Indirect Action Research Articles

Abstract LB170: HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers

Abstract Background: Interferon beta (IFN-β), a promising potent cytokine, has been attracting attention for treatment of cancer. The pleiotropic antitumor effects of IFN-β have been studied, with specific reference to their direct role on cancer cells and indirect action through the immune effector cells. However, its systemic toxicities and poor biophysical properties prevent IFN-β from being widely used for cancer therapy. Since the potential of cytokine therapies are impaired due to dose-limiting systemic toxicities, novel treatment methods should be developed to safely deliver effective drug quantities at the tumor sites. Like antibody-drug conjugates (ADCs), immunocytokine can be attempted to induce cytokine's organ-targeting and alleviate its systemic side effects. Here, we designed recombinant IFN-β mutein immunocytokines that comprise a HER2-targeting antibody and IFN-β mutein, and evaluate the antitumor properties against HER2-positive cancers.Method: A panel of human gastric cancer cell lines was treated with trastuzumab-IFN-β mutein to evaluate direct antitumor effect. In addition, to test the immune cell-mediated antitumor effect, cancer cells were co-cultured with effector cells (e.g. PBMC) in the absence or drug. The antitumor efficacy of trastuzumab-IFN-β mutein in vivo was tested in HER2-positive cancer xenograft models using nude mice or humanized mice. Result: Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein also displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Moreover, trastuzumab-IFN-β mutein significantly suppress tumor growth in HER2-positive cancer xenograft models. Tumor-infiltration of lymphocytes was enhanced by trastuzumab-IFN-β mutein, implying that the tumor-targeting IFN-β may have an antitumor effect through increased immune response. Conclusion: We have characterized and evaluated the antitumor properties of trastuzumab-IFN-β mutein in HER2-expressing cancers. Since IFN-β activates antitumor immune responses, it is expected to be administered in combination with immunotherapeutic drugs. Therefore, the study suggests that trastuzumab-IFN-β mutein is a promising candidate for the treatment of HER2-positive carcinoma. Citation Format: Chan Gyu Lee, Tae Eun Kim, Sungyoul Hong, Jongwan Chu, Ju Eun Kang, Hae Min Jeong, Young Kee Shin. HER2-targeted interferon-beta-1a mutein, a potent immunocytokine for the treatment of HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB170.

The unique role of parietal cortex in action observation: Functional organization for communicative and manipulative actions

Action observation is supported by a network of regions in occipito-temporal, parietal, and premotor cortex in primates. Recent research suggests that the parietal node has regions dedicated to different action classes including manipulation, interpersonal interactions, skin displacement, locomotion, and climbing. The goals of the current study consist of: 1) extending this work with new classes of actions that are communicative and specific to humans, 2) investigating how parietal cortex differs from the occipito-temporal and premotor cortex in representing action classes. Human subjects underwent fMRI scanning while observing three action classes: indirect communication, direct communication, and manipulation, plus two types of control stimuli, static controls which were static frames from the video clips, and dynamic controls consisting of temporally-scrambled optic flow information. Using univariate analysis, MVPA, and representational similarity analysis, our study presents several novel findings. First, we provide further evidence for the anatomical segregation in parietal cortex of different action classes: We have found a new site that is specific for representing human-specific indirect communicative actions in cytoarchitectonic parietal area PFt. Second, we found that the discriminability between action classes was higher in parietal cortex than the other two levels suggesting the coding of action identity information at this level. Finally, our results advocate the use of the control stimuli not just for univariate analysis of complex action videos but also when using multivariate techniques.

