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Juvenile Dermatomyositis (JDM) is the most common inflammatory myopathy in pediatrics. This study evaluates the role of Natural Killer (NK) cells in Juvenile Dermatomyositis (JDM) pathophysiology. The study included 133 untreated JDM children with an NK cell count evaluation before treatment. NK cell subsets (CD56low/dim vs. CD 56bright) were examined in 9 untreated children. CD56 and perforin were evaluated in situ in six untreated JDM and three orthopedic, pediatric controls. 56% of treatment-naive JDM had reduced circulating NK cell counts, designated "low NK cell". This low NK group had more active muscle disease compared to the normal NK cell group. The percentage of circulating CD56low/dim NK cells was significantly lower in the NK low group than in controls (0.55% vs. 4.6% p < 0.001). Examination of the untreated JDM diagnostic muscle biopsy documented an increased infiltration of CD56 and perforin-positive cells (p = 0.023, p = 0.038, respectively). Treatment-naive JDM with reduced circulating NK cell counts exhibited more muscle weakness and higher levels of serum muscle enzymes. Muscle biopsies from treatment-naive JDM displayed increased NK cell infiltration, with increased CD56 and perforin-positive cells.
Assuntos
Antígeno CD56 , Dermatomiosite , Células Matadoras Naturais , Debilidade Muscular , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Dermatomiosite/imunologia , Dermatomiosite/sangue , Dermatomiosite/patologia , Masculino , Criança , Debilidade Muscular/sangue , Feminino , Antígeno CD56/metabolismo , Pré-Escolar , Perforina/metabolismo , Adolescente , Contagem de LinfócitosRESUMO
Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.
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Barreira Hematoencefálica , Neoplasias Encefálicas , Doxorrubicina , Microbolhas , Receptor de Morte Celular Programada 1 , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/análogos & derivados , Animais , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Camundongos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/imunologia , Glioma/patologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Sistemas de Liberação de Medicamentos , Ondas Ultrassônicas , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos Endogâmicos C57BL , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , PolietilenoglicóisRESUMO
The parasite Leishmania resides as amastigotes within the macrophage parasitophorous vacuoles inflicting the disease Leishmaniasis. Leishmania selectively modulates mitogen-activated protein kinase (MAPK) phosphorylation subverting CD40-triggered anti-leishmanial functions of macrophages. The mechanism of any pathogen-derived molecule induced host MAPK modulation remains poorly understood. Herein, we show that of the fifteen MAPKs, LmjMAPK4 expression is higher in virulent L. major. LmjMAPK4- detected in parasitophorous vacuoles and cytoplasm- binds MEK-1/2, but not MKK-3/6. Lentivirally-overexpressed LmjMAPK4 augments CD40-activated MEK-1/2-ERK-1/2-MKP-1, but inhibits MKK3/6-p38MAPK-MKP-3, phosphorylation. A rationally-identified LmjMAPK4 inhibitor reinstates CD40-activated host-protective anti-leishmanial functions in L. major-infected susceptible BALB/c mice. These results identify LmjMAPK4 as a MAPK modulator at the host-pathogen interface and establish a pathogen-intercepted host receptor signaling as a scientific rationale for identifying drug targets.
Assuntos
Antígenos CD40 , Leishmania major , Leishmaniose Cutânea , Macrófagos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Animais , Leishmania major/imunologia , Leishmania major/fisiologia , Antígenos CD40/metabolismo , Camundongos , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Macrófagos/imunologia , Macrófagos/parasitologia , Humanos , Feminino , Fosforilação , Interações Hospedeiro-Parasita/imunologia , Sistema de Sinalização das MAP Quinases/imunologiaRESUMO
Substance use disorders (SUD) are chronic relapsing disorders governed by continually shifting cycles of positive drug reward experiences and drug withdrawal-induced negative experiences. A large body of research points to plasticity within systems regulating emotional, motivational, and cognitive processes as drivers of continued compulsive pursuit and consumption of substances despite negative consequences. This plasticity is observed at all levels of analysis from molecules to networks, providing multiple avenues for intervention in SUD. The cytoskeleton and its regulatory proteins within neurons and glia are fundamental to the structural and functional integrity of brain processes and are potentially the major drivers of the morphological and behavioral plasticity associated with substance use. In this review, we discuss preclinical studies that provide support for targeting the brain cytoskeleton as a therapeutic approach to SUD. We focus on the interplay between actin cytoskeleton dynamics and exposure to cocaine, methamphetamine, alcohol, opioids, and nicotine and highlight preclinical studies pointing to a wide range of potential therapeutic targets, such as nonmuscle myosin II, Rac1, cofilin, prosapip 1, and drebrin. These studies broaden our understanding of substance-induced plasticity driving behaviors associated with SUD and provide new research directions for the development of SUD therapeutics.
