Lymphocyte subsets and soluble forms of MIC-A and MIC-B are prognostic factors in non-Hodgkin lymphoma patients.

MIC-A and MIC-B are the natural ligands for NKG2D, an activator receptor expressed in NK cells. Soluble isoforms of MIC-A and MIC-B (sMICA, sMICB) have been identified in different malignancies, affecting NK cells' cytotoxicity. The study was performed to determine the levels of sMICA, sMICB, the expression of MIC-A, and MIC-B on tumor tissues, and lymphocyte subpopulations (CD4 + , CD8 + , NK, NKT, Tγδ cells, B cells, monocytes) in 94 patients with non-Hodgkin's lymphoma (NHL) and 72 healthy donors.The most frequent lymphoma was diffuse large B cell lymphoma (48%). Patients with NHL had decreased numbers of CD4 T cells, CD8 T cells, B cells, monocytes, NK cells, type 1 dendritic cells, γδ T cells, and increased iNKT cells. Patients showed higher levels of sMIC-A and similar serum levels of sMIC-B.Survival was poorer in patients having higher LDH values and lower numbers of CD4 T cells, type 1 dendritic cells, gamma-delta T cells, and high levels of sMIC-A.In conclusion, high levels of sMIC and decreased numbers in circulating lymphocyte subsets are related to poor outcomes in NHL.

LDH-A Promotes Metabolic Rewiring in Leucocytes from the Intestine of Rats Treated with TNBS.

Although the aetiology of inflammatory bowel diseases (IBDs) is still unknown, one of their main characteristics is that the immune system chronically affects the permeability of the intestinal lamina propria, in turn altering the composition of the microbiota. In this study, the TNBS rat model of colitis was used because it contains a complex inflammatory milieu of polymorphonuclear cells (PMN) and lymphocytes infiltrating the lamina propria. The aim of the present study was to investigate six dehydrogenases and their respective adaptations in the tissue microenvironment by quantifying enzymatic activities measured under substrate saturation conditions in epithelial cells and leukocytes from the lamina propria of rats exposed to TNBS. Our results show that in the TNBS group, an increased DAI score was observed due to the presence of haemorrhagic and necrotic areas in the colon. In addition, the activities of G6PDH and GADH enzymes were significantly decreased in the epithelium in contrast to the increased activity of these enzymes and increased lactate mediated by the LDH-A enzyme in leukocytes in the lamina propria of the colon. Over the past years, evidence has emerged illustrating how metabolism supports aspect of cellular function and how a metabolic reprogramming can drive cell differentiation and fate. Our findings show a metabolic reprogramming in colonic lamina propria leukocytes that could be supported by increased superoxide anion.

Estrogens as a Possible Therapeutic Strategy for the Management of Neuroinflammation and Neuroprotection in COVID-19.

The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies.

Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. AIM: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. METHOD: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. RESULTS: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. CONCLUSIONS: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.

Immunity to influenza: Impact of obesity.

Obesity is a health concern that is recognized as a critical factor for vulnerability to influenza A/pdmH1N1 virus infection, with epidemiological and clinical impacts. In humans, obesity induces disturbances in inflammatory and immune responses to the influenza virus and in some cases, this leads to severe complications, with fatal outcomes. Obesity impairs immunity by altering the response of cytokines, resulting in a decrease in the cytotoxic cell response of immunocompetent cells which have a key anti-viral role. Additionally, obesity seems to disturb the balance of endocrine hormones, such as leptin, that affect the interplay between metabolic and immune systems. This contribution focuses on reviewing the current epidemiologic data for the immune response to immunity in obese humans and animal models. In doing so, we aim to provide potential mechanisms to enhance immunity to influenza A/pdmH1N1 virus infection and protective factors in obese people.

Posterior Subdiaphragmatic Vagotomy Downmodulates the IgA Levels in the Small Intestine of BALB/c Mice.

OBJECTIVE: The posterior vagus nerve trunk innervates the entire small intestine, and elucidating its modulatory role in the IgA response was the aim of this study. METHODS: Two groups of six male BALB/c mice underwent sham or posterior subdiaphragmatic vagotomy and were euthanized on the 14th postoperative day; then, the small intestines were dissected. The intestinal fluid was harvested for antibody analysis by ELISA, and cell suspensions from Peyer's patches and lamina propria were prepared for cytofluorometric analysis of plasma cells and T lymphocytes. The CD4+ T cells were labeled for the intracellular IgA-producing interleukins (ILs)-4, -5, -6, and -10; transforming growth factor (TGF)-ß; and the inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-12. In the intestinal tissue samples, myeloperoxidase (MPO) visualization and the enzymatic activity were assessed by immunohistochemistry and ELISA, respectively. The data were analyzed by Student's t test, and the differences were considered significant at p < 0.05. RESULTS: In the vagotomy group, the IgA levels and the CD4+ T cells labeled with mediators that promote IgA secretion, including IL-4 (only at lamina propria), TNF-α, and IFN-γ, were decreased, whereas the lamina propria IgA+ plasma cells and MPO presence/activity were increased; changes in the IgM levels, IgM+ plasma cells, and CD4+ T cells labeled with TGF-ß, which have a role in class switch recombination, were not observed. CONCLUSION: The downmodulating impact of vagotomy on IgA levels may result from defective IgA secretion without affecting class switch recombination, whereas vagotomy evoked a proinflammatory response regarding MPO. These findings may reflect the role of the vagus nerve on the control of the IgA response in the small intestine.

