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Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases. [ABSTRACT FROM AUTHOR]

Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response. [ABSTRACT FROM AUTHOR]

Acute rejection (AR) is a process triggered via the recognition of grafted organderived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and metaanalysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival. [ABSTRACT FROM AUTHOR]

During hypertension an unbalance of short-chain fatty acids (SCFAs) production by intestinal bacteria is described. However, no data evaluate the association of SCFAs and vascular remodeling in hypertension, which is an important hallmark of this disease. Thus, the present study aims to evaluate the correlations between SCFAs availability and the resistance arteries remodeling in hypertension, as well as to identify the possible pathway by which the SCFAs could exert a structural and mechanical influence. Hence, male spontaneously hypertensive rats (SHR) and normotensive Wistar rats had blood pressure measured by tail-cuff plethysmography; fecal SCFAs content assessed by gas chromatography; gene expression of SCFAs-transporters in gut epithelium and SCFAs-sensing receptors on mesenteric resistance arteries (MRA) quantified by PCR; and MRA structural and mechanical parameters analyzed by pressure myograph. Reduced butyrate fecal content was found in SHR, with no changes in propionate and acetate, as well as decreased mRNA levels of SCFAs-transporters (MCT1, MCT4, and SMCT1) in the intestinal epithelium. In addition, lower gene expression of SCFAs-sensing receptors (GPR41, GPR43, and GPR109a, but not Olfr78) was identified in MRAs of SHR, which also shows inward eutrophic remodeling with stiffness. Butyrate content presented a negative correlation with systolic blood pressure and with the structural alterations found on MRAs, while a positive correlation between butyrate content and mechanical parameters was detected. Altogether the present study suggests that lower butyrate content due to ineffective SCFA bioavailability, associated with lower SCFAs-sensing receptors expression, could favor MRA remodeling, increasing peripheral vascular resistance and worsening hypertension prognosis. [ABSTRACT FROM AUTHOR]

Moderate aerobic training may be therapeutic for chronic low-grade inflammatory diseases due to the associated antiinflammatory response that is mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPARγ) regulates the Ml (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Against this background, the present study seeks to clarify whether the conditional deletion of PPARγ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic training. To test this hypothesis, two mice strains were used: PPARγ LyzCre+/+ (KO) and litter-mates control animals (WT). Each genotype was divided into 1) sedentary high-fat diet (HF) and 2) high-fat diet and moderate aerobic training (HFT) (n = 5-8 per group). The experimental protocol lasted for 12 weeks, comprising 4 weeks of HF diet only and 8 weeks of HF diet and aerobic training (5 times/week, 50-60 minutes/day at 60% of maximum speed). Metabolic analyses were carried out on the serum glucose homeostase, adipose tissue morphology and cytokine content, and macrophage cytokine production. Immunophenotyping and gene expression were also performed. KO male mice were more prone to hypertrophy in the subcutaneous adipose tissue, though only the IL-1β (p = 0.0049) was higher compared to the values observed in WT animals. Peritoneal macrophages from KO animals exhibited a marked inflammatory environment with an increase in TNF-α (p = 0.0008), IL- 1β (p = 0.0017), and IL-6 (p < 0.0001) after lipopolysaccharide stimulation. The moderate aerobic training protected both genotypes from weight gain and reduced the caloric intake in the KO animals. Despite the attenuation of the M2 marker CD206 (p < 0.001) in the absence of PPAR-γ, the aerobic training modulated cytokine production in LPS stimulated peritoneal macrophages from both genotypes, reducing proinflammatory cytokines such as TNF-α (p = 0.0002) and IL-6 (p < 0.0001). Overall, our findings demonstrate the essential role of PPARγ in macrophage immunophenotypes. However, the deletion of PPARγ did not inhibit the exercise-mediated anti-inflammatory effect, underscoring the important role of exercise in modulating inflammation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to compare the acute effects of resistance training (RT) and power training (PT) on the hemodynamic parameters and nitric oxide (NO) bioavailability of older women. Materials and methods: A randomized experimental design was used in this study. Twentyone older women (age: 67.1±4.6 years; body mass index: 28.03±4.9 kg/m2; systolic blood pressure: 135.1±21.1 mmHg) were recruited to participate in this study. Volunteers were randomly allocated into PT, RT, and control session (CS) groups. The PT and RT groups underwent a single session of physical exercise equalized by training volume, characterized by 3 sets of 8-10 repetitions in 8 different exercises. However, RT group performed exercise at a higher intensity (difficult) than PT (moderate) group. On the other hand, concentric contractions were faster in PT group than in RT group. Hemodynamic parameters and saliva samples (for NO quantification) were collected before and during an hour after exercise completion. Results: Results demonstrated post-exercise hypotension during 35 minutes in the PT when compared to rest period (P=0.001). In turn, RT showed decreased heart rate and double product (P,0.001) during the whole evaluation period after exercise completion compared with the rest period. NO levels increased in the PT and RT during the whole evaluation period in relation to rest period. However, there were no differences between PT, RT, and CS regarding hemodynamic and NO evaluations. Conclusion: Data indicate that an acute session of power and resistance exercise can be effective to cause beneficial changes on hemodynamic parameters and NO levels in older women. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57, and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor-specific antibodies (DSA). DSA-negative biopsies-from patients with acute T-cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells ( P = 0.004 and P = 0.001) in the interstitial compartment in comparison with DSA-positive biopsies from patients acute antibody-mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d-). CD16+ cells was increased ( P = 0.03) in the glomerular compartment in DSA-positive biopsies. We assume that CD16+ expression and antibody-dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN-γ release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection. [ABSTRACT FROM AUTHOR]