Assuntos
Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Citoesqueleto , Citoesqueleto de Actina/metabolismo , Encéfalo , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
Residing obligatorily as amastigotes within the mammalian macrophages, the parasite Leishmania donovani inflicts the potentially fatal, globally re-emerging disease visceral leishmaniasis (VL) by altering intracellular signaling through kinases and phosphatases. Because the phosphatases that modulate the VL outcome in humans remained unknown, we screened a human phosphatase siRNA-library for anti-leishmanial functions in THP-1, a human macrophage-like cell line. Of the 251 phosphatases, the screen identified the Ca++-activated K+-channel-associated phosphatase myotubularin-related protein-6 (MTMR6) as the only phosphatase whose silencing reduced parasite load and IL-10 production in human macrophages. Virulent, but not avirulent, L. donovani infection increased MTMR6 expression in macrophages. As virulent L. donovani parasites expressed higher lipophosphoglycan, a TLR2-ligand, we tested the effect of TLR2 stimulation or blockade on MTMR6 expression. TLR1/TLR2-ligand Pam3CSK4 enhanced, but TLR2 blockade reduced, MTMR6 expression. L. donovani infection of macrophages ex vivo increased, but miltefosine treatment reduced, MTMR6 expression. Corroboratively, compared to endemic controls, untreated VL patients had higher, but miltefosine-treated VL patients had reduced, MTMR6 expression. The phosphatase siRNA-library screening thus identified MTMR6 as the first TLR2-modulated ion channel-associated phosphatase with significant implications in VL patients and anti-leishmanial functions.
Assuntos
Leishmania donovani , Leishmaniose Visceral , Fosforilcolina , Animais , Humanos , Canais Iônicos , Leishmaniose Visceral/parasitologia , Ligantes , Mamíferos , Fosforilcolina/análogos & derivados , Proteínas Tirosina Fosfatases não Receptoras , RNA Interferente Pequeno/genética , Receptor 2 Toll-LikeRESUMO
As part of a symposium, current and former directors of Immune Monitoring cores and investigative oncologists presented insights into the past, present and future of immune assessment. Dr. Gnjatic presented a classification of immune monitoring technologies ranging from universally applicable to experimental protocols, while emphasizing the need for assay harmonization. Dr. Obeng discussed physiologic differences among CD8 T cells that align with anti-tumor responses. Dr. Lyerly presented the Soldano Ferrone lecture, commemorating the passionate tumor immunologist who inspired many, and covered a timeline of monitoring technology development and its importance to immuno-oncology. Dr. Sonabend presented recent achievements in glioblastoma treatment, accentuating the range of monitoring techniques that allowed him to refine patient selection for clinical trials. Dr. Guevara-Patiño focused on hypoxia within the tumor environment and stressed that T cell viability is not to be confused with functionality. Dr. Butterfield accentuated monitoring of dendritic cell metabolic (dys)function as a determinant for tumor vaccine success. Lectures were interspersed with select abstract presentations. To summarize the concepts, Dr. Maecker from Stanford led an informative forum discussion, pointing towards the future of immune monitoring. Immune monitoring continues to be a guiding light towards effective immunotherapeutic strategies.
