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IntroductionGMR 2019 have suggested fixed hours of self-directed learning (SDL) for all subjects for helping the students to develop their learning skills and sense of responsibility for a better learning in future. Presently, the trend of SDL is becoming more e learning centric in comparison to use of text books with its consequent advantages and disadvantages. The present study aimed to analyze the challenges associated with this trend in the phase 1 MBBS students. MethodsIn an interventional educative study 203 phase 1 students from an urban medical college were assessed for an SDL based project on clinical aspects of the urea cycle at the end of the topic ammonia metabolism in Department of Biochemistry. Output from students were analysed for their trend for using resource materials, selection of relevant materials and originality of their inputs during the SDL process. Data obtained were analysed for their percentage distribution anddifference of mean values as applicable. Results Out of 197 students who submitted their SDL projects in completed form, 61% students used internet information only, 20% used books only while 19% used both their resource materials. 32% of them could not use right key words for search and produced irrelevant materials in their topic. About 58% adopted copy and paste process without any change. Interestingly, the marks obtained by text book users were significantly higher than those using e resource materials. ConclusionsThe present study reveals that in spite of having a higher inclination to use e learning resources most of the students are yet to coordinate between their study topic & internet information. Moreover, the trend for copying without comprehension was found to be significantly higher among e learners. Hence, the investigators suggest that for proper use of SDL, guidance by expert faculties regarding how to search internet properly using appropriate keywords and how to comprehend the core information of the e-resources into their own language are necessary to make it a successful component of CBME.

Toll-like receptors (TLRs) are essential defensive mediators implicated in immune diseases. Tight regulation of TLR function is indispensable to avoid the damaging effects of chronic signaling. Several endogenous molecules have emerged as negative regulators of TLR signaling. In this review, we highlighted the structure, regulation, and function of RP105 and A20 in negatively modulating TLR-dependent inflammatory diseases, and in fibrosis and potential therapeutic approaches.

The health benefit of coffee consumption mainly depends on chlorogenic acid (CGA), one of its major active phenolic constituent.CGA have several biological properties like anticancer, antihypertensive, hepatoprotective, neuroprotective, renoprotective, antimicrobial etc. It is assumed that different forms of coffee contains different amount of CGA. In this regards, we developed and validated a simple and cost effective chromatographic technique to identify and quantify CGA in green coffee, roasted coffee and branded instant coffee available in Indian market.

Introduction: Medical Council of India (MCI) in the current competency based on the undergraduate curriculum for the Indian medical graduate has focussed on the development of critical thinking, reasoning and communicating abilities of the undergraduate students. This would enable them to apply their knowledge effectively and provide better patient care. In this context, concept mapping has proved to be a simple yet powerful tool. Aim: To assess the feasibility of implementing concept mapping module and perception of the students and faculty about use of concept mapping as complementary teaching aid in pharmacology using peer validated questionnaires and Focus Group Discussion (FGD). Materials and Methods: This cross-sectional interventional study was conducted in the Department of Pharmacology of a tertiary hospital in Eastern India. Study duration was six months, from September 2019 to February 2020. After obtaining permission from Institutional Ethics Committee (IEC), 64 consenting students of 2nd professional MBBS, Dean of student affairs, Medical Education Unit (MEU) Co-ordinator and 10 faculties of the Department of Pharmacology were sensitised about the concept mapping. A module for implementation and assessment rubric was decided. Participating students were randomly divided into eight groups (Group A, B, C, D, E, F, G, H), each group comprising eight students. Each group had to prepare one concept map on an allotted topic from General Pharmacology. They had to submit the maps within seven days. Students could use pen and paper or they could utilise computer software to prepare the maps. After submission, faculties other than the researcher assessed and gave feedback to the students. After one month, the second set of assignments was allotted on topics from autonomic nervous system. As before, submission had to be done in seven days. This set was also assessed and feedback given. At the end of second submission, perception of the students and faculties about implementation of the module was assessed through peer validated open as well as closed ended questionnaires. A FGD was also held among participating faculties. Open ended questions were analysed using verbatim and closed ended questions were analysed as percentage using Microsoft Excel. FGD was analysed using content analysis method. Results: Among the 64 participating students, 63 (98.43%) preferred concept mapping as complementary teaching tool in addition to traditional tutorial format and 62 (96.9%) students enjoyed making the concept maps. On analysis of students’ feedback, 56 (87.5%) students opined that this module could be included in Pharmacology curriculum. Out of 12 faculties, 7 (58.33%) graded feasibility of the module as 4 out of a maximum of 5. Conclusion: This study concludes that with proper selection of topics, concept mapping may be included as complementary teaching learning tool in Pharmacology curriculum for undergraduate students.