The mammalian gastrointestinal tract harbors a diverse microbial community with which dynamic interactions have been established over millennia of coevolution. Commensal bacteria and their products are sensed by innate receptors expressed in gut epithelia and in gut-associated immune cells, thereby promoting the proper development of mucosal immune system and host homeostasis. Many studies have demonstrated that host--microbiota interactions play a key role during local and systemic immunity. Therefore, this review will focus on how innate sensing of the gut microbiota and their metabolites through inflammasome and toll-like receptors impact the modulation of a distinct set of inflammatory and autoimmune diseases. We believe that a better understanding of the fine-tuning that governs host--microbiota interactions will further improve common prophylactic and therapeutic applications. Introduct [ABSTRACT FROM AUTHOR]

Background: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery. Methods: Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network. Results: Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress. Conclusion: These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function. [ABSTRACT FROM AUTHOR]

Background: Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD). Methods: Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring. Results: Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring's metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy. Conclusions: Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well. [ABSTRACT FROM AUTHOR]

Cigarette smoke-induced chronic obstructive pulmonary disease is a very debilitating disease, with a very high prevalence worldwide, which results in a expressive economic and social burden. Therefore, new therapeutic approaches to treat these patients are of unquestionable relevance. The use of mesenchymal stromal cells (MSCs) is an innovative and yet accessible approach for pulmonary acute and chronic diseases, mainly due to its important immunoregulatory, anti-fibrogenic, anti-apoptotic and pro-angiogenic. Besides, the use of adjuvant therapies, whose aim is to boost or synergize with their function should be tested. Low level laser (LLL) therapy is a relatively new and promising approach, with very low cost, no invasiveness and no side effects. Here, we aimed to study the effectiveness of human tube derived MSCs (htMSCs) cell therapy associated with a 30mW/3J—660 nm LLL irradiation in experimental cigarette smoke-induced chronic obstructive pulmonary disease. Thus, C57BL/6 mice were exposed to cigarette smoke for 75 days (twice a day) and all experiments were performed on day 76. Experimental groups receive htMSCS either intraperitoneally or intranasally and/or LLL irradiation either alone or in association. We show that cotherapy greatly reduces lung inflammation, lowering the cellular infiltrate and pro-inflammatory cytokine secretion (IL-1β, IL-6, TNF-α and KC), which were followed by decreased mucus production, collagen accumulation and tissue damage. These findings seemed to be secondary to the reduction of both NF-κB and NF-AT activation in lung tissues with a concomitant increase in IL-10. In summary, our data suggests that the concomitant use of MSCs + LLLT may be a promising therapeutic approach for lung inflammatory diseases as COPD. [ABSTRACT FROM AUTHOR]

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. In this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased pro inflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. In conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN. [ABSTRACT FROM AUTHOR]

Background: Previously, we have demonstrated that mucociliary clearance (MCC) is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation. Methods: Fifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls) were intraperitoneally injected with three 100 mL doses of phosphate buffered saline and eight mice (immunosuppressed) were injected with three 100 µL injections of tacrolimus (1 mg/kg), mycophenolate mofetil (30 mg/kg), and prednisone (2 mg/kg) once daily. Then, mice inhaled the radioisotope 99m technetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1-1.5 hrs and at 6-6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance. Results: Although there was a slowing of MCC at 1-1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1-1.5 hrs for the two groups of mice. At 6-6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78±5.9% cleared versus 23.01±11.7% cleared, respectively (p = 0.006). Conclusions: These preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the role of TLR2, TLR4 and MyD88 in sepsis-induced AKI. C57BL/6 TLR2-/-, TLR4-/- and MyD88-/- male mice were subjected to sepsis by cecal ligation and puncture (CLP). Twenty four hours later, kidney tissue and blood samples were collected for analysis. The TLR2-/-, TLR4-/- and MyD88-/- mice that were subjected to CLP had preserved renal morphology, and fewer areas of hypoxia and apoptosis compared with the wild-type C57BL/6 mice (WT). MyD88-/- mice were completely protected compared with the WT mice. We also observed reduced expression of proinflammatory cytokines in the kidneys of the knockout mice compared with those of the WT mice and subsequent inhibition of increased vascular permeability in the kidneys of the knockout mice. The WT mice had increased GR1+low cells migration compared with the knockout mice and decreased in GR1+high cells migration into the peritoneal cavity. The TLR2-/-, TLR4-/-, and MyD88-/- mice had lower neutrophil infiltration in the kidneys. Depletion of neutrophils in the WT mice led to protection of renal function and less inflammation in the kidneys of these mice. Innate immunity participates in polymicrobial sepsis-induced AKI, mainly through the MyD88 pathway, by leading to an increased migration of neutrophils to the kidney, increased production of proinflammatory cytokines, vascular permeability, hypoxia and apoptosis of tubular cells. [ABSTRACT FROM AUTHOR]