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The protozoan parasite Leishmania donovani resides within mammalian macrophages and alters its antigen-presenting functions to negatively regulate host-protective T cell responses. This negative regulation of human T cell responses in vitro is attributed to myotubularin-related protein-6 (MTMR6), an ion channel-associated phosphatase. As mouse and human MTMR6 share homology, we studied whether MTMR6 silencing by lentivirally expressed MTMR6shRNA (Lv-MTMR6shRNA) reduced Leishmania growth in macrophages and whether MTMR6 silencing in Leishmania-susceptible BALB/c mice reduced the infection and reinstated host-protective T cell functions. MTMR6 silencing reduced amastigote count and IL-10 production, increased IL-12 expression and, induced IFN-γ-secreting T cells with anti-leishmanial activity in macrophage-T cell co-cultures. Lv-MTMR6shRNA reduced the infection, accompanied by increased IFN-γ expression, in susceptible BALB/c mice. Delays in Lv-MTMR6shRNA treatment by 7 days post-infection significantly reduced the infection suggesting MTMR6 as a plausible therapeutic target. Priming of BALB/c mice with avirulent parasites and Lv-MTMR6shRNA reduced parasite burden in challenge infection. These results indicate that MTMR6 is the first receptor-regulated ion channel-associated phosphatase regulating anti-leishmanial immune responses.
Assuntos
Leishmania donovani , Leishmaniose Visceral , Leishmaniose , Camundongos , Humanos , Animais , Proteínas Tirosina Fosfatases não Receptoras/genética , Camundongos Endogâmicos BALB C , Canais Iônicos , MamíferosRESUMO
Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the molecular and cellular impact of sepsis across organs remains rudimentary. Here, we characterize the pathogenesis of sepsis by measuring dynamic changes in gene expression across organs. To pinpoint molecules controlling organ states in sepsis, we compare the effects of sepsis on organ gene expression to those of 6 singles and 15 pairs of recombinant cytokines. Strikingly, we find that the pairwise effects of tumor necrosis factor plus interleukin (IL)-18, interferon-gamma or IL-1ß suffice to mirror the impact of sepsis across tissues. Mechanistically, we map the cellular effects of sepsis and cytokines by computing changes in the abundance of 195 cell types across 9 organs, which we validate by whole-mouse spatial profiling. Our work decodes the cytokine cacophony in sepsis into a pairwise cytokine message capturing the gene, cell and tissue responses of the host to the disease.
Assuntos
Citocinas , Sepse , Camundongos , Animais , Interleucina-6/genética , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama , Sepse/genéticaRESUMO
Preclinical studies show that inhibiting the actin motor ATPase nonmuscle myosin II (NMII) with blebbistatin (Blebb) in the basolateral amgydala (BLA) depolymerizes actin, resulting in an immediate, retrieval-independent disruption of methamphetamine (METH)-associated memory in male and female adult and adolescent rodents. The effect is highly selective, as NMII inhibition has no effect in other relevant brain regions (e.g., dorsal hippocampus [dPHC], nucleus accumbens [NAc]), nor does it interfere with associations for other aversive or appetitive stimuli, including cocaine (COC). To understand the mechanisms responsible for drug specific selectivity we began by investigating, in male mice, the pharmacokinetic differences in METH and COC brain exposure . Replicating METH's longer half-life with COC did not render the COC association susceptible to disruption by NMII inhibition. Therefore, we next assessed transcriptional differences. Comparative RNA-seq profiling in the BLA, dHPC and NAc following METH or COC conditioning identified crhr2, which encodes the corticotropin releasing factor receptor 2 (CRF2), as uniquely upregulated by METH in the BLA. CRF2 antagonism with Astressin-2B (AS2B) had no effect on METH-associated memory after consolidation, allowing for determination of CRF2 influences on NMII-based susceptibility. Pretreatment with AS2B prevented the ability of Blebb to disrupt an established METH-associated memory. Alternatively, combining CRF2 overexpression and agonist treatment, urocortin 3 (UCN3), in the BLA during conditioning rendered COC-associated memory susceptible to disruption by NMII inhibition, mimicking the Blebb-induced, retrieval-independent memory disruption seen with METH. These results suggest that BLA CRF2 receptor activation during memory formation in male mice can prevent stabilization of the actin-myosin cytoskeleton supporting the memory, rendering it vulnerable to disruption by NMII inhibition. CRF2 represents an interesting target for BLA-dependent memory destabilization via downstream effects on NMII.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Cocaína , Metanfetamina , Receptores de Hormônio Liberador da Corticotropina , Animais , Feminino , Masculino , Camundongos , Actinas , Complexo Nuclear Basolateral da Amígdala/metabolismo , Cocaína/farmacologia , Metanfetamina/farmacologia , Miosina Tipo II/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismoRESUMO
Systemic Lupus Erythematosus (SLE) or Lupus is a multifactorial autoimmune disease of multiorgan malfunctioning of extremely heterogeneous and unclear etiology that affects multiple organs and physiological systems. Some racial groups and women of childbearing age are more susceptible to SLE pathogenesis. Impressive progress has been made towards a better understanding of different immune components contributing to SLE pathogenesis. Recent investigations have uncovered the detailed mechanisms of inflammatory responses and organ damage. Various environmental factors, pathogens, and toxicants, including ultraviolet light, drugs, viral pathogens, gut microbiome metabolites, and sex hormones trigger the onset of SLE pathogenesis in genetically susceptible individuals and result in the disruption of immune homeostasis of cytokines, macrophages, T cells, and B cells. Diagnosis and clinical investigations of SLE remain challenging due to its clinical heterogeneity and hitherto only a few approved antimalarials, glucocorticoids, immunosuppressants, and some nonsteroidal anti-inflammatory drugs (NSAIDs) are available for treatment. However, the adverse effects of renal and neuropsychiatric lupus and late diagnosis make therapy challenging. Additionally, SLE is also linked to an increased risk of cardiovascular diseases due to inflammatory responses and the risk of infection from immunosuppressive treatment. Due to the diversity of symptoms and treatment-resistant diseases, SLE management remains a challenging issue. Nevertheless, the use of next-generation therapeutics with stem cell and gene therapy may bring better outcomes to SLE treatment in the future. This review highlights the autoimmune responses as well as potential therapeutic interventions for SLE particularly focusing on the recent therapeutic advancements and challenges.
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Leishmania major and L. donovani cause cutaneous leishmaniasis and visceral leishmaniasis, respectively. Available chemotherapies suffer from toxicity, drug-resistance or high cost of production prompting the need for the discovery of new anti-leishmanials. Here, we test a novel aminosteriodal compound- 3-alpha-amino-cholestane [3AC] - that shows selective inhibition of SHIP1, an inositol-5'-phosphate-specific phosphatase with potent effects on the immune system. We report that 3AC-sensitive SHIP1 expression increases in Leishmania-infected macrophages. Treatment of BALB/c mice, a Leishmania-susceptible host, with 3AC increased anti-leishmanial, but reduced pro-leishmanial, cytokines' production and reduced the parasite load in both L. major and L. donovani infections. These findings implicate SHIPi as a potential novel immunostimulant with anti-leishmanial function.
Assuntos
Leishmania donovani , Leishmaniose Visceral , Animais , Camundongos , Leishmaniose Visceral/tratamento farmacológico , Camundongos Endogâmicos BALB CRESUMO
While the seasonal testicular cycle has been well studied regarding internal components, no attention has been given to the testicular capsule (tunica albuginea and tunica serosa). This study elucidated the structure-function modulations of intra-testicular functions by its capsule in the finch red munia (Amandava amandava) during the annual testicular cycle. The birds were studied during breeding (preparatory and breeding) and nonbreeding (regressive and quiescent) reproductive phases using hematoxylin-eosin and acridine orange-ethidium bromide capsule staining, hormonal ELISA (LH and testosterone) and immunohistochemical expression of neuropeptides (GnRH, GnIH) and androgen receptor (AR). The thickness of the tunica albuginea was significantly increased with multiple myoid layers during the nonbreeding phases (p < 0.05). The thickness of the tunica serosa was not altered, although characteristics and distribution of squamous cells showed significant seasonal alterations. Immunoreactive (-ir) AR and GnIH cells were differentially localized on both layers of the capsule. Strong AR-ir cells on tunica serosa during breeding phases showed increased expression of the receptor; a significant increase in plasma LH and testosterone was also observed during the breeding cycle (p < 0.01). Contrarily, intense GnIH-ir cells on both the capsular layers peaked during testicular regression. Differential structural alterations of the testicular capsule provide mechanical support and help maintain internal homeostasis in tune with changing seasons. The seasonal expressions and alterations of reproduction-related receptors, hormones, and neuropeptides provide evidence for the potential regulatory roles of the capsule in the peripheral modulation of intratesticular functions.
