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Abstract Purpose To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation by transforming growth factor (TGF)-β1 in rat Tenon’s capsule fibroblasts. Methods Cultured rat Tenon’s capsule fibroblasts were treated with TGF-β1 and analyzed with microarrays for mRNA profiling to validate miR-146a as the target. The Tenon’s capsule fibroblasts were then respectively treated with lentivirus-mediated transfection of miR-146a mimic or inhibitor following TGF-β1 stimulation in vitro, while GFS was performed in rat eyes with respective intraoperative administration of miR-146a, mitomycin C (MMC), or 5-fluorouracil (5-FU) in vivo. Profibrotic genes expression levels (fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin) were determined through qPCR, Western blotting, immunofluorescence staining and/or histochemical analysis in vitro and in vivo. SMAD4 targeting siRNA was further used to treat the fibroblasts in combination with miR-146a intervention to confirm its role in underlying mechanisms. Results Upregulation of miR-146a reduced the proliferation rate and profibrotic changes of rat Tenon’s capsule fibroblasts induced by TGF-β1 in vitro, and mitigated subconjunctival fibrosis to extend filtering blebs survival after GFS in vivo, where miR-146a decreased expression levels of NF-KB-SMAD4-related genes, such as fibronectin, collagen Iα, NF-KB, IL-1β, TNF-α, SMAD4, and α-smooth muscle actin(α-SMA). Additionally, SMAD4 is a key target gene in the process of miR-146a inhibiting fibrosis. Conclusions MiR-146a effectively reduced TGF-β1-induced fibrosis in rat Tenon’s capsule fibroblasts in vitro and in vivo, potentially through the NF-KB-SMAD4 signaling pathway. MiR-146a shows promise as a novel therapeutic target for preventing fibrosis and improving the success rate of GFS.

Abstract Background Preeclampsia is a severe complication of pregnancy which is attributed to placental dysfunction. The retrotransposon, Paternal Expressed Gene 10 (PEG10) harbours critical placental functions pertaining to placental trophoblast cells. Limited evidence exists on whether PEG10 is involved in preeclampsia pathogenesis. This study characterised the expression and regulation of PEG10 in placentas from patients with early-onset preeclampsia compared to gestation-matched controls. Methods PEG10 expression was measured in plasma and placentas collected from patients with early-onset preeclampsia (

Abstract Efforts to develop effective disease-modifying drugs to treat osteoarthritis have so far proved unsuccessful with a number of promising drug candidates from pre-clinical studies failing to show efficacy in clinical trials. It is therefore timely to re-evaluate our current understanding of osteoarthritis pathogenesis and the similarities and differences in disease development between commonly used pre-clinical mouse models and human patients. There is substantial heterogeneity between patients presenting with osteoarthritis and mounting evidence that the pathways involved in osteoarthritis (e.g. Wnt signalling) differ between patient sub-groups. There is also emerging evidence that the pathways involved in osteoarthritis differ between the STR/ort mouse model (the most extensively studied mouse model of spontaneously occurring osteoarthritis) and injury-induced osteoarthritis mouse models. For instance, while canonical Wnt signalling is upregulated in the synovium and cartilage at an early stage of disease in injury-induced osteoarthritis mouse models, this does not appear to be the case in the STR/ort mouse. Such findings may prove insightful for understanding the heterogeneity in mechanisms involved in osteoarthritis pathogenesis in human disease. However, it is important to recognise that there are differences between mice and humans in osteoarthritis pathogenesis. A much more extensive array of pathological changes are evident in osteoarthritic joints in individual mice with osteoarthritis compared to individual patients. There are also specified differences in the pathways involved in disease development. For instance, although increased TGF-β signalling is implicated in osteoarthritis development in both mouse models of osteoarthritis and human disease, in mice, this is mainly mediated through TGF-β3 whereas in humans, it is through TGF-β1. Studies in other tissues have shown TGF-β1 is more potent than TGF-β3 in inducing the switch to SMAD1/5 signalling that occurs in osteoarthritic cartilage and that TGF-β1 and TGF-β3 have opposing effects on fibrosis. It is therefore possible that the relative contribution of TGF-β signalling to joint pathology in osteoarthritis differs between murine models and humans. Understanding the similarities and differences in osteoarthritis pathogenesis between mouse models and humans is critical for understanding the translational potential of findings from pre-clinical studies.

