A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response Study of the Safety and Efficacy of H-1337 in Subjects With Primary Open Angle Glaucoma (POAG) or Ocular Hypertension

The trial will evaluate the safety and efficacy of 3 dose regimens of H-1337 [0.6% twice daily (b.i.d.), 1.0% b.i.d. and 1.0% once in the morning (q.a.m.), and timolol maleate (0.5%, b.i.d.) in both eyes for 28 days.

Start Date28 Aug 2023

Sponsor / Collaborator

D. Western Therapeutics Institute, Inc.

NCT03452033

/ CompletedPhase 1/2

A Phase 1/2a Randomized, Double-masked, Placebo Controlled, Dose-ranging Study of the Safety and Efficacy of H-1337 in Subjects With Primary Open Angle Glaucoma (POAG) or Ocular Hypertension

The study will evaluate the safety, tolerability, and preliminary efficacy of three concentrations of H-1337 and vehicle administered twice daily in a parallel group, double-masked design for 28 days of dosing in patients with elevated intraocular pressure (IOP).

Start Date15 Mar 2018

Sponsor / Collaborator

Allysta Pharmaceuticals, Inc.Startup

100 Clinical Results associated with Protein kinase N (PKN) family

100 Translational Medicine associated with Protein kinase N (PKN) family

0 Patents (Medical) associated with Protein kinase N (PKN) family

1,174

Literatures (Medical) associated with Protein kinase N (PKN) family

01 Dec 2024·International Journal of Biological Macromolecules

Treponema Pallidum protein Tp47 triggers macrophage inflammatory senescence via PKM2-mediated metabolic reprogramming

Article

Author: Zhang, Yan ; Zhang, Hui-Lin ; Zhang, Yi ; Guo, Yin-Feng ; Fan, Shu-Hao ; Xie, Jia-Wen ; Lin, Li-Rong ; Zheng, Ying

Syphilis is a sexually transmitted disease caused by Treponema pallidum. The mechanisms enabling T. pallidum to persist despite macrophage eradication efforts in syphilis remain unclear. Pathogens can exploit senescent cells to enhance host susceptibility, and cellular senescence can be induced by pyroptosis, which known as inflammatory senescence. While recent studies have linked metabolic reprogramming to inflammatory senescence, their role in syphilis remained to be clarified. This study investigated the mechanisms of Tp47 on metabolic reprogramming and inflammatory senescence in macrophages. The results demonstrated that Tp47 triggered NLRP3 inflammasome-mediated pyroptosis by activating the phosphorylation of EIF2AK2 (a protein kinase), increasing senescence-associated pro-inflammatory cytokines secretion and leading to inflammatory senescence in macrophages. Additionally, Tp47 competitively bound to pyruvate kinase M2 (PKM2) with STUB1(a ubiquitin ligase), thereby inhibiting PKM2 ubiquitination degradation. By promoting the Y105 phosphorylation of PKM2, Tp47 modulated the intracellular function of PKM2, and facilitated PKM2-mediated metabolic reprogramming, which produced lactate that subsequently led to EIF2AK2 phosphorylation. Furthermore, inhibitors targeting EIF2AK2, lactate, glycolysis, and PKM2 effectively suppressed the inflammatory senescence induced by Tp47. In conclusion, Tp47 could mediate immune metabolic reprogramming through interaction with PKM2 to trigger macrophage inflammatory senescence. These discoveries offer a novel perspective for targeted therapies against syphilis.

01 Dec 2024·Current Medicinal Chemistry

Identifying Hub Genes for Glaucoma based on Bulk RNA Sequencing Data and Multi-machine Learning Models