Assuntos
Hormônio Liberador de Gonadotropina , Testículo , Masculino , Animais , Estações do Ano , Hormônio Liberador de Gonadotropina/metabolismo , Reprodução/fisiologia , TestosteronaRESUMO
Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.
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Antígenos , Imunidade Inata , Animais , Camundongos , Humanos , Dieta , Glutens , Células Dendríticas , Tolerância ImunológicaRESUMO
Leishmania infection of macrophages results in altered Ras isoforms expression and Toll-like receptor-2 (TLR2) expression and functions. Therefore, we examined whether TLR2 would selectively alter Ras isoforms' expression in macrophages. We observed that TLR2 ligands- Pam3CSK4, peptidoglycan (PGN), and FSL- selectively modulated the expression of Ras isoforms in BALB/c-derived elicited macrophages. Lentivirally-expressed TLR1-shRNA significantly reversed this Ras isoforms expression profile. TLR2-deficient L. major-infected macrophages and the lymph node cells from the L. major-infected mice showed similarly reversed Ras isoforms expression. Transfection of the macrophages with the siRNAs for the adaptors- Myeloid Differentiation factor 88 (MyD88) and Toll-Interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP)- or Interleukin-1 Receptor-Associated Kinases (IRAKs)- IRAK1 and IRAK4- significantly inhibited the L. major-induced down-regulation of K-Ras, and up-regulation of N-Ras and H-Ras, expression. The TLR1/TLR2-ligand Pam3CSK4 increased IL-10 and TGF-ß expression in macrophages. Pam3CSK4 upregulated N-Ras and H-Ras, but down-regulated K-Ras, expression in C57BL/6 wild-type, but not in IL-10-deficient, macrophages. IL-10 or TGF-ß signaling inhibition selectively regulated Ras isoforms expression. These observations indicate the specificity of the TLR2 regulation of Ras isoforms and their selective modulation by MyD88, TIRAP, and IRAKs, but not IL-10 or TGF-ß, signaling.
Assuntos
Leishmania major , Leishmaniose Cutânea , Macrófagos , Receptor 2 Toll-Like , Proteínas ras , Leishmaniose Cutânea/metabolismo , Animais , Camundongos , Camundongos Endogâmicos BALB C , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Macrófagos/metabolismo , Ligantes , Proteínas ras/metabolismo , Peptidoglicano/metabolismo , Quinases Associadas a Receptores de Interleucina-1 , Camundongos Endogâmicos C57BL , Isoformas de Proteínas/metabolismo , Regulação para BaixoRESUMO
The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.
Assuntos
Limosilactobacillus reuteri , Melanoma , Microambiente Tumoral , Humanos , Dieta , Inibidores de Checkpoint Imunológico , Limosilactobacillus reuteri/metabolismo , Melanoma/terapia , Triptofano/metabolismo , Linfócitos T CD8-Positivos/imunologia , Receptores de Hidrocarboneto Arílico/agonistasRESUMO
Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the impact of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of the effects of sepsis across tissues. These data revealed two interorgan mechanisms key in sepsis. First, we discover a simplifying principle in the systemic behavior of the cytokine network during sepsis, whereby a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1ß explains half of all the cellular effects of sepsis on 195 cell types across 9 organs. Second, we find that the secreted phospholipase PLA2G5 mediates hemolysis in blood, contributing to organ failure during sepsis. These results provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the body.