Transforming Growth Factor β1 Increases Expression of Contractile Genes in Human Pulmonary Arterial Smooth Muscle Cells by Potentiating Sphingosine-1-Phosphate Signaling.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and carries a very poor prognosis. Understanding of PAH pathogenesis is needed to support the development of new therapeutic strategies. Transforming growth factor β (TGF-β) drives vascular remodeling and increases vascular resistance by regulating differentiation and proliferation of smooth muscle cells (SMCs). Also, sphingosine-1-phosphate (S1P) has been implicated in PAH, but the relation between these two signaling mechanisms is not well understood. Here, we characterize the signaling networks downstream of TGF-β in human pulmonary arterial smooth muscle cells (HPASMCs), which involves mothers against decapentaplegic homolog (SMAD) signaling as well as Rho GTPases. Activation of Rho GTPases regulates myocardin-related transcription factor (MRTF) and serum response factor (SRF) transcription activity and results in upregulation of contractile gene expression. Our genetic and pharmacologic data show that in HPASMCs upregulation of α smooth muscle actin (αSMA) and calponin by TGF-β is dependent on both SMAD and Rho/MRTF-A/SRF transcriptional mechanisms.The kinetics of TGF-β-induced myosin light chain (MLC) 2 phosphorylation, a measure of RhoA activation, are slow, as is regulation of the Rho/MRTF/SRF-induced αSMA expression. These results suggest that TGF-β1 activates Rho/phosphorylated MLC2 through an indirect mechanism, which was confirmed by sensitivity to cycloheximide treatment. As a potential mechanism for this indirect action, TGF-β1 upregulates mRNA for sphingosine kinase (SphK1), the enzyme that produces S1P, an upstream Rho activator, as well as mRNA levels of the S1P receptor (S1PR) 3. SphK1 inhibitor and S1PR3 inhibitors (PF543 and TY52156/VPC23019) reduce TGF-β1-induced αSMA upregulation. Overall, we propose a model in which TGF-β1 activates Rho/MRTF-A/SRF by potentiating an autocrine/paracrine S1P signaling mechanism through SphK1 and S1PR3. SIGNIFICANCE STATEMENT: In human pulmonary arterial smooth muscle cells, transforming growth factor β depends on sphingosine-1-phosphate signaling to bridge the interaction between mothers against decapentaplegic homolog and Rho/myocardin-related transcription factor (MRTF) signaling in regulating α smooth muscle actin (αSMA) expression. The Rho/MRTF pathway is a signaling node in the αSMA regulatory network and is a potential therapeutic target for the treatment of pulmonary arterial hypertension.

Investigating the real life energy consumption of refrigeration appliances in Germany: Are present policies sufficient?

Domestic refrigeration appliances are standard household commodities. Although policies, such as the energy labelling, prompted technical improvements and decreased appliance energy consumption throughout recent decades, important parameters were disregarded. These refer to the efficiency loss over time and the consumer behaviour. The objective of this contribution was to develop a dynamic energy model to determine the power consumption of refrigeration appliances considering degradation factors and behaviour. These were included by model parameters for direct consumer interactions, such as the storage behaviour, door openings and temperature setting, as well as indirect actions, e.g. exposing an appliance to specific temperature conditions at an installation site. For this, an online-survey was conducted to evaluate the consumer behaviour. A total of 706 consumers participated in the national questionnaire, serving as input for the dynamic energy model. It was found that the efficiency loss increases the power consumption by at least 1% annually, leading to an excess of 10% after 10 years of usage. Another important finding was that 32.5% of appliance's power consumption results from consumer behaviour, whereas the promotion of behavioural changes leads to a significant decrease of the consumer-induced consumption. Consequently, this study provides a tool to evaluate the impact of policies targeting refrigeration appliances, stressing that efficiency loss and behaviour should be integrated into future policy approaches.

Cardiovascular and temperature adverse actions of stimulants.

The vast majority of illicit stimulants act at monoaminergic systems, causing both psychostimulant and adverse effects. Stimulants can interact as substrates or antagonists at the nerve terminal monoamine transporter that mediates the reuptake of monoamines across the nerve synaptic membrane and at the vesicular monoamine transporter (VMAT-2) that mediates storage of monoamines in vesicles. Stimulants can act directly at presynaptic or postsynaptic receptors for monoamines or have indirect monoamine-mimetic actions due to the release of monoamines. Cocaine and other stimulants can acutely increase the risk of sudden cardiac death. Stimulants, particularly MDMA, in hot conditions, such as that occurring at a "rave," have caused fatalities from the consequences of hyperthermia, often compounding cardiac adverse actions. This review examines the pharmacology of the cardiovascular and temperature adverse actions of stimulants.

Effects of empagliflozin in different phases of diabetes mellitus-related cardiomyopathy: a prospective observational study

BackgroundDiabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.MethodsThirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) were compared.ResultsECV was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001). At baseline, each group had a similar background. After 12 months, the EMPA group, especially the early DMCMP group, showed remarkable improvements in LVGLS (ΔLVGLS: 2.9 ± 3.0% (EMPA) vs. 0.6 ± 2.2% (controls), p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e′ (ΔE/e′: − 1.5 ± 4.7 vs. − 0.3 ± 3.0, p = 0.253, and − 3.4 ± 5.5 vs. − 0.1 ± 3.5, p = 0.043).ConclusionsThe positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.

ADP Induces Blood Glucose Through Direct and Indirect Mechanisms in Promotion of Hepatic Gluconeogenesis by Elevation of NADH.

Extracellular ADP, a derivative of ATP, interacts with the purinergic receptors in the cell membrane to regulate cellular activities. This signaling pathway remains unknown in the regulation of blood glucose in vivo. We investigated the acute activity of ADP in mice through a peritoneal injection. In the lean mice, in response to the ADP treatment, the blood glucose was elevated, and pyruvate tolerance was impaired. Hepatic gluconeogenesis was enhanced with elevated expression of glucogenic genes (G6pase and Pck1) in the liver. An elevation was observed in NADH, cAMP, AMP, GMP and citrate in the liver tissue in the targeted metabolomics assay. In the primary hepatocytes, ADP activated the cAMP/PKA/CREB signaling pathway, which was blocked by the antagonist (2211) of the ADP receptor P2Y13. In the circulation, gluconeogenic hormones including glucagon and corticosterone were elevated by ADP. Insulin and thyroid hormones (T3 and T4) were not altered in the blood. In the diet-induced obese (DIO) mice, NADH was elevated in the liver tissue to match the hepatic insulin resistance. Insulin resistance was intensified by ADP for further impairment in insulin tolerance. These data suggest that ADP induced the blood glucose through direct and indirect actions in liver. One of the potential pathways involves activation of the P2Y13/cAMP/PKA/CREB signaling pathway in hepatocytes and the indirect pathway may involve induction of the gluconeogenic hormones. NADH is a signal for gluconeogenesis in the liver of both DIO mice and lean mice.

A Review on Response of Neem Seed and Leaf Extract on Crop Protection and Production

Neem products including conventional preparations and formulations have been used widely for improving the growth, yield, and management of insect pests attacking especially on field crops. Phytochemicals are extracted from distinguish parts of the neem plant vary significantly due to abiotic and biotic factors from collection of the raw material to extract preparation and product formulation. Content of highly active ingredient, insect species and growth stage, type of formulation, and combined of products with another control method. In this manuscript, the direct and indirect actions of neem extract on growth, yield, and insect pests are delineated and realistic implications for future strategies are discussed.

Arginine vasopressin: Direct and indirect action on metabolism

From its identification and isolation in 1954, arginine vasopressin (AVP) has attracted attention, not only for its peripheral functions such as vasoconstriction and reabsorption of water from kidney, but also for its central effects. As there is now considerable evidence that AVP plays a crucial role in feeding behavior and energy balance, it has become a promising therapeutic target for treating obesity or other obesity-related metabolic disorders. However, the underlying mechanisms for AVP regulation of these central processes still remain largely unknown. In this review, we will provide a brief overview of the current knowledge concerning how AVP controls energy balance and feeding behavior, focusing on physiological aspects including the relationship between AVP, circadian rhythmicity, and glucocorticoids.

The Role of Toxic Metals and Metalloids in Nrf2 Signaling.

Nuclear factor erythroid 2-related factor 2 (Nrf2), an emerging regulator of cellular resistance to oxidants, serves as one of the key defensive factors against a range of pathological processes such as oxidative damage, carcinogenesis, as well as various harmful chemicals, including metals. An increase in human exposure to toxic metals via air, food, and water has been recently observed, which is mainly due to anthropogenic activities. The relationship between environmental exposure to heavy metals, particularly cadmium (Cd), lead (Pb), mercury (Hg), and nickel (Ni), as well as metaloid arsenic (As), and transition metal chromium (Cr), and the development of various human diseases has been extensively investigated. Their ability to induce reactive oxygen species (ROS) production through direct and indirect actions and cause oxidative stress has been documented in various organs. Taking into account that Nrf2 signaling represents an important pathway in maintaining antioxidant balance, recent research indicates that it can play a dual role depending on the specific biological context. On one side, Nrf2 represents a potential crucial protective mechanism in metal-induced toxicity, but on the other hand, it can also be a trigger of metal-induced carcinogenesis under conditions of prolonged exposure and continuous activation. Thus, this review aims to summarize the state-of-the-art knowledge regarding the functional interrelation between the toxic metals and Nrf2 signaling.