Summary The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD+) that is due to dysregulation of NAD+ homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD+-synthesizing enzymes is unaltered. Boosting NAD+ via genetic or pharmacological CD38 targeting or NAD+ precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD+ levels and sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD+ homeostasis as a fundamental mechanism driving fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target., Graphical Abstract, Highlights • CD38 shows elevated expression in skin biopsies of patients with systemic sclerosis • Elevated CD38 is associated with reduced NAD+ and augmented fibrotic responses • Genetic loss of CD38 is associated with increased NAD+ levels and attenuated fibrosis • NAD+ boosting via CD38 inhibition or NR supplementation prevents multi-organ fibrosis, Human Metabolism; Molecular Biology; Immunology

Objective : Schizophrenia is a serious disease characterized by impairment in the perception or expression of reality, leading to occupational and social dysfunction. The use of antipsychotic medication is now universal in the first-line treatment of schizophrenia. This study was undertaken to compare the efficacy of asenapine with a standard atypical antipsychotic, olanzapine in treating this disease. Methods It was designed as a single blind, randomized, controlled, parallel group, single centre Phase IV trial of a newer atypical antipsychotic, asenapine versus existing standard atypical antipsychotic, olanzapine. Total 80 subjects were enrolled as per eligibility criteria.Each recruited subject received daily treatment with the trial medication (Olanzapine 10 mg or Asenapine 10 mg daily) for duration of 12 weeks. BPRS, CGI-S, CGI-I, Laboratory parameters and compliance was assessed and analyzed. Continuous variables were compared by t test and non-parametric data was analyzed by Mann-Whitney U test and Wilcoxon signed rank test. Likely categorical variables were analyzed by chi-square test or Fisher's exact test, as appropriate. Results The duration of schizophrenia at presentation was comparable in both the treatment groups. There was significant reduction of BPRS score between any two visits of each treatment groups. The decline in CGI-S and CGI-I scores was statistically significant (p < 0.001) when compared between visits of any of the both treatment arms. Adherence to treatment was excellent for all patients. Conclusion Newer atypical antipsychotic asenapine is more effective than standard olanzapine in reducing the symptoms of schizophrenia in this study and further larger studies are to be done.

Systemic sclerosis (SSc) is an idiopathic autoimmune disease characterised by inflammation, vascular problems, cytokine dysregulation and ultimately fibrosis, which accounts for poor prognosis and eventual mortality. At present no curative treatments exist, hence there is an urgent need to better understand the aetiology and develop improved therapies accordingly. Although still widely debated, significant evidence points to upregulation of the innate immune response via the activity of Toll-like receptors (TLRs) and the NLRP3 inflammasome as the start points in a cascade of signaling events which drives excessive extracellular matrix protein production, causing fibrosis. Herein the recent breakthroughs which have implicated TLR signaling and the NLRP3 inflammasome in SSc and the novel therapeutic possibilities this introduces to the field will be discussed.