Skin ageing is defined, in part, by collagen depletion and fragmentation that leads to a loss of mechanical tension. This is currently believed to reflect, in part, the accumulation of senescent cells. We compared the expression of genes and proteins for components of the extracellular matrix (ECM) as well as their regulators and found that in vitro senescent cells produced more matrix metalloproteinases (MMPs) than proliferating cells from adult and neonatal donors. This was consistent with previous reports of senescent cells contributing to increased matrix degradation with age; however, cells from adult donors proved significantly less capable of producing new collagen than neonatal or senescent cells, and they showed significantly lower myofibroblast activation as determined by the marker α-SMA. Functionally, adult cells also showed slower migration than neonatal cells. We concluded that the increased collagen degradation of aged fibroblasts might reflect senescence, the reduced collagen production likely reflects senescence-independent processes.

Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

Abstract The tubuloglomerular feedback (TGF) mechanism modulates renal hemodynamics and glomerular filtration rate in individual nephrons. Our study aimed to evaluate the TGF‐induced vascular responses by inhibiting Na‐K‐2Cl co‐transporters and sodium‐glucose co‐transporters in rats. We assessed cortical hemodynamics with high‐resolution laser speckle contrast imaging, which enabled the evaluation of blood flow in individual microvessels and analysis of their dynamical patterns in the time‐frequency domain. We demonstrated that a systemic administration of furosemide abolishes TGF‐mediated hemodynamic responses. Furthermore, we showed that the local microcirculatory blood flow decreased, and the TGF‐induced hemodynamic oscillations were sustained but weakened after inhibiting sodium‐glucose co‐transporters in Sprague–Dawley rats.

Early lethality of mice with complete deletion of the matrix metalloproteinase MMP14 emphasized the proteases’ pleiotropic functions. MMP14 deletion in adult dermal fibroblasts (MMP14Sf-/-) caused collagen type I accumulation and upregulation of MMP3 expression. To identify the compensatory role of MMP3, mice were generated with MMP3 deletion in addition to MMP14 loss in fibroblasts. These double deficient mice displayed a fibrotic phenotype in skin and tendons as detected in MMP14Sf-/- mice, but no additional obvious defects were detected. However, challenging the mice with full thickness excision wounds resulted in delayed closure of early wounds in the double deficient mice compared to wildtype and MMP14 single knockout controls. Over time wounds closed and epidermal integrity was restored. Interestingly, on day seven, post-wounding myofibroblast density was lower in the wounds of all knockout than in controls, they were higher on day 14. The delayed resolution of myofibroblasts from the granulation tissue is paralleled by reduced apoptosis of these cells, although proliferation of myofibroblasts is induced in the double deficient mice. Further analysis showed comparable TGFβ1 and TGFβR1 expression among all genotypes. In addition, in vitro, fibroblasts lacking MMP3 and MMP14 retained their ability to differentiate into myofibroblasts in response to TGFβ1 treatment and mechanical stress. However, in vivo, p-Smad2 was reduced in myofibroblasts at day 5 post-wounding, in double, but most significant in single knockout, indicating their involvement in TGFβ1 activation. Thus, although MMP3 does not compensate for the lack of fibroblast-MMP14 in tissue homeostasis, simultaneous deletion of both proteases in fibroblasts delays wound closure during skin repair. Notably, single and double deficiency of these proteases modulates myofibroblast formation and resolution in wounds.

