Arxxant (ruboxistaurin oral) / Eli Lilly, Takeda - LARVOL DELTA

Enhanced vascular contraction induced by exposure to angiotensin II mediated by endothelin-1 biosynthesis following PKCβ activation. (PubMed, Am J Physiol Heart Circ Physiol) - "Enhanced contraction induced by Ang II was markedly diminished by knockout of the PKCβ gene or treatment with LY333531 and CGP53353 (PKCβ inhibitors)...In vivo treatment with Ang II (250 ng/kg/min) for 7 days increased phosphorylation of PKCβ S660 in rat vascular tissue and increased the in vitro contractile responses to 5-HT and in vivo systolic blood pressure, but these changes were largely absent in PKCβ-knockout experiments. These data suggest that long-term exposure to Ang II increases vascular smooth muscle contraction and blood pressure elevation, mediated by activation of PKCβ and subsequent biosynthesis of ET-1 in vascular smooth muscle cells."

Journal • Cardiovascular • Hypertension • EDN1 • PRKCB

Protein Kinase C-β Inhibition and Survival Signaling after Simulated Cardioplegic Ischemia/Reperfusion in Non-Diabetic and Diabetic Human Coronary Arterial Endothelial Cells. (PubMed, J Am Coll Surg) - "PKC-β inhibitor treatment increased pro-survival signaling and decreased pro-apoptotic signaling in nondiabetic and diabetic HCAECs subjected to simulated I/R, with mechanistic differences observed between these cohorts."

IO biomarker • Journal • Cardiovascular • Metabolic Disorders • Reperfusion Injury • BCL2 • CASP3 • PRKCB

Modified Lipoprotein-induced sFlt1 Production in Human Placental Trophoblasts is Mediated by Protein Kinase C. (PubMed, Eur J Pharmacol) - "Modified lipoproteins upregulate sFlt1 in trophoblasts via a PKC-mediated mechanism, involving at least α and β isoforms. The data suggest potential therapeutic targets to reduce the risk of preeclampsia in women with diabetes."

Journal • Diabetes • Dyslipidemia • Gynecology • Metabolic Disorders • FLT1 • PRKCB

Protein Kinase C Inhibition Increases Pro-Survival Signaling in Human Vascular Endothelial Cells Following Simulated Cardioplegic Ischemia/Reperfusion (Quick-Shot) (ACS-CLINCON 2024) - "HCAECs were cultured in normal conditions (D and C), subjected to hypoxia/reoxygenation alone (DH and CH), or subjected to hypoxia/reoxygenation and PKC-b inhibitor LY333531 (DHT and CHT)... PKC-b inhibitor treatment increased pro-survival signaling in nondiabetic HCAECs subjected to simulated I/R, with more subtle changes in diabetic HCAECs. Cardioprotective strategies that incorporate PKC-b inhibition warrant further investigation."

Cardiovascular • Metabolic Disorders • Reperfusion Injury • CASP3 • CASP9 • NOS3

L-Glutamine mitigates bile acid-induced inhibition of growth factor activity in rat hepatocyte cultures. (PubMed, Growth Factors) - "GCDC significantly increased the NADPH oxidase activity and NOX-1 protein expression that were markedly reduced by L-Gln and protein kinase c (PKC) inhibitor, LY-333531. Apocynin (APCN) and diphenyliodonium (DPI) significantly blocked the GCDC-mediated inhibition of GF-induced DNA synthesis. This study demonstrates that bile acid-induced hepatotoxicity involves dysfunction of certain growth factors via protein kinase c (PKC)- mediated NOX modulation which can be corrected, at least partly, by L-glutamine."

Journal • Preclinical • Cholestasis • Hepatology • HGF

LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells. (PubMed, J Asthma) - "Furthermore, western blot and immunofluorescence analysis were performed. The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-β2, CPI-17 and MLC, while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system."

Journal • Asthma • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • PRKCB • TNFA

Role of Protein Kinase C in Metabolic Regulation of Coronary Endothelial Small Conductance Calcium-Activated Potassium Channels. (PubMed, J Am Heart Assoc) - "NADH-induced inhibition of endothelial SK channel function is mediated via PKC. These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease."

Journal • Cardiovascular • Diabetes • Metabolic Disorders

Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis. (PubMed, Redox Biol) - "EMPA reduced NOX activity via attenuation of the NHE/Na/NCX/Ca/PKC axis, leading to less ROS generation in HCAECs exposed to 10 % stretch."

Journal • PRKCB

The rapid activation of cPKCβII by progesterone results in the negative regulation of Ca 2+ influx in human resting T cells. (PubMed, J Chin Med Assoc) - "Nongenomic membrane activation of cPKCβII by progesterone causes immunosuppression via negative regulation of Ca 2+ influx into human resting T cells. This prevents resting T cell activation and proliferation, which protects the fetus from maternal immune attack while decreasing maternal autoimmune disease flare-ups during pregnancy. Thus, cPKCβII modulators might provide a new therapeutic approach to balancing T cell tolerance and immunity."