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

Objective Although transforming growth factor β (TGFβ) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin fibrosis in SSc and in mouse models of experimental fibrosis. Methods Expression and localization of TLR9 were evaluated in SSc skin biopsy specimens and explanted skin fibroblasts. Fibrotic responses elicited by type A CpG oligonucleotide and mitochondrial DNA (mtDNA) were examined in human skin fibroblasts by a combination of real-time quantitative polymerase chain reaction, Western blot analysis, transient transfection, immunofluorescence microscopy, and functional assays. Expression of TLR9 was examined in 2 distinct mouse models of experimental fibrosis. Results Skin biopsy specimens obtained from 2 independent cohorts of SSc patients showed up-regulation of TLR9, and myofibroblasts were the major cellular source. Moreover, SSc skin biopsy specimens showed evidence of TLR9 pathway activation. CpG induced robust TLR9-dependent fibrotic responses in explanted normal fibroblasts that could be blocked by bortezomib and were mediated through the action of endogenous TGFβ. Mice with experimental fibrosis showed a time-dependent increase in TLR9 localized primarily to myofibroblasts in the dermis. Conclusion In isolated fibroblasts, TLR9 elicits fibrotic responses mediated via endogenous TGFβ. In patients with SSc, mtDNA and other damage-associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGFβ production, and consequent fibroblast activation. Disrupting this fibrotic process with inhibitors targeting TLR9 or its downstream signaling pathways might therefore represent a novel approach to SSc therapy.

Concept is a major learning activity in a class of software engineering. The success of a practitioner in a technical domain depends much on how he or she is able to contextualize and apply a concept that he or she learned in the classroom. Concept learning has many similarities with vocabulary learning because keywords are used to teach concepts in a technical subject. Traditional vocabulary learning has a strong criticism of being passive, boring and learners' inability for contextualized learning. Hence there are attempts to include fun and active learning in vocabulary learning, because modern education acknowledges that learning with fun contributes to students' success. The e-learning system, proposed in this paper, aims to help students of software engineering master the important concepts of the subject through keywords. The system is modelled on vocabulary learning and includes games to make the learning fun-filled for the students. The architecture of the system is developed based on a learning system and a testing system. The learning system was developed based on simple jigsaw puzzle games and can engage the student to develop the right answer based on hints provided by the system. The testing system has used word cloud and fill-the-blanks method. As the setup of the system is generic, it can be used for any subject and for any level of learners. The researchers made the effort to make the system simple by using jigsaw puzzle and word cloud, spirited by engaging learners actively, and scalable by making the system adaptable for any number of courses by changing only the content.

Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation.

Significance: This review provides current overview of the emerging role of innate immunity in driving fibrosis, and preventing its resolution, in scleroderma (systemic sclerosis, SSc). Understanding the mechanisms of dysregulated innate immunity in fibrosis and SSc will provide opportunities for therapeutic interventions using novel agents and repurposed existing drugs. Recent Advances: New insights from genomic and genetic studies implicate components of innate immune signaling such as pattern recognition receptors (PRRs), downstream signaling intermediates, and endogenous inhibitors, in fibrosis in SSc. Recent studies distinguish innate immune signaling in tissue-resident myofibroblasts and bone marrow-derived immune cells and define their roles in the development and persistence of tissue fibrosis. Critical Issues: Activation of toll-like receptors (TLRs) and other PRR mechanisms occurs in resident nonimmune cells within injured tissue microenvironments. These cells respond to damage-associated molecular patterns (DAMPs), such as tenascin-C that are recognized as danger signals, and elicit matrix production, cytokine secretion, and myofibroblast transformation and survival. When these responses persist due to constitutive TLR activation or impaired termination by endogenous inhibitors, they interfere with fibrosis resolution. The genetic basis and molecular mechanisms of these phenomena in the context of fibrosis are under current investigation. Future Directions: Precise delineation of the pathogenic DAMPs, their interaction with TLRs and other PRRs, the downstream signaling pathways and transcriptional events, and the fibroblast-specific regulation and function of endogenous inhibitors of innate immunity, will form the foundation for innovative targeted therapies to block fibrosis by reestablishing balanced innate immune signaling in fibroblasts.

Fibrosis, the hallmark of scleroderma or systemic sclerosis (SSc), is a complex, dynamic and generally irreversible pathophysiological process that leads to tissue disruption, and lacks effective therapy. While early-stage fibrosis resembles normal wound healing, in SSc fibrosis fails to resolve. Innate immune signaling via toll-like receptors (TLRs) has recently emerged as a key driver of persistent fibrotic response in SSc. Recurrent injury in genetically predisposed individual causes generation of "damage-associated molecular patterns" (DAMPs) such as fibronectin-EDA and tenascin-C. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation, and appears to sensitize fibroblasts to the profibrotic stimulatory effect of TGF-β. Thus, DAMPs induce TLR4-mediated innate immune signaling on resident mesenchymal cells which drives the emergence and persistence of fibrotic cells in tissues, and underlies the switch from a self-limited repair response to non-resolving pathological fibrosis characteristic of SSc. In this review, we present current views of the DAMP-TLR4 axis in driving sustained fibroblasts activation and its pathogenic roles in fibrosis progression in SSc, and potential anti-fibrotic approaches for selective therapeutic targeting of TLR4 signaling.