Effect of platelet-rich plasma on patients after blepharoplasty surgery.

AIM: To evaluate the effect of platelet-rich plasma (PRP) treatment on patients after blepharoplasty surgery. MATERIALS AND METHODS: After undergoing blepharoplasty, 20 patients were randomly divided into two groups (n = 10 each). One was treated with autologous PRP and the other was not given any post-surgery treatment (basal group). Autologous PRP application was performed intradermically 24 h, 1 month, and 2 months post-surgery, and the outcome of the applications was assessed 1, 2, and 3 months post-surgery. The postoperative wound was assessed on a patient and observer scar assessment scale (POSAS) by patients and by an unblinded clinical observer. Statistical comparison between the two groups was analyzed by using the Mann-Whitney unpaired, two-tailed test. Significant differences were considered with P ≤ 0.05. RESULTS: Patient-reported data indicate that compared to the basal group, the PRP group showed no significant differences regarding pain, itching, or color, but had better values for stiffness and thickness (months 1 and 2) as well as scar irregularity (month 1). Data reported by the clinical observer showed that in comparison with the basal group, the PRP group showed no differences in vascularization or pigmentation, but had lower (better) scores regarding thickness, relief, and pliability (at all assessment times). The total assessment values from patients and the observer were significantly better for the PRP than the basal group. CONCLUSION: Autologous PRP treatment enhanced some parameters associated with healing properties, suggesting a potential therapeutic value after blepharoplasty surgery.

Modulation by bovine lactoferrin of parameters associated with the IgA response in the proximal and distal small intestine of BALB/c mice.

BACKGROUND: Secretory IgA (SIgA) and the polymeric immunoglobulin receptor (pIgR) have a pivotal role in gut homeostasis. Bovine lactoferrin (bLf) has been shown to modulate intestinal immunity and endogenous corticosterone. Considering the regionalization of the intestinal immune response, the aim of this work was to compare the impact of bLf on the IgA response in the proximal versus distal small intestine under physiological conditions. METHODS: Groups of healthy male BALB/c mice were orally treated with one daily dose of bLf (50, 500, or 5000 µg) or untreated (control) for 7 d, and then sacrificed. From plasma samples, corticosterone levels were determined by an enzyme-linked immunosorbent assay (ELISA) kit. From distal and proximal segments of the small intestine, the following material was obtained: intestinal secretions to evaluate IgA levels by ELISA; epithelial cell extracts for protein-analysis of α-chain and pIgR by Western blot; mucosa samples for mRNA analysis of α-/J-chain, pIgR, and interleukin (IL)-2, -4, -5, and -6 by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: With 5000 µg of bLf, there were greater modulatory effects in the distal (versus proximal) segment, evidenced by an increase in the (i) level of total and specific IgA, (ii) protein expression of α-chain and pIgR, (iii) mRNA transcripts of α-chain, IL-2 and IL-5, and (iv) level of plasma corticosterone. CONCLUSIONS: Endogenous corticosterone elicited by bLf may have allowed for an IL profile that favored the IgA antibody response. The latter has a key role in maintaining intestinal homeostasis.

Effect of Bovine Lactoferrin Treatment Followed by Acute Stress on the IgA-Response in Small Intestine of BALB/c Mice.

Secretory IgA (SIgA) has a pivotal role in gut homeostasis, which can be disturbed by stress. SIgA is formed by IgA-dimers (associated by the J-chain) and the secretory component, a protein derivative of polymeric immunoglobulin receptor (pIgR). Given the gut immuno-modulatory properties of bovine lactoferrin (bLf), the aim of this study was to compare, after bLf treatment followed by acute stress, the IgA response and IgA-associated parameters in proximal versus distal small intestine. Male BALB/c mice (n = 6) were orally treated with bLf (50, 500, and 5000 µg) for 7 days, then stressed by immobilization for 1 h, and sacrificed. In proximal and distal segments, levels were determined of IgA in gut secretions (enzyme-linked immunosorbent assay [ELISA]), the α-/J-chain and pIgR proteins in epithelial cells (Western-blot), and mRNA expression of the α-/J-chain, pIgR, and interleukins (ILs) in mucosa (RT-PCR). Data were compared by two-way analysis of variance (ANOVA) (significance at P < 0.05). Under acute stress, bLf triggered higher levels of IgA, SIgA, and anti-bLf-IgA as well as greater mRNA expression of pIgR, IL-4, and IL-6 (500 µg) in proximal intestine, while inducing higher levels of the total IgA, α-/J-chain, and pIgR proteins as well as greater mRNA expression of the α-chain and IL-4 (5000 µg) in distal intestine. Compared to unstressed/bLf-untreated mice, plasma corticosterone (a stress biomarker, measured by ELISA) increased in stressed/bLf-treated (0, 50 and 500 µg) and unstressed/bLf-treated (5000 µg) mice. The interplay of corticosterone with gut neuroendocrine factors may have elicited signals creating anti-inflammatory conditions for an IgA-response profile in each intestinal region, according to the bLf concentration administered.

