNDF levels independently of its effect on pain. This study provides additional evidence regarding the analgesic effects of melatonin on EACPP and melatonin's ability to improve sleep quality. Additionally, the study revealed that melatonin modulates the secretion of BDNF and pain through distinct mechanisms.
Endometriosis is a chronic gynaecological condition characterized by inflammatory and immune abnormalities. Likewise, these dysfunctions are important hallmarks of systemic lupus erythematosus (SLE), ...a condition that also has a high prevalence among women in reproductive age. Therefore, we conducted a systematic review and meta-analysis to investigate the association between endometriosis and SLE. We searched Medline and Web of Science for articles published from database inception to March 1, 2021. Random-effects meta-analysis was performed to provide a pooled risk ratio (RR). Individual study quality was evaluated following the National Heart, Lung, and Blood Institute Quality Assessment Tools (NHLBI QAT). From the 225 articles identified through our search, five studies-assessing 152,355 women-were included. Included studies presented an overall poor or fair quality rating. We observed a significant association between endometriosis and SLE (RR = 2.47, 95% confidence interval: 1.33-4.59, P < 0.004, I
= 54%). Sensitivity analyses stratifying articles by study design demonstrated that the association was significant in cross-sectional and case-control studies (RR = 5.07, 95% confidence interval: 1.42-18.11, P < 0.012), as well as in cohort studies (RR = 2.07, 95% confidence interval: 1.02-4.20, P < 0.044). In spite of the limited quality of included studies, our results suggest the existence of an association between endometriosis and SLE. These findings can aid medical assessment of patients with endometriosis, as well as provide further insights to better understand this gynaecological disorder.
This study compared autonomic modulation in swimmers and non-athletes in relation to body composition. A total of 28 athletes with a mean age of 19.7 ± 2.9 years were evaluated who had at least 2 ...years of swimming training, trained approximately 7,000 m per day, with a frequency of 5 days per week, and who competed at national level. The control group was made up of 21 volunteers (23.0 ± 2.5 years), who did not practice regular physical activity (<2 hours per week). Body composition was estimated using dual-energy x-ray absorptiometry, and autonomic modulation was assessed by heart rate variability (HRV). The results show that there were significant differences in autonomic modulation and body composition between the groups, and that the athletes had a higher overall variability (standard deviation of all normal intervals between consecutive heart beats SDNN: 78.1 72.5-93.5 × 61.1 56.4-75.7, p = 0.022) and greater autonomic balance (LF/HF: 0.96 0.88-1.35 × 0.71 0.56-0.93, p = 0.023), compared with the non-athletes, respectively. In addition, a moderate and positive relation was obtained between fat-free mass and the square root of the squared differences between consecutive heartbeat intervals (RMSSD: r = 0.526, p = 0.004 × r = 0.456, p = 0.038), (SDNN: r = 0.617, p = 0.001 × r = 0.571, p = 0.007) and low frequency (LFms: r = 0.517, p = 0.005 × r = 0.600, p = 0.004) in the athletes and non-athletes, respectively, without a correlation between fat mass (FM). The conclusion is that young highly trained swimmers had lower FM, increased fat-free mass, and better HRV than young adult non-athletes and suggests that a lower quantity of FM and, especially, a greater fat-free mass (FFM) are linked to better autonomic modulation. Thus, this study could contribute to coaches and trainers establishing greater performance by better autonomic modulation and greater quantity of FFM.
Current sequencing-based analyses of faecal microbiota quantify microbial taxa and metabolic pathways as fractions of the sample sequence library generated by each analysis. Although these relative ...approaches permit detection of disease-associated microbiome variation, they are limited in their ability to reveal the interplay between microbiota and host health. Comparative analyses of relative microbiome data cannot provide information about the extent or directionality of changes in taxa abundance or metabolic potential. If microbial load varies substantially between samples, relative profiling will hamper attempts to link microbiome features to quantitative data such as physiological parameters or metabolite concentrations. Saliently, relative approaches ignore the possibility that altered overall microbiota abundance itself could be a key identifier of a disease-associated ecosystem configuration. To enable genuine characterization of host-microbiota interactions, microbiome research must exchange ratios for counts. Here we build a workflow for the quantitative microbiome profiling of faecal material, through parallelization of amplicon sequencing and flow cytometric enumeration of microbial cells. We observe up to tenfold differences in the microbial loads of healthy individuals and relate this variation to enterotype differentiation. We show how microbial abundances underpin both microbiota variation between individuals and covariation with host phenotype. Quantitative profiling bypasses compositionality effects in the reconstruction of gut microbiota interaction networks and reveals that the taxonomic trade-off between Bacteroides and Prevotella is an artefact of relative microbiome analyses. Finally, we identify microbial load as a key driver of observed microbiota alterations in a cohort of patients with Crohn's disease, here associated with a low-cell-count Bacteroides enterotype (as defined through relative profiling).
Accurate diagnosis and treatment of pain is dependent on knowledge of the variables that might alter this response. Some of these variables are the locality of the noxious stimulus, the sex of the ...individual, and the presence of chronic diseases. Among these chronic diseases, hypertension is considered a serious and silent disease that has been associated with hypoalgesia. The main goal of this study was to evaluate the potential nociceptive differences in spontaneously hypertensive rats (SHR) regarding the locality of the stimulus, i.e., the temporomandibular joint or paw, the sex, and the role of ovarian hormones in a model of mechanical nociception (Von Frey test) or formalin-induced inflammatory nociception. Our results indicate that SHR had lower orofacial mechanical nociception beyond the lower mechanical nociception in the paw compared with WKY rats. In a model of formalin-induced inflammatory nociception, SHR also had decreased nociception compared with normotensive rats. We also sought to evaluate the influence of sex and ovarian hormones on orofacial mechanical nociception in SHR. We observed that female SHR had higher mechanical nociception than male SHR only in the paw, but it had higher formalin-induced orofacial nociception than male SHR. Moreover, the absence of ovarian hormones caused an increase in mean arterial pressure and a decrease in paw nociception in female SHR.
DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates ...developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed gene promotes the annealing of the nascent RNA to the template DNA strand, leading to the formation of an R-loop. Depletion of TET enzymes reduced global R-loops in the absence of gene expression changes, whereas CRISPR-mediated tethering of TET to an active gene promoted the formation of R-loops. The genome-wide distribution of 5hmC and R-loops shows a positive correlation in mouse and human stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, disclosing new mechanisms of gene expression regulation.
Abstract
Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is a key factor activated by DNA damage and replication stress. An alternative pathway for ATR activation has been proposed to ...occur via stalled RNA polymerase II (RNAPII). However, how RNAPII might signal to activate ATR remains unknown. Here, we show that ATR signaling is increased after depletion of the RNAPII phosphatase PNUTS-PP1, which dephosphorylates RNAPII in its carboxy-terminal domain (CTD). High ATR signaling was observed in the absence and presence of ionizing radiation, replication stress and even in G1, but did not correlate with DNA damage or RPA chromatin loading. R-loops were enhanced, but overexpression of EGFP-RNaseH1 only slightly reduced ATR signaling after PNUTS depletion. However, CDC73, which interacted with RNAPII in a phospho-CTD dependent manner, was required for the high ATR signaling, R-loop formation and for activation of the endogenous G2 checkpoint after depletion of PNUTS. In addition, ATR, RNAPII and CDC73 co-immunoprecipitated. Our results suggest a novel pathway involving RNAPII, CDC73 and PNUTS-PP1 in ATR signaling and give new insight into the diverse functions of ATR.
The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus ...stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.
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