Article

Author: Xie, Yangyang ; Yu, Kai

Aims:The aims of this study were to determine hub genes in glaucoma through multiple machine learning algorithms.Background:Glaucoma has afflicted many patients for many years, with excessive pressure in the eye continuously damaging the nervous system and leading to severe blindness. An effective molecular diagnostic method is currently lacking.Objective:The present study attempted to reveal the molecular mechanism and gene regulatory network of hub genes in glaucoma, followed by an attempt to reveal the drug-gene-disease network regulated by hub genes.Methods:A microarray sequencing dataset (GSE9944) was obtained through the Gene Expression Omnibus database. The differentially expressed genes in Glaucoma were identified. Based on these genes, we constructed three machine learning models for feature training, Random Forest model (RF), Least absolute shrinkage and selection operator regression model (LASSO), and Support Vector Machines model (SVM). Meanwhile, Weighted Gene Co-Expression Network Analysis (WGCNA) was performed for GSE9944 expression profiles to identify Glaucoma-related genes. The overlapping genes in the four groups were considered as hub genes of Glaucoma. Based on these genes, we also constructed a molecular diagnostic model of Glaucoma. In this study, we also performed molecular docking analysis to explore the gene-drug network targeting hub genes. In addition, we evaluated the immune cell infiltration landscape in Glaucoma samples and normal samples by applying CIBERSORT method.Results:8 hub genes were determined: ATP6V0D1, PLEC, SLC25A1, HRSP12, PKN1, RHOD, TMEM158 and GSN. The diagnostic model showed excellent diagnostic performance (area under the curve=1). GSN might positively regulate T cell CD4 naïve as well as negatively regulate T cell regulation (Tregs). In addition, we constructed gene-drug networks in an attempt to explore novel therapeutic agents for Glaucoma.Conclusion:Our results systematically determined 8 hub genes and established a molecular diagnostic model that allowed the diagnosis of Glaucoma. Our study provided a basis for future systematic studies of Glaucoma pathogenesis.

01 Dec 2024·Metabolism

Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models

Article

Author: Carollo, Sandro ; Baier-Bitterlich, Gabriele ; Zlotek, Dominik ; Baier, Gottfried ; Hotze, Madlen ; Nedden, Stephanie zur ; Cameron, Angus ; Kwiatkowski, Marcel ; Garmsiri, Carolin ; Skvortsova, Ira-Ida ; Weber, Dido ; Safari, Motahareh S. ; Safari, Motahareh S ; Ostermaier, Florian ; Savic, Dragana ; Trajanoski, Zlatko ; Zur Nedden, Stephanie ; Faserl, Klaus ; Krogsdam, Anne ; Kuenkel, Louisa ; Lang, Luisa ; Freret, Tom ; Sarg, Bettina ; Oberacher, Herbert ; Orset, Cyrille ; Haelewyn, Benoît

BACKGROUND AND AIMWe recently identified protein kinase N1 (PKN1) as a master regulator of brain development. However, its function in the adult brain has not been clearly established. In this study, we assessed the cerebral energetic phenotype of wildtype (WT) and global Pkn1 knockout (Pkn1^-/-) animals under physiological and pathophysiological conditions.METHODSCerebral energy metabolism was analyzed by ¹³C₆-glucose tracing in vivo and real time seahorse analysis of extracellular acidification rates as well as mitochondrial oxygen consumption rates (OCR) of brain slice punches in vitro. Isolated WT and Pkn1^-/- brain mitochondria were tested for differences in OCR with different substrates. Metabolite levels were determined by mass spectrometric analysis in brain slices under control and energetic stress conditions, induced by oxygen-glucose deprivation and reperfusion, an in vitro model of ischemic stroke. Differences in enzyme activities were assessed by enzymatic assays, western blotting and bulk RNA sequencing. A middle cerebral artery occlusion stroke model was used to analyze lesion volumes and functional recovery in WT and Pkn1^-/- mice.RESULTSPkn1 deficiency resulted in a remarkable upregulation of cerebral energy metabolism, in vivo and in vitro. This was due to two separate mechanisms involving an enhanced glycolytic flux and higher pyruvate-induced mitochondrial OCR. Mechanistically we show that Pkn1^-/- brain tissue exhibits an increased activity of the glycolysis rate-limiting enzyme phosphofructokinase. Additionally, glucose-1,6-bisphosphate levels, a metabolite that increases mitochondrial pyruvate uptake, were elevated upon Pkn1 deficiency. Consequently, Pkn1^-/- brain slices had more ATP and a greater accumulation of ATP degradation metabolites during energetic stress. This translated into increased phosphorylation and activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) during in vitro stroke. Accordingly, Pkn1^-/- brain slices showed a post-ischemic transcriptional upregulation of energy metabolism pathways and Pkn1 deficiency was strongly protective in in vitro and in vivo stroke models. While inhibition of mitochondrial pyruvate uptake only moderately affected the protective phenotype, inhibition of AMPK in Pkn1^-/- slices increased post-ischemic cell death in vitro.CONCLUSIONThis is the first study to comprehensively demonstrate an essential and unique role of PKN1 in cerebral energy metabolism, regulating glycolysis and mitochondrial pyruvate-induced respiration. We further uncovered a highly protective phenotype of Pkn1 deficiency in both, in vitro and in vivo stroke models, validating inhibition of PKN1 as a promising new therapeutic target for the development of novel stroke therapies.

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