Targeted and non-targeted effects of radiation in mammalian cells: An overview

Radiation of different wavelengths can kill living organisms, although, the mechanism of interactions differs depending on their energies. Understanding the interaction of radiation with living cells is important to assess their harmful effects and also to identify their therapeutic potential. Temporally, this interaction can be broadly divided in three stages – physical, chemical and biological. While radiation can affect all the important macromolecules of the cells, particularly important is the damage to its genetic material, the DNA. The consequences of irradiation include- DNA damage, mutation, cross-linkages with other molecules, chromosomal aberrations and DNA repair leading to altered gene expression and/or cell death. Mutations in DNA can lead to heritable changes and is important for the induction of cancer. While some of these effects are through direct interaction of radiation with the target, radiation can interact with the surrounding environment to result in its indirect actions. The effects of radiation depend not only on the total dose but also on the dose rate, LET etc. and also on the cell types. However, action of radiation on organisms is not restricted to interactions with irradiated cells, i.e. target cells alone; it also exerts non-targeted effects on neighboring unexposed cells to produce productive responses; this is known as bystander effect. The bystander effects of ionizing radiations are well documented and contribute largely to the relapse of cancer and secondary tumors after radiotherapy. Irradiation of cells with non-ionizing Ultra-Violet light also exhibits bystander responses, but such responses are very distinct from that produced by ionizing radiations.

The Effects of Dimethylsulfoxide and Oxygen on DNA Damage Induction and Repair Outcomes for Cells Irradiated by 62 MeV Proton and 3.31 MeV Helium Ions.

Reactive oxygen species (ROS) play an essential role in radiation-induced indirect actions. In terms of DNA damage, double strand breaks (DSBs) have the greatest effects on the repair of DNA damage, cell survival and transformation. This study evaluated the biological effects of the presence of ROS and oxygen on DSB induction and mutation frequency. The relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) of 62 MeV therapeutic proton beams and 3.31 MeV helium ions were calculated using Monte Carlo damage simulation (MCDS) software. Monte Carlo excision repair (MCER) simulations were used to calculate the repair outcomes (mutation frequency). The RBE values of proton beams decreased to 0.75 in the presence of 0.4 M dimethylsulfoxide (DMSO) and then increases to 0.9 in the presence of 2 M DMSO while the RBE values of 3.31 MeV helium ions increased from 2.9 to 5.7 (0–2 M). The mutation frequency of proton beams also decreased from 0.008–0.065 to 0.004–0.034 per cell per Gy by the addition of 2 M DMSO, indicating that ROS affects both DSB induction and repair outcomes. These results show that the combined use of DMSO in normal tissues and an increased dose in tumor regions increases treatment efficiency.

The peculiarities of coping behavior of the women with different family status

The goal of this research is to examine the peculiarities of psychological protection among women with different family status. The subject of this research is the mechanisms of psychological defense, coping strategies, marital coping, situational and personal anxiety, and satisfaction with marriage. The empirical object is the sampling of 73 women with different marital status aged from 18 to 40 years. Pearson correlation coefficient and Kruskal&amp;ndash;Wallis H test were used for data processing. The provided materials and acquired conclusion augment the scientific knowledge on the peculiarities of psychological protection and coping behavior of women, and possibilities of rendering psychological aid for the development of&amp;nbsp; adaptive behavior in stressful environment and constructive behavioral strategies. The following conclusions were made: 1) majority of young women regardless of their marital status, have a high level of constructive behavior; equally high rate of denial and compensation as the mechanisms of psychological protection; 2) there are differences in the scale of repression as psychological protection; his indicator prevails among unmarried women who have a permanent sexual partner, unlike the other three groups; 3) positive correlation is observed between personal anxiety and projection, indirect actions and compensation, cautious actions and intellectualization, aggressive actions and substitution. The author determines a strong positive correlation between the avoiding style and projection, selfish style and projection, conflicting style and aggressive actions. The average negative correlation is revealed between conflicting style and satisfaction with marriage.