In this study, we aimed to explore the hepatoprotective effects of the gemmotherapy bud extract of Corylus avellana in a model of liver fibrosis on diabetic mice. An evaluation of total flavonoids and polyphenols contents and LC/MS analyses were performed. Experimental fibrosis was induced with CCl4 (2 mL/kg by i.p. injections twice a week for 7 weeks) in streptozotocin-induced diabetic mice. Our results showed a content of 6–7% flavonoids, while hyperoside and chlorogenic acids were highlighted in the bud extract. Toxic administration of CCl4 increased oxidative stress, mRNA expression of the transforming growth factor-β1 (TGF-β1) and Smad 2/3, and reduced Smad 7 expression. Furthermore, up-regulation of α-smooth muscle actin (α-SMA) revealed an activation of hepatic stellate cells (HSCs), while collagen I (Col I) up-regulation and matrix metalloproteinases (MMPs) unbalance led to an altered extracellular matrix enriched in collagen, confirmed as well by a trichrome stain and electron microscopy analysis. Treatment with gemmotherapy extract significantly restored the liver architecture and the antioxidant balance, and significantly decreased collagen deposits in the liver and improved the liver function. Our results suggest that Corylus avellana gemmotherapy extract may have anti-fibrotic effects and could be useful in the prevention and treatment of liver fibrosis. The hepatoprotective mechanism is based on HSC inhibition, a reduction in oxidative stress and liver damage, a downregulation of the TGF-β1/Smad signaling pathway and a MMPs/TIMP rebalance.

Abstract We present concept of a new multi-satellite Universat-SOCRAT project aimed to study transient phenomena in the upper atmosphere such as transient luminous events (TLEs) and terrestrial gamma-ray flashes (TGFs). It is a new space project of Lomonosov Moscow State University based on the use of a few satellites in the near-Earth orbit for real-time monitoring of radiation environment, natural (asteroids, meteoroids) and artificial (space debris) potentially dangerous objects, electromagnetic transients including cosmic gamma-ray bursts, terrestrial gamma-ray flashes, and optical and ultraviolet bursts in the Earth’s atmosphere.Study of TLEs and TGFs remains an important and demanding task despite of a multitude of recently acquired data for these phenomena. This might be explained by the absence of comprehensive theoretical understanding of physical nature of high-energy processes in the Earth’s atmosphere. Multi-wavelength synchronous observations with moderate accuracy of localization of TGF and TLE events are necessary to gain an insight of physics governing these high-energy processes in the Earth’s atmosphere. In the article, we present results of TLE observations in space experiments of Moscow State University and discuss advanced instruments for optical observations of TLEs, as well as gamma-ray burst monitor and tracking gamma spectrometer for TGFs observations.

Typical features of lightning distribution in the mountain area of Mt. Cimone (2165 m a.s.l., Northern-Central Italy) have been studied through detections provided by the ground-based LIghtning NETwork data (LINET) and the Lightning Imaging Sensor (LIS) onboard the International Space Station (ISS-LIS). This study was performed within the context of the Gamma-Flash program, which includes the in situ observation of high-energy radiation (e.g., Terrestrial Gamma-ray Flashes (TGFs), gamma-ray glows) and neutron emissions from thunderstorms at the mountain-top “O. Vittori” climate observatory. LINET VLF/LF radio measurements allowed the characterization of both cloud-to-ground (CG) and intra-cloud (IC) strokes’ geographical distribution and an altitude of occurrence from 2012 through 2020. The lightning distribution showed a remarkable clustering of CGs at the mountain top in contrast to a homogeneous distribution of ICs, highlighting the likely impact of orography. IC strokes peaked around 4 to 6 km altitude, in agreement with the observed typical cloud range. The joint exploitation of ISS-LIS optical observations of LINET detections extended the study to further features of flashes not seen in radio wavelengths and stands as the cross-validation of the two detection methods over such a complex orography. These results gave the quantitative indication of the expected occurrence of lightning and ionizing radiation emissions in the Mt. Cimone area and an example of mountain-driven changes in lightning occurrence.