Journal • Immunology • PRKCB

Ginsenoside Rg1 attenuates diabetic vascular endothelial dysfunction by inhibiting the calpain-1/ROS/PKC-β axis. (PubMed, Life Sci) - "These findings reveal that Rg1 can protect against VED by suppressing the calpain-1/ROS/PKC-β axis and alleviating the development of mitochondrial dysfunction and oxidative stress."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • CAPN1 • NOS3 • PRKCB

Protein kinase C-β distinctly regulates blood-brain barrier-forming capacity of Brain Microvascular endothelial cells and outgrowth endothelial cells. (PubMed, Metab Brain Dis) - "It is therefore possible that the therapeutic concentration of LY333531 (0.05 µM) may neutralise the activity of NADPH oxidase and thus trigger a negative feedback mechanism which in turn exacerbate the detrimental effects of ischaemic injury. In conclusion, targeting PKC-β signalling pathway in ischaemic settings requires close attention while using OECs as cellular therapeutic."

Journal • Cardiovascular • Diabetes • PRKCB

Ruboxistaurin in New York Heart Failure Classification III-IV Patients (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: University of Tennessee | N=30 ➔ 0 | Trial completion date: Mar 2021 ➔ Jan 2022 | Trial primary completion date: Dec 2020 ➔ Jan 2022

Enrollment change • Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Effects of typical PKC subtypes on the proliferation of mouse pulmonary artery smooth muscle cells and the expression of ERK1/2 and Akt induced by hypoxia (PubMed, Zhonghua Jie He He Hu Xi Za Zhi) - "The cells were intervened by PKC agonist (PMA), PKCα inhibitor (safingol), PKCβⅠ inhibitor (Go6976) and PKCβⅡ inhibitor (LY333531) respectively, and the changes in protein expressions of cPKCs, and the phosphorylation levels of ERK1/2 and Akt were observed by immunoblotting under the condition of normal oxygen or hypoxia...Regulation of the expression of cPKCα, cPKCβⅠ and cPKCβⅡ may help to attenuate the formation of pulmonary vascular remodeling. Target therapy based on cPKCs is expected to be a new direction for HPH therapy in the future."

Journal • Preclinical • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • AKT1 • PRKCB

Dendritic cell-mediated chronic low-grade inflammation is regulated by the RAGE-TLR4-PKCβ signaling pathway in diabetic atherosclerosis. (PubMed, Mol Med) - "Diabetes mellitus aggravates chronic inflammation, and promotes atherosclerotic plaques in conjunction with hyperlipidemia, which at least in part through inducing the immune maturation of DCs, and its possible mechanism of action is through the RAGE-TLR4-pPKCβ signaling pathway."

IO biomarker • Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Immunology • Inflammation • Metabolic Disorders • APOE • CD86 • IFNG • PRKCB • TLR4 • TNFA

[VIRTUAL] Role of PKC in Metabolic Regulation of Endothelial SK Channels (AHA 2021) - "The metabolite NADH dysregulation of endothelial SK channels and impairment of endothelium-dependent relaxation function was via the PKCβ signaling pathway."

Cardiovascular • Diabetes • Metabolic Disorders • PRKCB

[VIRTUAL] Acute Protein Kinase C Beta Inhibition Preserves Coronary Endothelial Function After Cardioplegic Hypoxia/Reoxygenation (AHA 2021) - "The vessels undergoing CP-H/R were divided into 2 groups: those treated with the selective PKCβ inhibitor Ruboxistaurin (RBX, 50 nM, CP-H/R + RBX group) 5 minutes before and during CP-H/R, and those that received no treatment... Acute inhibition of PKCβ significantly improved the recovery of coronary endothelial function after a period of CP-H/R injury in the mouse coronary microvasculature, suggesting that acute PKCβ inhibition may be a novel approach for protecting coronary endothelial function during CP-H/R."

EDN1 • PRKCB • PRKCH

Signaling Pathway of Histamine H Receptor-Mediated Histamine H Receptor Gene Upregulation Induced by Histamine in U-373 MG Cells. (PubMed, Curr Issues Mol Biol) - "Histamine-induced H1R gene upregulation was inhibited by H1R antagonist d-chlorpheniramine, but not by ranitidine, ciproxifan, or JNJ77777120, and H2R, H3R, or H4R antagonists, respectively. Ro-31-8220 and Go6976 also suppressed this upregulation, however, the PKCδ selective inhibitor rottlerin and the PKCβ selective inhibitor Ly333531 did not...These data suggest that the H1R-activated H1R gene expression signaling pathway in U-373 MG cells is different from that in HeLa cells, possibly by using different promoters. The involvement of PKCα also suggests that compounds that target PKCδ could work as peripheral type H1R-selective inhibitors without a sedative effect."