Sjogren’s syndrome in clinical trials of traditional Chinese medicine: protocol for the development of a core outcome set

BackgroundSjogren’s syndrome (SS) is a chronic autoimmune rheumatic disease with an incidence of 0.03 to 0.3%. In recent years, there are an increasing number of randomized controlled trials of traditional Chinese medicine (TCM) for SS. However, there are generally some problems in these published clinical trials: lack of reporting primary or long-term outcomes and the heterogeneous in different clinical trials’ outcome. Our study aims to determine the priority outcomes and standard TCM syndromes for all stakeholders and reach agreement on the COS and syndromes to be measured and reported in all future TCM trials in patients with SS.Methods and analysisA phase-wise refinement approach will be used, consisting of three phases, yet complementary, sub-work phases, whereby each phase will inform the next coming phases. The following are the three phases: (I-a) identifying of a long initial list of outcomes through systematic literature review and semi-structured qualitative interviews and (I-b) identifying an initial list of TCM syndromes through (1) systematic literature review, (2) referencing ancient Chinese medical books, and (3) retrospective studies of medical records; (II) prioritization of outcomes using Delphi survey with different stakeholders, such as health professionals and patients; and (III) through consensus meetings with patients and professionals to agree on the final COS and TCM syndromes.DiscussionWe summarized the actions of COS into three points: direct action, indirect action, and final action. After the final COSs is completed, we will publish this research in a journal to promote communication.Trial registrationCore Outcome Measures in Effectiveness Trials Initiative (COMET) number 1429. Registered on 01 December 2019.

Ex vivo approach supports both direct and indirect actions of melatonin on immunity in pike-perch Sander lucioperca

The melatonin hormone, which is a multifunctional molecule in vertebrates, has been shown to exert complex actions on the immune system of mammals. In teleosts, the immunomodulatory capacity of this hormone has seldom been investigated. In the present experiment, we exposed ex vivo spleen and head kidney tissues of pike-perch to melatonin (Mel) and cortisol (Cort). We applied three concentrations of both hormones, alone and in combination, namely (1) Mel (10, 100 or 1000 pg mL−1) (2) Cort (50, 500 or 5000 ng mL−1) (3) Mel + Cort (10 + 50, 100 + 500 or 1000 pg mL−1+5000 ng mL−1). Pure medium without Mel or Cort served as control. After 15 h of incubation, we assessed the expression of a set of immunity-related genes, including genes encoding for pro-inflammatory proteins (il-1β, cxcl8 and tnf-α), acute-phase proteins (fgl2, fth1, hepc, hp and saa1) and key factors of the adaptive immune system (fκbp4 and tcrg). Both Mel and Cort, when used alone or combined at physiological concentrations, significantly influenced immune gene expressions that may lead to a global immune stimulation. Our results support both, an indirect action of the Mel hormone on the immune system through the regulation of intermediates such as Cort, as well as a direct action on immune targets through specific receptors.

Potential role of microRNAs in theregulation of pyroptosis (Review).

MicroRNAs (miRNAs) perform a variety of important cellular functions, including regulating the cell cycle, apoptosis and differentiation, amongst others. Recent research has demonstrated an essential function performed by miRNAs in regulating pyroptosis, which is a type of programmed cell death associated with inflammatory responses that plays a critical role in numerous diseases. Through direct or indirect action on proteins associated with the pyroptosis signaling pathway, miRNAs are involved in the pathological processes of cardiovascular, kidney and immune diseases, among others. The present review discusses the maturation process of miRNAs and the process of pyroptosis, with a specific focus on the transport of miRNAs to damaged cells via exosomes, shedding vesicles and protein stabilized complexes, as well as the role of different miRNAs in the regulation of pyroptosis through different gene and protein targets. The aim of the present review was to provide a novel insight into the regulatory role of miRNAs in pyroptosis and new treatment options for pyroptosis‑associated diseases.

Lethal DNA Lesions Caused by Direct and Indirect Actions of X rays are Repaired via Different DSB Repair Pathways under Aerobic and Anoxic Conditions.

We examined lethal damages of X rays induced by direct and indirect actions, in terms of double-strand break (DSB) repair susceptibility using two kinds of repair-deficient Chinese hamster ovary (CHO) cell lines. These CHO mutants (51D1 and xrs6) are genetically deficient in one of the two important DNA repair pathways after genotoxic injury [homologous recombination (HR) and non-homologous end binding (NHEJ) pathways, respectively]. The contribution of indirect action on cell killing can be estimated by applying the maximum level of dimethylsulfoxide (DMSO) to get rid of OH radicals. To control the proportion of direct and indirect actions in lethal damage, we irradiated CHO mutant cells under aerobic and anoxic conditions. The contributions of indirect action on HR-defective 51D1 cells were 76% and 57% under aerobic and anoxic conditions, respectively. Interestingly, these percentages were similar to those of the wild-type cells even if the radiosensitivity was different. However, the contributions of indirect action to cell killing on NHEJ-defective xrs6 cells were 52% and 33% under aerobic and anoxic conditions, respectively. Cell killing by indirect action was significantly affected by the oxygen concentration and the DSB repair pathways but was not correlated with radiosensitivity. These results suggest that the lethal damage induced by direct action is mostly repaired by NHEJ repair pathway since killing of NHEJ-defective cells has significantly higher contribution by the direct action. In other words, the HR repair pathway may not effectively repair the DSB by direct action in place of the NHEJ repair pathway. We conclude that the type of DSB produced by direct action is different from that of DSB induced by indirect action.