Renal transplantation is presently the best treatment for end-stage renal disease, although considered contraindicated for elderly patients. However, more investigation is needed due to higher life expectancy rates of the general population and the increasing number of over 60-yr-old patients with chronic renal failure dependant upon dialysis. This study aims to determine graft and patient survival rates of renal transplant patients 60 yr and older compared to a younger group (50–59 yr old). Relevant pre- and post-transplant clinical data related to graft and patient survival in both groups were also investigated. Three-hundred and twenty consecutive renal transplant patients were enrolled in this study and grouped based on age at the time of the transplantation: one-hundred and ten patients at or over 60 yr old (elderly group) and 210 patients ranging from 50 to 59 yr old (younger group). There were no statistical differences in either group regarding clinical characteristics and immunological risk factors. The incidence of acute rejection was higher in the younger group (37.6%) than in the elderly (22.7%) (p = 0.01). Censored to death graft survivals at five yr were respectively 86.7% for patients ≥ 60 yr and 82.1% for patients 50–59 yr old (p = 0.49). Patient survival rates at five yr were respectively 76.2% for patients ≥ 60 yr and 81.6% for patients 50–59 yr old (p = 0.33). Our data show that renal transplantation for elderly patients has similar results to those found in younger individuals, which does not make age, in and of itself, a contraindication for transplantation. [ABSTRACT FROM AUTHOR]

Background: The widespread use of prophylactic ganciclovir and anti-lymphocyte/thymocyte therapies are associated with increased induction of ganciclovir-resistant cytomegalovirus (CMV) strains. The use of sirolimus has been associated with a lower incidence of CMV infection in transplant recipients. We questioned whether it could also be effective as a therapeutic treatment of resistant CMV infection. Methods: Patients with ganciclovir-resistant CMV infections determined clinically and by DNA sequencing analysis were enrolled. Antigenaemia and DNA sequencing were used to diagnosis and follow the mutations. Results: Nine transplant patients were given sirolimus plus mycophenolate mofetil (n = 4) or a calcineurin inhibitor (n = 5). Seven out of nine recipients were CMV IgG negative before transplantation. We observed a rapid decrease in antigenaemia levels, reaching zero in eight out of nine (88.9%) patients within a median of 20.3 ± 10.1 d. Graft function remained stable and no patient presented acute rejection or recurrence of the CMV infection. Conclusions: This suggests that the use of sirolimus plus ganciclovir therapy could be useful in ganciclovir-resistant CMV infections. [ABSTRACT FROM AUTHOR]

Abstract: There are still lacking data supporting a role for natural killer T (NKT) cells in the maintenance of human tissue-specific tolerance. We are interested to study NKT cell frequency in kidney transplant recipients and its correlation with graft function. Peripheral blood T cell receptors (TCR) Vα24+Vβ11+ NKT cells were phenotyped according to CD4 and CD8 expression in normal controls (NC), in 10 years rejection-free cadaver kidney allografts maintained with minimal immunosuppression (long-term rejection free [LTRF]), in patients with acute rejection (AR) and in patients with acute tubular necrosis (ATN). Results were expressed as percentages of CD4+CD8− (CD4+ NKT) or CD4−CD8− (double negative—DN NKT) Vα24+Vβ11+ cells. The percentages of Vα24+Vβ11+ cells were 0.09%, 0.14%, 0.02% and 0.09% on gated lymphocytes respectively in AR, ATN, LTRF and NC groups (p=0.263). DN NKT cells were more frequent in NC patients (52.11%) and less present in ATN patients (11.04%). In contrast, CD4+ NKT (IL-4-producing NKT cells subset) was more frequent in AR (42.86%), and corresponded to almost 3 to 7 folds more what we obtained in the other groups. Although total Vα24+Vβ11+ cells did not significantly differ among the groups, the lowest frequency was observed in the LTRF group. In conclusion, we observed that total number of NKT cells did not differ significantly among transplant patients when compared to normal controls, although specific-subsets seem to be more frequent in determined events. [Copyright &y& Elsevier]