Background: Pulmonary hypertension is the major cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). Mutations in several genes that encode signaling molecules of the transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways have previously been associated with CDH. Since studies on the activation of these pathways in CDH are scarce, and have yielded inconsistent conclusions, the downstream activity of both pathways was assessed in the nitrofen-CDH rat model.Methods and Results: Pregnant Sprague-Dawley rats were treated with nitrofen at embryonic day (E) 9.5 to induce CDH in offspring. At E21, lungs were screened for the expression of key factors of both signaling pathways, at both the mRNA transcript and protein levels. Subsequently, paying particular attention to the pulmonary vasculature, increased phosphorylation of SMAD2, and decreased phosphorylation of Smad5 was noted in the muscular walls of small pulmonary vessels, by immunohistochemistry. This was accompanied by increased proliferation of constituent cells of the smooth muscle layer of these vessels.Conclusions: Increased activation of the TGFβ pathway and decreased activation of the BMP pathway in the pulmonary vasculature of rats with experimentally-induced CDH, suggesting that the deregulated of these important signaling pathways may underlie the development of pulmonary hypertension in CDH.

Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.

Growth factor profiles could be influenced by the utilization of exogenous insulin. The data presented shows the relationship between pre-existing use of injectable insulin in women diagnosed with breast cancer and type 2 diabetes mellitus, the growth factor profiles at the time of breast cancer diagnosis, and subsequent cancer outcomes. A Pearson correlation analysis evaluating the relationship between growth factors stratified by of insulin use and controls is also provided.

Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.

Foxp3 has been studied as a biomarker of Treg cells in many solid malignant diseases, although its role as an immunomodulator in B-NHL remain poorly understood and the effect of traditional chemotherapy on its expression remains unclear. In this study the role of circulating and intra-tumoral Treg and TGF-β in patients with B-NHL before and after chemotherapy was evaluated. Enumeration of Treg cells was carried out by flow cytometric staining of their cell surface markers CD4 and CD25 as well as by molecular analysis of its signature transcription factor FoxP3. Expression of FoxP3 was done using quantitative real-time PCR while TGF-β mRNA expression was semi-quantitatively assayed by the conventional reverse transcription-PCR. In addition, spontaneous versus mitogen-induced release of TGF-β by PBMCs was assessed by a short term cell culture followed by ELISA. This was done before and after six cycles of CHOP chemotherapy. The results were evaluated in relation to the clinicopathological data. A significant increase in mRNA transcripts of both Fox P3 and TGF-β as well as the percentage of CD4+/CD25+ in B-NHL patients before receiving the chemotherapy were recorded, when compared either to healthy controls or to patients after completion the treatment regimen. Interestingly 6 cycles of CHOP treatment caused significant reduction in all parameters under study, relative to the situation before treatment. A significant enhancement in spontaneous TGF-β release in B-NHL patient either before or after chemotherapy was obtained. These results strongly confirm the possible involvement of Treg cells and TGF-β in orienting the clinical course of the disease as well as the ability of targeting them in immunotherapeutic approaches.