We show that Tenascin-C, an asthma-associated extracellular matrix glycoprotein, promotes hematopoietic progenitors and suppresses the IL-5-driven maturation of murine lung eosinophils. The extracellular matrix’s regulation of in situ hematopoiesis has significant implications for targeting tissue eosinophils.

Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN. Scleroderma patients with progressive skin fibrosis display an IFN-regulated gene signature, implicating TLR3 signaling in the disease. In this study, we show that TLR3 expression was detected on foreskin, adult skin, and lung fibroblasts, and TLR3 levels were significantly elevated in a subset of scleroderma skin biopsies. In explanted skin and lung fibroblasts, the synthetic TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)), a dsRNA analog, caused dose- and time-dependent stimulation of IFN-β production and generation of an IFN-response gene signature that was accompanied by substantial downregulation of collagen and α-smooth muscle actin gene expression. Furthermore, poly(I:C) abrogated TGF-β–induced fibrotic responses and blocked canonical Smad signaling via upregulation of inhibitory Smad7. Surprisingly, the inhibitory effects of poly(I:C) in fibroblasts were independent of TLR3 and were mediated by the cytosolic receptors retinoic acid–inducible gene 1 and melanoma differentiation-associated gene 5, and involved signaling via the IFN receptor. Taken together, these results demonstrate that induction of a fibroblast IFN response gene signature triggered by dsRNA is associated with potent TLR3-independent anti-fibrotic effects. The characteristic IFN response gene signature seen in scleroderma lesions might therefore signify a tissue-autonomous protective attempt to restrict fibroblast activation during injury.

A case of visceral dracunculiasis in a female patient is reported from east Medinipur district, West Bengal, India. It is the first report from the eastern India. The patient from rural West Bengal underwent laparoscopic cholecystectomy on 13th March 2002 and after 3 days the patient was released with a drain in the upper abdomen because of persistence of fluid of about 50 ml per day. The patient was to readmit after 8 days with a history of expulsion of one worm through the drain tube and next day another four living worms were expelled through the tube. Subsequently the drain dried up and the patient was released after removing the tube. The worms are identified as Dracunculus medinensis, possibly remaining within the abscess developing adjacent to the gall bladder and it is a case of visceral dracunculiasis reported first time from eastern India.

Heterogeneity in systemic sclerosis (SSc) confounds clinical trials. We previously identified "intrinsic" gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with modified Rodnan skin score (MRSS) improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients' biopsies and 10 controls at baseline, and from serial biopsies of 1 cyclophosphamide-treated patient and 9 MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. A total of 321 genes (false discovery rate (FDR)

Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by persistent fibroblast activation triggered by transforming growth factor-β (TGF-β). As the acetyltransferase p300 has a key role in fibrosis and its availability governs the intensity of fibrotic responses, we investigated p300 expression in SSc and the molecular basis of its regulation. We found that expression of p300 was markedly elevated in SSc skin biopsies and was induced by TGF-β in explanted normal skin fibroblasts. Stimulation of p300 by TGF-β was independent of Smads and involved the early-immediate transcription factor Egr-1 (early growth response 1), a key regulator of profibrotic TGF-β signaling. Indeed, Egr-1 was both sufficient and necessary for p300 regulation in vitro and in vivo. Increased p300 accumulation in TGF-β-treated fibroblasts was associated with histone hyperacetylation, whereas p300 depletion, or selective pharmacological blockade of its acetyltransferase activity, attenuated TGF-β-induced responses. Moreover, TGF-β enhanced both p300 recruitment and in vivo histone H4 acetylation at the COL1A2 (collagen, type I, α2) locus. These findings implicate p300-mediated histone acetylation as a fundamental epigenetic mechanism in fibrogenesis and place Egr-1 upstream in TGF-β-driven stimulation of p300 gene expression. The results establish a firm link between fibrosis with aberrant p300 expression and epigenetic activity that, to our knowledge, is previously unreported. Targeted disruption of p300-mediated histone acetylation might therefore represent a viable antifibrotic strategy.

Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis. Moreover, TLR4 dramatically enhanced the sensitivity of fibroblasts to the stimulatory effect of transforming growth factor-β1. These profibrotic responses were abrogated by both genetic and pharmacological disruption of TLR4 signaling in vitro, and skin fibrosis induced by bleomycin in vivo was attenuated in mice harboring a mutated TLR4. Activation of TLR4 in fibroblasts augmented the intensity of canonical Smad signaling, and was accompanied by suppression of anti-fibrotic microRNA expression. Together, these results suggest a novel model to account for persistent fibrogenesis in scleroderma, in which activation of fibroblast TLR4 signaling, triggered by damage-associated endogenous TLR4 ligands, results in augmented transforming growth factor-β1 sensitivity with increased matrix production and progressive connective tissue remodeling. Under these conditions, fibroblast TLR4 serves as the switch for converting self-limited tissue repair into intractable fibrosis.

The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc., Systemic sclerosis (SSc) is a fibrotic disease affecting multiple organs. Here the authors use patient samples plus mouse studies to show a central role for tenascin C as a TLR4 activator responsible for persistence of fibrosis in the context of SSc and SSc-like disease.

Fibroblasts and myofibroblasts are the key effector cells executing physiological tissue repair leading to regeneration on the one hand, and pathological fibrogenesis leading to chronic fibrosing conditions on the other. Recent studies identify the multifunctional transcription factor early growth response-1(Egr-1) as an important mediator of fibroblast activation triggered by diverse stimuli. Egr-1 has potent stimulatory effects on fibrotic gene expression, and aberrant Egr-1 expression or function is associated with animal models of fibrosis and human fibrotic disorders, including emphysema, pulmonary fibrosis, pulmonary hypertension and systemic sclerosis. Pharmacological suppression or genetic targeting of Egr-1 blocks fibrotic responses in vitro and ameliorates experimental fibrosis in the skin and lung. In contrast, Egr-1 appears to act as a negative regulator of hepatic fibrosis in mouse models, suggesting a context-dependent role in fibrosis. The Egr-1-binding protein Nab2 is an endogenous inhibitor of Egr-1-mediated signalling and abrogates the stimulation of fibrotic responses induced by transforming growth factor-β (TGFβ). Moreover, mice deficient in Nab2 show excessive collagen accumulation in the skin. These observations highlight a previously unsuspected fundamental physiological function for the Egr-1-Nab2 signalling axis in regulating fibrogenesis, and suggest that Egr-1 may be a potential novel therapeutic target in human diseases complicated by fibrosis. This review summarizes recent advances in understanding the regulation and complex functional role of Egr-1 and its related proteins and inhibitors in pathological fibrosis.

The intractable process of fibrosis underlies the pathogenesis of systemic sclerosis (SSc) and other diseases, and in aggregate contributes to 45% of deaths worldwide. Because currently there is no effective anti-fibrotic therapy, a better understanding of the pathways and cellular differentiation programs underlying fibrosis are needed. Emerging evidence points to a fundamental role of the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPAR-γ) in modulating fibrogenesis. While PPAR-γ has long been known to be important in lipid metabolism and in glucose homeostasis, its role in regulating mesenchymal cell biology and its association with pathological fibrosis had not been appreciated until recently. This article highlights recent studies revealing a consistent association of fibrosis with aberrant PPAR-γ expression and activity in various forms of human fibrosis and in rodent models, and reviews studies linking genetic manipulation of the PPAR-γ pathway in rodents and fibrosis. We survey the broad range of anti-fibrotic activities associated with PPAR-γ and the underlying mechanisms. We also summarize the emerging data linking PPAR-γ dysfunction and pulmonary arterial hypertension (PAH), which together with fibrosis is responsible for the mortality in patients in SSc. Finally, we consider current and potential future strategies for targeting PPAR-γ activity or expression as a therapy for controlling fibrosis.