Journal • PRKCB

Mechanism by which Huoxue Tongluo Qiwei Decoction improves the erectile function of rats with diabetic erectile dysfunction. (PubMed, J Ethnopharmacol) - "Huoxue Tongluo Qiwei Decoction can inhibit the expression of protein and mRNA of the PKCβ signaling pathway related molecules in DIED rats to cure the injury of vascular endothelial, enhance antioxidant capacity, and prevent the activation of platelet, thus improving erectile function in rats with DIED."

Journal • Preclinical • Diabetes • Erectile Dysfunction • Metabolic Disorders • ICAM1 • PCR • PRKCB

Coordinated regulation of endothelial calcium signaling and shear stress-induced nitric oxide production by PKCβ and PKCη. (PubMed, Cell Signal) - "We have, for the first time, shown in a single species in vitro that shear stress- and ATP-stimulated NO production are differentially regulated by classical and novel PKCs. This study furthers our understanding of the PKC isozyme interplay that optimizes NO production. These considerations will inform the ongoing design of drugs for the treatment of PKC-sensitive cardiovascular pathologies."

Journal • Cardiovascular • NOS3 • PRKCB

Therapeutic hypothermia augments the restorative effects of PKC-β and Nox2 inhibition on an in vitro model of human blood-brain barrier. (PubMed, Metab Brain Dis) - "Cells cultured in normoglycaemic (5.5 mM) or hyperglycaemic (25 mM, 6 to 120 h) conditions were treated with therapeutic hypothermia (35 °C) in the absence or presence of a PKC-β inhibitor (LY333531, 0.05 μM) or a Nox2 inhibitor (gp91ds-tat, 50 μM)...Similarly, the combinatory approaches were more effective in suppressing actin stress fibre formation and maintaining normal cytoskeletal structure. Therapeutic hypothermia augments the cerebral barrier-restorative capacity of agents specifically targeting PKC-β or Nox2 pathways."

Journal • Preclinical • Cardiovascular • Diabetes • PRKCB

PKC-β/Alox5 axis activation promotes Bcr-Abl-independent TKI-resistance in chronic myeloid leukemia. (PubMed, J Cell Physiol) - "Blockage of its expression in CD34+ cells and CML cell lines increased sensitivity to imatinib. In vivo experiment, PKC-β elective inhibitor LY333531 prolonged survival time in CML-PDX mice model. In conclusion, targeted on PKC-β overexpression might be a novel therapy mechanism to overcome TKI-resistance in CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • PTEN

The time to develop treatments for diabetic neuropathy. (PubMed, Expert Opin Investig Drugs) - "We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to..."

Journal • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain • AKR1B1 • NGF

The α1-adrenergic receptors in the amygdala regulate the induction of learned despair through protein kinase C-beta signaling. (PubMed, Behav Pharmacol) - "Intra-amygdala injection of WB4101 (1.7 nmol/0.1 µl), an α1 adrenoreceptor antagonist, but not propranolol (250 pmol/0.1 µl), a β-adrenoreceptor antagonist, blocked the induction of learned despair during TST. Intra-amygdala injection of ruboxistaurin (10 pmol/0.1 µl), a PKCβ inhibitor, blocked the induction of learned despair during TST, whereas neither TAT-[Latin Small Letter Open E]V1-2 (500 ng/0.1 μl), a cell-permeant PKC[Latin Small Letter Open E] inhibitory peptide, nor HBDDE (50 pmol/0.1 µl), an inhibitor of PKCα and -γ, affected the duration of immobility during TST. These data suggest that the α1-adrenoreceptor in amygdala regulates the induction of learned despair via PKCβ."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • PRKCH

Machine Learning for Discovery of GSK3β Inhibitors. (PubMed, ACS Omega) - "Subsequent testing of selected compounds revealed a selective small-molecule inhibitor, ruboxistaurin, with activity against GSK3β (avg IC = 97.3 nM) and GSK3α (IC = 695.9 nM)...We are now applying this machine learning approach to additional AD targets to identify approved drugs or clinical trial candidates that can be repurposed as AD therapeutics. This represents a viable approach to accelerate drug discovery and do so at a fraction of the cost of traditional high throughput screening."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • GSK3B

Intermittent Hypoxia Augments Pulmonary Vasoconstrictor Reactivity through PKCβ/Mitochondrial Oxidant Signaling. (PubMed, Am J Respir Cell Mol Biol) - "Chronic oral administration of the antioxidant Tempol or the PKCβ inhibitor LY-333531 abolished IH-induced increases in right ventricular systolic pressure and right ventricular hypertrophy...We conclude that a PKCβ/mitoROS signaling axis contributes to enhanced vasoconstriction and pHTN following IH. Furthermore, PKCβ mediates pulmonary vasoconstriction through interaction with PICK1, activation of mitoK, and subsequent mitoROS generation."

Journal • Hypertension • Obstructive Sleep Apnea • Pulmonary Arterial Hypertension • Sleep Apnea