زمینه و هدف: تعیین تأثیر برنامه‌ی تمرین در آب، بر سطوح کورتیزول وTGF-β در مردان مبتلا به مولتیپل‌اسکلروزیس می‌باشد. مواد و روش‌ها: تحقیق حاضر از نوع نیمه‌تجربی و کاربردی با طرح پیش‌آزمون و پس‌آزمون می‌باشد. جامعه‌ی آماری این پژوهش، شامل بیماران مرد مبتلا به MS مراجعه کننده به مطب خصوصی پزشک متخصص مغز و اعصاب در شهر مشهد می‌باشد که از این بین 30 نفر انتخاب شده و به‌صورت تصادفی به دو گروه (کنترل و تجربی) تقسیم شده‌اند. برنامه‌ی تمرینی گروه‌ تجربی، شامل 24 جلسه‌ی 40 دقیقه‌ای تمرین هوازی در آب به‌مدت هشت هفته و با تواتر 3 بار در هفته بوده‌است. به‌طوری‌که بر طبق اصل اضافه بار، بعد از هر هشت جلسه، 10 دقیقه به زمان جلسه‌ی تمرینی اضافه ‌شده‌است. قبل و بعد از انجام برنامه‌ی تمرینی خون‌گیری از آزمودنی‌ها که شامل متغیرهای کوتیزول و TGF-β می‌باشد انجام‌شده‌است. تحلیل داده-ها با استفاده از آزمون t مستقل (تفاوت بین گروهی) و آزمون t همبسته (تفاوت درون گروهی) درسطح 05/0≥p صورت‌ گرفته‌است. یافته‌ها: یافته‌های پژوهش نشان داد بین دو گروه، در سطوح کورتیزول تفاوت معنی‌دار بود (001/0 P=)؛ به نحوی‌که تمرین موجب کاهش معنی‌دار این فاکتور شد و علیرغم کاهش در سطح TGF-β تفاوت معنی‌داری بین دو گروه مشاهده نشد (09/0P=). نتیجه‌گیری: نتایج نشان داده بیماران مبتلا بهMS برای بهبود عملکرد سیستم ایمنی خود، می‌توانند با کاهش در سطوح TGF- به‌واسطه‌ی شرکت در تمرین هوازی در آب، البته با یک دوره‌ی تمرینی طولانی‌تر سود ببرند.

A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process.

The anti-hyperglycemic drug, Metformin, is effective in treating early stages of diabetes and has been associated with a 37% decrease in cancer incidence. While the precise mechanisms for the anti-cancer effects of Metformin remain to be elucidated, this review shows the multiplicity of its effects on interdicting signaling and crosstalk, anti-inflammatory effects and in restoring homeostasis, which, taken together, go beyond its well-known anti-hyperglycemic effect that serves as the basis for its use in type 2 diabetes. Metformin is much more than a one-trick pony. The recent discovery of several signaling pathways influenced by Metformin appears to have potential value in cancer therapy. Based on what we know at present, Metformin promotes beneficial effects attributed to its anti-inflammatory and anti-fibrotic effects largely demonstrated in vitro. Metformin activates or upregulates while it simultaneously inhibits or downregulates multiple signaling pathways of cell-cycle arrest and apoptosis accompanied by oxidative stress, which are in accordance with the 6-step sequence of carcinogenesis. Furthermore, in vivo studies in laboratory animals and in cancer patients are beginning to address the magnitude of the anti-cancer effects and delineate its anti-cancer effects. In this context, results from prior pancreatic and non-pancreatic cancer trials, which contained a significant proportion of the patient population treated with Metformin, will have to be reexamined in light of the observed anti-cancerous effects to gain additional insights. The detailed exploration of Metformin in the context of the “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” can provide helpful insights into the anti-proliferative mechanisms and could play a relevant role in anti-cancer therapy in the future.

It is increasingly evident that carcinogenesis, in the vast majority of cancers, cannot be explained simply through an accumulation of somatic mutations, or epigenetics, the stem cell theory, or the Warburg effect. Here, decades of thinking based on incorrect assumptions has resulted in an incorrect hypothesis on the origin of cancer. Many papers studying DNA, genetics, RNA, miRNA, proteomics, and epigenetics have increased our understanding of biology. Our paradigm, though more complex, is more reliable and plausible. It states that cancer originates from a disruption of homeostasis. This essential biological phenomenon, homeostasis, maintains the interrelationships of various signaling pathways and induced crosstalk which modify cellular functions together with the interactions of surrounding cells and structures such that the equilibrium lies towards the optimal health of the organism. This Special Issue “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” provides compelling evidence that carcinogenesis is explained by a six-step sequence of events for the vast majority of cancers. These six steps include, (1) a pathogenic stimulus followed by (2) chronic inflammation, from which develops (3) fibrosis with associated remodeling in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, and (6) the transition of a normal cell to a cancer cell occurs. This paradigm provides opportunities to move away from a symptom-oriented understanding of cancer and is much closer to a cause-based understanding, which opens the door for early preventative strategies to mitigate cancer as a disease, and to interdict metastases. This is underpinned by the fact that an independent recently published proof of this paradigm showed how a stimulus trigger the proposed multi-sequence cascade of events as abrupt involution-induced chronic inflammation, followed by fibrosis with remodeling, which describes the pre-cancerous niche followed by hyperplasia, metaplasia, and cancer.

A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g. corticosteroids or immunosuppressant drugs. Here we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e. the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the μM range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases

Signal transducer and activator of transcription 3 (STAT3) signaling plays critical roles in regulating skeletal muscle mass, repair, and diseases. In this review, we discuss the upstream activators of STAT3 in skeletal muscles, with a focus on interleukin 6 (IL6) and transforming growth factor beta 1 (TGF-β1). We will also discuss the double-edged effect of STAT3 activation in the muscles, including the role of STAT3 signaling in muscle hypertrophy induced by exercise training or muscle wasting in cachectic diseases and muscular dystrophies. STAT3 is a critical regulator of satellite cell self-renewal after muscle injury. STAT3 knock out affects satellite cell myogenic progression by impairing proliferation and inducing premature differentiation. Recent studies in STAT3 signaling demonstrated its direct role in controlling myogenic capacity of myoblasts and satellite cells, as well as the potential benefit in using STAT3 inhibitors to treat muscle diseases. However, prolonged STAT3 activation in muscles has been shown to be responsible for muscle wasting by activating protein degradation pathways. It is important to balance the extent of STAT3 activation and the duration and location (cell types) of the STAT3 signaling when developing therapeutic interventions. STAT3 signaling in other tissues and organs that can directly or indirectly affects skeletal muscle health are also discussed.

Organ fibrosis is a pathological condition associated with chronic inflammatory diseases. In fibrosis, excessive deposition of extracellular matrix severely impairs tissue architecture and function, eventually resulting in organ failure. This process is mediated primarily by the induction of myofibroblasts, which produce large amounts of collagen I, the main component of the extracellular matrix. Accordingly, the origin, developmental pathways and mechanisms of myofibroblast regulation are attracting increasing attention as potential therapeutic targets. The fibrotic cascade, from initial epithelial damage to eventual myofibroblast induction, is mediated by complex biological processes such as macrophage infiltration, a shift from Th1 to Th2 phenotype, and by inflammatory mediators such as transforming growth factor-beta. Here, we review the current understanding of the cellular and molecular mechanisms underlying organ fibrosis.

The generation of x- and gamma-rays in atmospheric discharges has been studied intensively since the discovery of terrestrial gamma-ray flashes (TGFs) by the Compton gamma-ray Observatory in 1991. Emissions are bremsstrahlung from high energy particles accelerated in large scale atmospheric electric fields associated with thunderstorms. Whereas observations now are many, both from lightning and the laboratory, the phases of the discharge where emissions are generated are still debated and several processes for electron acceleration have been put forward by theorists. This paper address the electron acceleration in streamer region of lightning. We present the first ‘beam-bulk’ model of self-consistent streamer dynamics and electron acceleration. The model combines a Monte Carlo Collision code that simulates the high-energy electrons ( $>$ 100 eV) and a fluid code that simulates the bulk of the low-energy electrons and ions. For a negative streamer discharge, we show how electrons are accelerated in the large electric field in the tip of the streamer and travel ahead of the streamer where they ionize the gas. In comparison to the results obtained with a classical fluid model for a negative streamer, the beam-bulk model predicts a decrease of the magnitude of the peak electric field and an increase of the streamer velocity. Furthermore, we show that a significant number of runaway electrons is lost by diffusion outside of the streamer tip. The results presented here do not yet include extra amplification nor acceleration far away from the streamer to explain the electron energies seen in TGFs. Still, in the light of those results, we emphasize that the production of runaway electrons from streamers needs to be simulated including the self-consistent feedback of runaways on the streamer. Simulations with a beam-bulk model may not only help to understand the fundamental atmospheric processes behind TGFs, but also pave the way for the interpretation of remote sensing of the most energetic discharges in the Earthʼs atmosphere and thus help to address their environmental impact.