Butyrate Improves Skin/Lung Fibrosis and Intestinal Dysbiosis in Bleomycin-Induced Mouse Models.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.

Detection of Alterations in the Gut Microbiota and Intestinal Permeability in Patients With Hashimoto Thyroiditis.

Hashimoto thyroiditis (HT) is the most common autoimmune disease worldwide, characterized by chronic inflammation and circulating autoantibodies against thyroid peroxidase and thyroglobulin. Patients require hormone replacement with oral levothyroxine, and if untreated, they can develop serious adverse health effects and ultimately death. There is a lot of evidence that the intestinal dysbiosis, bacterial overgrowth, and increased intestinal permeability favor the HT development, and a thyroid–gut axis has been proposed, which seems to impact our entire metabolism. Here, we evaluated alterations in the gut microbiota in Brazilian patients with HT and correlated this data with dietary habits, clinical data, and systemic cytokines and zonulin concentrations. Stool samples from 40 patients with HT and 53 controls were analyzed using real-time PCR, the serum cytokine levels were evaluated by flow cytometry, zonulin concentrations by ELISA, and the dietary habits were recorded by a food frequency questionnaire. We observed a significant increase (p < 0.05) in the Bacteroides species and a decrease in Bifidobacterium in samples of patients with HT. In addition, Lactobacillus species were higher in patients without thyroid hormone replacement, compared with those who use oral levothyroxine. Regarding dietary habits, we demonstrated that there are significant differences in the consumption of vegetables, fruits, animal-derived proteins, dairy products, saturated fats, and carbohydrates between patients and control group, and an inverse correlation between animal-derived protein and Bacteroides genus was detected. The microbiota modulation by diet directly influences the inflammatory profile due to the generated microbiota metabolites and their direct or indirect action on immune cells in the gut mucosa. Although there are no differences in systemic cytokines in our patients with HT, we detected increased zonulin concentrations, suggesting a leaky gut in patients with HT. These findings could help understand the development and progression of HT, while further investigations to clarify the underlying mechanisms of the diet–microbiota–immune system axis are still needed.

Social Profit of Legal Metrology in the Brazilian Electricity Sector

In Brazil, despite of the undeniable importance of metrology in society, there is still no consensus as to the most effective way to “quantify” this statement. The aims of this study is to present a method to quantify the social impact caused by legal metrological control, focusing on voluntary verification and legal metrology expertise in electrical energy meter . In this sense, this article presents a model, developed exclusively for the public sector, with the objective of quantifying the return or economy in favor of society through National Legal Metrology System direct and indirect actions in the Brazilian electricity sector, considering the 2017 year. This model is an adaptation of Social Profit mode the “Brazilian Agricultural Research Corporation – Embrapa”. . Only laboratories under the control of the Legal Metrology Board, through their delegated bodies, which perform or supervise voluntary checks and metrological examinations performed by the technicians of the Brazilian Network of Legal Metrology and Quality – RBMLQ, were considered. Next step, performance indicators were proposed and validated to obtain social profit. The data show that Inmetro’s actions enable a return to society of US$ 32 million for each US$ 1 million of investment in this activity, pointing to the effectiveness of the model in quantifying the social profit of the agency. In a more detailed analysis it was possible to evaluate a potential revenue recovery for the states, throughTaxes, of the order of US$ 400 million, if the actions of expertise and verification are intensified, pointing to a promising horizon of revenue increase for the Brazilian government through the fight against fraud. Preliminary analyzes show both the massive presence and extreme remoteness of the state are not the best management models to be adopted for the electricity sector. The study suggests, at first, a direct correlation of Inmetro intervention and participation actions in partnership with the private sector in the electricity sector and revenue recovery with reduction in the increase of electric bills. Thus, we infer that the presence of the state as regulator in this case can be effective if adapted to reality. Further studies, however, need to be done. Social profit proved to be effective for use in actions to improve public governance, another point to be explored further on.