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Alzheimer's disease (AD) is a neurological illness that causes memory loss over time. Currently, available pharmaceutical medicines and products are limited, and they have side effects at a higher price. Researchers and scientists have observed significant effects of nutraceuticals. Various preclinical and clinical studies were investigated for the Anti-Alzheimer's activity of nutraceuticals. The increasing ability of the pathogenesis of AD has led to the analysis of novel therapeutic targets, including the pathophysiological mechanisms and distinct cascades. So, current improvement will show the most adequate and prominent nutraceuticals and suggested concise mechanisms involving autophagy regulation, anti-inflammatory, antioxidant, mitochondrial homeostasis, and others. The effects of nutraceuticals cannot be ignored; it is important to investigate high-quality clinical trials. Given the potential of nutraceuticals to battle AD as multi-targeted therapies, it's vital to evaluate them as viable lead compounds for drug discovery and development. To the best of the authors 'knowledge, modification of blood-brain barrier permeability, bioavailability, and aspects of randomized clinical trials should be considered in prospective investigations. PRACTICAL APPLICATIONS: Advancements in molecular diagnostic and fundamentals have implemented particular usefulness for drug evaluation. An excess of experimental knowledge occurs regarding the effect of nutraceuticals on AD. There are various preclinical and clinical studies that have been done on nutraceuticals. In addition, various substitute inhibit and enhance some pathophysiological levels associated with AD. Nutraceuticals are easily available and have fewer side effects with cost-effective advantages. However, further investigations and clinical trials are required to encourage its effect on disease.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Estudos Prospectivos , Suplementos Nutricionais , Antioxidantes/uso terapêutico , Anti-InflamatóriosRESUMO
The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.
Assuntos
Proteínas de Ligação a DNA , Dioxigenases , Hepatite Autoimune , Limosilactobacillus reuteri , Fígado , Microbiota , Animais , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Disbiose/complicações , Hepatite Autoimune/etiologia , Hepatite Autoimune/patologia , Interferon gama , Ligantes , Fígado/imunologia , Fígado/microbiologia , Camundongos , Microbiota/genética , Microbiota/imunologia , Linfócitos T CitotóxicosRESUMO
Trimethylsilyl trifluoromethanesulfonate mediated dimerization reaction of vinylogous carbamates of carbazoles gave highly fluorescent pyridocarbazoles through a Povarov-type formal [4 + 2] cycloaddition-retro-aza-Michael cascade. The developed strategy was used to access indolo pyridocarbazole and quinolizinocarbazolone in an expeditious manner. Various coupling reactions were successfully performed on synthesized pyridocarbazoles to study the effect of electronics of substitution on photophysical properties. Synthesized carbazoles possess excellent photophysical properties with high quantum yields (ΦF). Fluorescent carbazole dicarboxylic acid showed potential as a pH probe to give a linear response to pH over a very wide range (7.0-3.0) reflecting high efficiency.
Assuntos
Carbamatos , Reação de CicloadiçãoRESUMO
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease that causes dementia by impairing mental capacity growth and disrupting neurocognitive activity. Despite recent advancements in AD therapy, therapeutic effectiveness has been small, noncurative, and susceptible to drug resistance. The reality that AD's origin remains unknown and that the blood-brain barrier limits treatment effectiveness are two significant impediments to science. Plants are repositories for novel chemical entities, which provide an exciting avenue for Alzheimer's disease studies. Although several herbal remedies are unquestionably efficient, only a small number have been clinically tested for their active chemical constituents and biological activities. Using published data in the literature, we summarized commonly used medicinal plants and herbs and their phyto components for the care and diagnosis of Alzheimer's disease as an alternative therapy. In this, we summarize the main compounds found in 30 different herbal medicines that target neurodegenerative diseases. Using the experimental study of physicochemical properties, we put forward a hypothesis about potential medicinal plants and the management of Alzheimer's disease. The summary analysis demonstrates that conventional herbal medicines produce compounds with physicochemical properties with a high degree of similarities with existing approved medicines.