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Circulation Jan 2024
Randomized Controlled Trial
Topics: Humans; Anticoagulants; Factor Xa Inhibitors; Hypertension, Pulmonary; Pyridines; Single-Blind Method; Thiazoles; Treatment Outcome; Warfarin
PubMed: 37956127
DOI: 10.1161/CIRCULATIONAHA.123.067528 -
Trends in Pharmacological Sciences Aug 2023Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma.... (Review)
Review
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.
Topics: Humans; Proteasome Inhibitors; Multiple Myeloma; Mitochondria; Immunotherapy; Drug Resistance, Neoplasm
PubMed: 37344251
DOI: 10.1016/j.tips.2023.05.006 -
Gut Dec 2023Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating...
OBJECTIVE
Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS).
DESIGN
EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared.
RESULTS
Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls.
CONCLUSIONS
Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease.
Topics: Humans; Animals; Mice; Multiple Sclerosis; Trypsin Inhibitors; Triticum; Amylases; Leukocytes, Mononuclear; Mice, Inbred C57BL; Inflammation; Central Nervous System; Glutens; Diet
PubMed: 37595983
DOI: 10.1136/gutjnl-2023-329562 -
Communications Biology Jul 2023Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and...
Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and found 7 commonly dysregulated genes in endocrine-resistant breast cancer cells. Here we show that downregulation of serine protease inhibitor clade A member 3 (SERPINA3) which is a direct target gene of estrogen receptor α contributes to aromatase inhibitor resistance. Ankyrin repeat domain containing 11 (ANKRD11) works as a downstream effector of SERPINA3 in mediating endocrine-resistance. It induces aromatase inhibitor insensitivity by interacting with histone deacetylase 3 (HDAC3) and upregulating its activity. Our study suggests that aromatase inhibitor therapy downregulates SERPINA3 and leads to the ensuing upregulation of ANKRD11, which in turn promotes aromatase inhibitor resistance via binding to and activating HDAC3. HDAC3 inhibition may reverse the aromatase inhibitor resistance in ER-positive breast cancer with decreased SERPINA3 and increased ANKRD11 expression.
Topics: Humans; Female; Breast Neoplasms; Aromatase Inhibitors; Drug Resistance, Neoplasm; Histone Deacetylases; Repressor Proteins; Serpins
PubMed: 37414914
DOI: 10.1038/s42003-023-05065-w -
Structure (London, England : 1993) Sep 2023Main protease (M) is a highly conserved cysteine protease that plays a vital role in the replication of coronaviruses, making it an attractive pan-coronaviral...
Main protease (M) is a highly conserved cysteine protease that plays a vital role in the replication of coronaviruses, making it an attractive pan-coronaviral therapeutic target. Ensitrelvir (S-217622), developed by Shionogi, is the first orally active non-covalent, non-peptidic SARS-CoV-2 M inhibitor, which also displays antiviral efficacy against other human coronaviruses as well as SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). Here, we report the crystal structures of the main proteases from SARS-CoV-2, SARS-CoV-2 VOC/VOIs, SARS-CoV, MERS-CoV, and HCoV-NL63 bound to the inhibitor S-217622. A detailed analysis of these structures illuminates key structural determinants essential for inhibition and elucidates the binding modes of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of coronaviral infection, structural insights obtained from this study could accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.
Topics: Humans; SARS-CoV-2; COVID-19; Protease Inhibitors; Antiviral Agents; Peptide Hydrolases
PubMed: 37421945
DOI: 10.1016/j.str.2023.06.010 -
Frontiers in Immunology 2023Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil... (Review)
Review
Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition.
Topics: Humans; Neutrophils; Serine Proteases; Protease Inhibitors; Cathepsin C; Inflammation
PubMed: 38162644
DOI: 10.3389/fimmu.2023.1239151 -
BMC Medicine Oct 2023Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Fotagliptin monotherapy with alogliptin as an active comparator in patients with uncontrolled type 2 diabetes mellitus: a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial.
BACKGROUND
Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM.
METHODS
Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded.
RESULTS
After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group.
CONCLUSIONS
In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM.
TRIAL REGISTRATION
ClinicalTrail.gov NCT05782192.
Topics: Humans; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Blood Glucose; Hypoglycemic Agents; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Treatment Outcome
PubMed: 37814306
DOI: 10.1186/s12916-023-03089-x -
Investigative Ophthalmology & Visual... Feb 2024Serine protease inhibitors A1 (SerpinA1) and A3 (SerpinA3) are important members of the serpin family, playing crucial roles in the regulation of serine proteases and... (Review)
Review
Serine protease inhibitors A1 (SerpinA1) and A3 (SerpinA3) are important members of the serpin family, playing crucial roles in the regulation of serine proteases and influencing various physiological processes. SerpinA1, also known as α-1-antitrypsin, is a versatile glycoprotein predominantly synthesized in the liver, with additional production in inflammatory and epithelial cell types. It exhibits multifaceted functions, including immune modulation, complement activation regulation, and inhibition of endothelial cell apoptosis. SerpinA3, also known as α-1-antichymotrypsin, is expressed both extracellularly and intracellularly in various tissues, particularly in the retina, kidney, liver, and pancreas. It exerts anti-inflammatory, anti-angiogenic, antioxidant, and antifibrotic activities. Both SerpinA1 and SerpinA3 have been implicated in conditions such as keratitis, diabetic retinopathy, age-related macular degeneration, glaucoma, cataracts, dry eye disease, keratoconus, uveitis, and pterygium. Their role in influencing metalloproteinases and cytokines, as well as endothelial permeability, and their protective effects on Müller cells against oxidative stress further highlight their diverse and critical roles in ocular pathologies. This review provides a comprehensive overview of the etiology and functions of SerpinA1 and SerpinA3 in ocular diseases, emphasizing their multifaceted roles and the complexity of their interactions within the ocular microenvironment.
Topics: Antioxidants; Apoptosis; Eye; Liver; Humans; Eye Diseases; Serpins
PubMed: 38324301
DOI: 10.1167/iovs.65.2.16 -
European Journal of Medicinal Chemistry Sep 2023The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (M) of... (Review)
Review
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. The main protease (M) of SARS-CoV-2 plays a central role in viral replication and transcription and represents an attractive drug target for fighting COVID-19. Many SARS-CoV-2 M inhibitors have been reported, including covalent and noncovalent inhibitors. The SARS-CoV-2 M inhibitor PF-07321332 (Nirmatrelvir) designed by Pfizer has been put on the market. This paper briefly introduces the structural characteristics of SARS-CoV-2 M and summarizes the research progress of SARS-CoV-2 M inhibitors from the aspects of drug repurposing and drug design. These information will provide a basis for the drug development of treating the infection of SARS-CoV-2 and even other coronaviruses in the future.
Topics: Humans; COVID-19; SARS-CoV-2; Antiviral Agents; Protease Inhibitors; Viral Nonstructural Proteins; Molecular Docking Simulation
PubMed: 37244162
DOI: 10.1016/j.ejmech.2023.115491 -
Communications Biology Oct 2023Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M), its moderate...
Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M), its moderate activity in M inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin's efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.
Topics: Humans; COVID-19; SARS-CoV-2; Cathepsins; Antiviral Agents; Protease Inhibitors; Cysteine Endopeptidases
PubMed: 37853179
DOI: 10.1038/s42003-023-05317-9