Intermittent fasting favored the resolution of Salmonella typhimurium infection in middle-aged BALB/c mice.

Intermittent fasting (IF) reportedly increases resistance and intestinal IgA response to Salmonella typhimurium infection in mature mice. The aim of this study was to explore the effect of aging on the aforementioned improved immune response found with IF. Middle-aged male BALB/c mice were submitted to IF or ad libitum (AL) feeding for 40 weeks and then orally infected with S. typhimurium. Thereafter, infected animals were all fed AL (to maximize their viability) until sacrifice on day 7 or 14 post-infection. We evaluated body weight, bacterial load (in feces, Peyer's patches, spleen and liver), total and specific intestinal IgA, lamina propria IgA+ plasma cells, plasma corticosterone, and messenger RNA (mRNA) expression of α-chain, J-chain, and the polymeric immunoglobulin receptor (pIgR) in liver and intestinal mucosa. In comparison with the infected AL counterpart, the infected IF group (long-term IF followed by post-infection AL feeding) generally had lower intestinal and systemic bacterial loads as well as higher total IgA on both post-infection days. Both infected groups showed no differences in corticosterone levels, body weight, or food and caloric intake. The increase in intestinal IgA was associated with enhanced pIgR mRNA expression in the intestine (day 7) and liver. Thus, to maintain body weight and caloric intake, IF elicited metabolic signals that possibly induced the increased hepatic and intestinal pIgR mRNA expression found. The increase in IgA probably resulted from intestinal IgA transcytosis via pIgR. This IgA response along with phagocyte-induced killing of bacteria in systemic organs (not measured) may explain the resolution of the S. typhimurium infection.

Modulatory Effects of Oral Bovine Lactoferrin on the IgA Response at Inductor and Effector Sites of Distal Small Intestine from BALB/c Mice.

Bovine lactoferrin (bLf) up-modulates intestinal IgA that is essential for homeostasis and which might confer protection to the distal small intestine that is vulnerable to inflammation. This study analyzed the effects of bLf administered orally on the IgA response at inductive (Peyer's patches) and effector (lamina propria) sites of the distal small intestine in mice. Groups of five healthy male BALB/c mice were orally treated with 5 mg of bLf for 7, 14, 21, or 28 days. Then, mice were killed and the distal small intestine was dissected. Intestinal fluid samples were analyzed to determine IgA and IgM levels by enzyme-immuno assay. Peyer's patches and lamina propria were analyzed for IgA(+) or IgM(+) plasma cells, B, CD4(+) T and CD8(+) T cells as well as CD4(+) T cells positive for either pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon-γ and interleukin (IL)-12] or for IgA-producing ILs (IL-4, -5, -10 and -6) by cytofluorometry. Antibodies, antibody-secreting cells, and B and T responses in both Peyer's patches and lamina propria were higher in bLf-treated than bLf-untreated mice. The generation of IL-10 and IL-6 CD4(+) T cells in Peyer's patches or TNF-α and IL-12 CD4(+) T cells in lamina propria showed similar response patterns. On days 14 and 28, cytokine/IL CD4(+) T cell responses were increased in Peyer's patches or decreased in lamina propria. The effect of bLf on the elicitation of IgA indicates a potential application of bLf as a nutraceutical to control inflammation in the distal small intestine.

Intermittent fasting modulates IgA levels in the small intestine under intense stress: a mouse model.

Intermittent fasting prolongs the lifespan and unlike intense stress provides health benefits. Given the role of the immunoglobulin A (IgA) in the intestinal homeostasis, the aim of this study was to assess the impact of intermittent fasting plus intense stress on secretory IgA (SIgA) production and other mucosal parameters in the duodenum and ileum. Two groups of six mice, with intermittent fasting or fed ad libitum for 12weeks, were submitted to a session of intense stress by a bout of forced swimming. Unstressed ad libitum fed or intermittently fasted groups were included as controls. After sacrifice, we evaluated intestinal SIgA and plasma adrenal hormones, lamina propria IgA+ plasma-cells, mRNA expression of polymeric immunoglobulin receptor, α- and J-chains in the liver and intestinal mucosa, as well as pro- (tumor necrosis factor-α, interleukin-6 and Interferon-γ) and anti- (interleukin-2, -4, -10 and transforming growth factor-ß) inflammatory cytokines in mucosal samples. Under intense stress, intermittent fasting down- or up-modulated the levels of most parameters in the duodenum and ileum, respectively while up-regulated corticosterone levels without affecting epinephrine. Our data suggest intermittent fasting plus intense stress elicited neuroendocrine pathways that differentially controlled IgA and pIgR expression in duodenum and ileum. These findings provide experimental foundations for a presumable impact of intermittent fasting under intense stress on the intestinal homeostasis or inflammation by triggering or reducing the IgA production in ileum or duodenum respectively.