GnIH secreted by green light exposure, regulates bone mass through the activation of Gpr147.

Reproductive hormones associated with the hypothalamic-pituitary-gonadal (HPG) axis are closely linked to bone homeostasis. In this study, we demonstrate that Gonadotropin inhibitory hormone (GnIH, one of the key reproductive hormones upstream of the HPG axis) plays an indispensable role in regulating bone homeostasis and maintaining bone mass. We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density (BMD) in mice primarily by enhancement of osteoclast activation in vivo and in vitro.

Design, synthesis and biological evaluation of bisnoralcohol derivatives as novel IRF4 inhibitors for the treatment of multiple myeloma.

Interferon regulatory factor 4 (IRF4) is specifically overexpressed in multiple myeloma (MM) and mediates MM progression and survival, making it an emerging target for MM treatment. However, no chemical entity with a defined structure capable of directly binding to and inhibiting IRF4 has been reported. We screened our small library of steroid analogs and identified bisnoralcohol (BA) derivative 18 as a novel hit compound capable of inhibiting IRF4, with an IC of 13.

Subtle Structural Modifications Spanning from EP4 Antagonism to EP2/EP4 Dual Antagonism: A Novel Class of Thienocyclic-Based Derivatives.

The development of dual prostaglandin E receptors 2/4 (EP2/EP4) antagonists represents an attractive strategy for cancer immunotherapy. Herein, a series of 4,7-dihydro-5-thieno[2,3-]pyran derivatives with potent EP2/EP4 dual antagonism were discovered by fine-tuned structural modifications. The biphenyl side chain was found to be the key pharmacophore for the transition from EP4 antagonism to EP2/EP4 dual antagonism.

Design, synthesis, and biological evaluations of 5-aryl-pyrazole-3-carboxamide derivatives as selective CB2 receptor agonists for the treatment of colitis.

Synthetic CB2 receptor agonists exhibit great potential in the treatment of neurodegenerative diseases, chronic and neuropathic pain, cancer, and inflammation-associated pathologies while avoiding adverse psychoactive effects caused by interactions with CB1 receptors. Herein, a class of 5-aryl-pyrazole-3-carboxamide derivatives was thus designed, synthesized, and biologically evaluated. Among the compounds tested, compound 33, one of the most potent leads, showed a remarkably high potency and selectivity at the CB2 receptor (EC = 16.

IRE1α inhibitor reduces cisplatin resistance in ovarian cancer by modulating IRE1α/XBP1 pathway.

Ovarian cancer, a leading cause of gynecological cancer deaths globally, poses significant treatment challenges. Cisplatin (CDDP) is the first treatment choice for ovarian cancer and it is initially effective. However, 80% of ovarian cancer patients eventually relapse and develop resistance, resulting in chemotherapy failure.

Ischemia/Reperfusion Upregulates Genes Related to PANoptosis in Human Lung Transplants.

Background: Activation of multiple programmed cell death (PCD) pathways has been reported in cellular and animal studies of ischemia/reperfusion injury in lung transplantation. However, the status of these pathways in human lung transplants remains unknown. This study investigates the involvement of PCD pathways and their relationship with inflammation and signaling pathways in human lung transplants.

Improving prognostic accuracy in lung transplantation using unique features of isolated human lung radiographs.

Ex vivo lung perfusion (EVLP) enables advanced assessment of human lungs for transplant suitability. We developed a convolutional neural network (CNN)-based approach to analyze the largest cohort of isolated lung radiographs to date. CNNs were trained to process 1300 longitudinal radiographs from n = 650 clinical EVLP cases.

Protective effects of 10 °C preservation on donor lungs with lipopolysaccharide-induced acute lung injury.

Objectives: Hypothermic lung preservation at 10 °C has been recently shown to enhance quality of healthy donor lungs during ischemia. This study aims to show generalizability of the 10 °C lung preservation using an endotoxin-induced lung injury with specific focus on the benefits of post-transplant lung function and mitochondrial preservation.

Methods: Lipopolysaccharide (3 mg/kg) was injected intratracheally in rats to induce lung injury.

Ischemia-reperfusion responses in human lung transplants at the single-cell resolution.

Ischemia-reperfusion is an unavoidable step of organ transplantation. Development of therapeutics for lung injury during transplantation has proved challenging; understanding lung injury from human data at the single-cell resolution is required to accelerate the development of therapeutics. Donor lung biopsies from 6 human lung transplant cases were collected at the end of cold preservation and 2-hour reperfusion and underwent single-cell RNA sequencing.

Metabolomic studies reveal an organ-protective hibernation state in donor lungs preserved at 10 °C.

Objective: Previous reports showed enhanced graft function in both healthy and injured porcine lungs after preservation at 10 °C. The objective of the study is to elucidate the mechanism of lung protection by 10 °C and identify potential therapeutic targets to improve organ preservation.

Methods: Metabolomics data were analyzed from healthy and injured porcine lungs that underwent extended hypothermic preservation on ice and at 10 °C.

Engineering IscB to develop highly efficient miniature editing tools in mammalian cells and embryos.

The IscB proteins, as the ancestors of Cas9 endonuclease, hold great promise due to their small size and potential for diverse genome editing. However, their activity in mammalian cells is unsatisfactory. By introducing three residual substitutions in IscB, we observed an average 7.

L-Alanyl-L-Glutamine Alleviated Ischemia-Reperfusion Injury and Primary Graft Dysfunction in Rat Lung Transplants.

Background: Concern of ischemia-reperfusion injury reduces utilization of donor lungs. We hypothesized adding L-alanyl-L-glutamine (L-AG) to preservation solution may protect donor lungs from ischemia-reperfusion injury through its multiple cytoprotective effects.

Methods: A lung transplantation cell culture model was used on human lung epithelial cells and pulmonary microvascular endothelial cells, and the effects of adding different concentrations of L-AG on basic cellular function were tested.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.

Therapeutic Use of Carbon Monoxide in Ex-Vivo Lung Perfusion in Donor With Prolonged Cold Ischemia.

Introduction: Carbon monoxide (CO) has been shown to exert protective effects in multiple organs following ischemic injury, including the lung. The purpose of this study was to examine the effects of CO administration during ex vivo lung perfusion (EVLP) on lung grafts exposed to prolonged cold ischemia.

Methods: Ten porcine lungs were subjected to 18 h of cold ischemia followed by 6 h of EVLP.

A Rapid Human Lung Tissue Dissociation Protocol Maximizing Cell Yield and Minimizing Cellular Stress.

The human lung is a complex organ that comprises diverse populations of epithelial, mesenchymal, vascular, and immune cells, which gains even greater complexity during disease states. To effectively study the lung at a single-cell level, a dissociation protocol that achieves the highest yield of viable cells of interest with minimal dissociation-associated protein or transcription changes is key. Here, we detail a rapid collagenase-based dissociation protocol (Col-Short) that provides a high-yield single-cell suspension that is suitable for a variety of downstream applications.

IRE1α inhibitor enhances paclitaxel sensitivity of triple-negative breast cancer cells.

Purpose: Breast cancer is the most commonly diagnosed cancer in women, and triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of all breast cancers. TNBC is highly invasive and malignant. Due to the lack of relevant receptor markers, the prognosis of TNBC is poor and the five-year survival rate is low.

PPIA dictates NRF2 stability to promote lung cancer progression.

Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability.