Utilization of 2-nitrophenols in annulations with aryl isothiocyanates towards the synthesis of 2-aminobenzoxazoles.

A method for the annulation of 2-nitrophenols with aryl isothiocyanates is reported. The reactions proceeded in the presence of an iron(iii) acetylacetonate catalyst, elemental sulfur, NaOH as a base, and DMSO as a solvent. Derivatives of 2-aminobenzoxazoles bearing nitro, cyano, acetyl, sulfone, secondary amine, and pyrrolyl groups were successfully isolated.

Refractory Immune Thrombocytopenic Purpura with Abdominal Splenosis: A Complex Case.

Immune thrombocytopenia (ITP) is an acquired thrombocytopenia resulting from immune-mediated platelet destruction via antiplatelet antibodies and T cells. Medical management of ITP includes corticosteroids and multiple other adjunct therapies, with splenectomy generally being reserved for severe, refractory cases. In this clinical case report, we describe the evaluation of a 35-year-old male with a history of prior traumatic splenic injury who presented to the emergency department endorsing easy bruising and a petechial rash, ultimately found to have severe thrombocytopenia. The patient was diagnosed with primary ITP that proved to be refractory to a number of first- and second-line medical therapies. His course was complicated by the presence of abdominal splenosis discovered at the time of planned splenectomy and intra-abdominal hemorrhage requiring splenic artery embolization thereafter. To our knowledge, this is one of few published cases of ITP complicated by abdominal splenosis, highlighting the need to consider splenosis and the presence of accessory splenic tissue in cases of refractory ITP.

Modulating donor mitochondrial fusion/fission delivers immunoprotective effects in cardiac transplantation.

Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8+ T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.

T-cell Immunometabolism: Therapeutic Implications in Organ Transplantation.

Although solid-organ transplantation has evolved steadily with many breakthroughs in the past 110 y, many problems remain to be addressed, and advanced therapeutic strategies need to be considered. T-cell immunometabolism is a rapidly advancing field that has gathered much attention recently, providing ample mechanistic insight from which many novel therapeutic approaches have been developed. Applications from the field include antitumor and antimicrobial therapies, as well as for reversing graft-versus-host disease and autoimmune diseases. However, the immunometabolism of T cells remains underexplored in solid-organ transplantation. In this review, we will highlight key findings from hallmark studies centered around various metabolic modes preferred by different T-cell subtypes (categorized into naive, effector, regulatory, and memory T cells), including glycolysis, glutaminolysis, oxidative phosphorylation, fatty acid synthesis, and oxidation. This review will discuss the underlying cellular signaling components that affect these processes, including the transcription factors myelocytomatosis oncogene, hypoxia-inducible factor 1-alpha, estrogen-related receptor alpha, and sterol regulatory element-binding proteins, along with the mechanistic target of rapamycin and adenosine monophosphate-activated protein kinase signaling. We will also explore potential therapeutic strategies targeting these pathways, as applied to the potential for tolerance induction in solid-organ transplantation.

Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

BACKGROUND: Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. After reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers on the whole allograft instead of ECs. This study aimed to elucidate the relationship between EC mPTP opening and their immunophenotype. METHODS: Mitochondrial metabolic fitness and glycolysis in ECs were assessed in parallel with metabolic gene microarray postreperfusion. NIM811 was used to inhibit mPTP opening to rescue mitochondrial fitness. The immunogenicity of NIM811-treated ECs was determined via levels of EC's proinflammatory cytokines and allogeneic CD8 T cell cocultures. Finally, EC surface expression of adhesion, costimulatory, coinhibitory, MHC-I molecules, and MHC-I machinery protein levels were characterized. RESULTS: Genes for glycolysis, tricarboxylic acid cycle, fatty acid synthesis, gluconeogenesis were upregulated at 6 hours postreperfusion but either normalized or downregulated at 24 hours postreperfusion. As mitochondrial fitness was reduced, glycolysis increased during the first 6 hours postreperfusion. Endothelial cell treatment with NIM811 during the early postreperfusion period rescued mitochondrial fitness and reduced EC immunogenicity by decreasing CCL2, KC release, and VCAM-1, MHC-I, TAP1 expression. CONCLUSIONS: Static cold storage and warm reperfusion leads to a reduction in mitochondrial fitness in microvascular ECs due to mPTP opening. Further, mPTP opening promotes increased EC immunogenicity that can be prevented by NIM811 treatment.