Protein Inhibitor Research Articles

Potential MAO‐B Inhibitors from Cissampelos capensis L.f.: ADMET, Molecular Docking, Dynamics, and DFT Insights

This study explores the therapeutic potential of three proaporphine alkaloids—cissamaline, cissamanine, and cissamdine, which were recently isolated from Cissampelos capensis L.f., against Parkinson's disease (PD). Using computational techniques, we investigated their efficacy as inhibitors of a key protein in PD. ADMET analysis demonstrated that these alkaloids conform to the Lipinski, Pfizer, Golden Triangle, and GSK rules, indicating favorable safety, oral bioavailability, and a high probability of passing the human intestinal and blood‐brain barriers. They were neither substrates nor inhibitors of any CYP enzymes tested, indicating minimal metabolic interference and an enhanced safety profile. Molecular docking studies revealed strong binding energies with MAO‐B, PD's target. MD simulations supported these findings, showing stable interactions with MAO‐B, while Density Functional Theory (DFT) calculations highlighted the electrophilic nature of cissamanine, enhancing its potential as an effective inhibitor. These results advocate further in vitro and in vivo studies to evaluate their potential as PD therapeutics.

Drug repurposing: An antidiabetic drug Ipragliflozin as Mycobacterium tuberculosis sirtuin-like protein inhibitor that synergizes with anti-tuberculosis drug isoniazid

The surge of drug-resistant Mycobacterium tuberculosis (DR-TB) impedes the World Health Organization's efforts in ending TB and calls for new therapeutic formulations. M. tuberculosis sirtuin-like protein Rv1151c is a bifunctional enzyme with both deacetylation and desuccinylation activities, which plays an important role in M. tuberculosis drug resistance and stress responses. Thus, it appears to be a promising target for the development of new TB therapeutics. In this study, we screened 31,057 ligand compounds from seven compound libraries in silico to identify inhibitors of Rv1151c. Ipragliflozin can bind to Rv1151c and interact stably. Ipragliflozin can change the acylation level of M. tuberculosis by inhibiting Rv1151c and effectively inhibit the growth of M. tuberculosis H37Rv and M. smegmatis. It can potentiate the first-front anti-TB drug isoniazid. As an antidiabetic drug, Ipragliflozin can be potentially included in the regimen to treat diabetes-tuberculosis comorbidity.

Recent Updates of PET in Lymphoma: FDG and Beyond

Lymphoma is one of the most common cancers worldwide, categorized into Hodgkin lymphoma and non-Hodgkin lymphoma. 18F-fluorodeoxyglucose positron emission tomography (FDG PET) has become an essential imaging tool for evaluating patients with lymphoma in terms of initial diagnosis, staging, prognosis, and treatment response assessment. Recent advancements in imaging technology and methodologies, along with the development of artificial intelligence, have revolutionized the evaluation of complex imaging data, enhancing the diagnostic and predictive power of PET in lymphoma. However, FDG is not cancer-specific, but it primarily reflects glucose metabolism, which has prompted the investigation of alternative PET tracers to address this limitation. Novel PET radiotracers, such as fibroblast activation protein inhibitors targeting the tumor microenvironment, have recently shown promising results in evaluating various malignancies compared to FDG PET. Furthermore, with the rapid advancements in immunotherapy and the favorable imaging properties of 89Zr, immunoPET has emerged as a promising modality, offering insights into the functional and molecular status of the immune system. ImmunoPET can also facilitate the development of new antibody therapeutics and radioimmunotherapy by providing pharmacokinetic and pharmacodynamic data. This review provides comprehensive insights into the current clinical applications of FDG PET in lymphoma, while also exploring novel PET imaging radiotracers beyond FDG, discussing their mechanisms of action and potential impact on patient management.

CTR-FAPI PET enables precision management of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.

Comparative efficacy of colchicine and intensive LDL-C lowering in patients with ASCVD receiving statins: a network meta-analysis of randomised controlled trials

Abstract Background Adding intensive low-density lipoprotein cholesterol (LDL-C) lowering treatments or colchicine to statins resulted in additional cardiovascular benefits. However, the relative efficacy and priority of these agents are unclear. Purpose We aimed to compare the effects of these supplementary agents on cardiovascular outcomes in patients with atherosclerotic cardiovascular diseases (ASCVD) receiving statins. Methods We performed a systematic review and frequentist network meta-analysis on randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death and all-cause mortality. The safety endpoints were treatment discontinuation and non-cardiovascular death. Colchicine was used as reference treatment. Random-effects model was used in case of high heterogeneity, the fixed-effects model was preferred otherwise. We ranked the comparative effects of all drugs with surface under the cumulative ranking (SUCRA) probabilities. Results 17 trials totaling 85823 participants treated with colchicine, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor and ATP citrate lyase (ACL) inhibitor were included. Compared with colchicine, NPC1L1 inhibitor was associated with increased risk of MACE (risk ratio [RR]: 1.39, 1.21-1.59), stroke (RR: 1.81, 1.09-3.00) and coronary revascularization (RR: 1.36, 1.11-1.68), and PCSK9 inhibitor was associated with increased risk of MACE (RR: 1.27, 1.10-1.46). However, NPC1L1 inhibitor (RR: 0.68, 0.48-0.96) and PCSK9 inhibitor (RR: 0.64, 0.44-0.93) were associated with reduced risk of non-cardiovascular death in comparison to colchicine. PCSK9 inhibitors had a lower risk of MACE (RR: 0.91, 95% CI: 0.85-0.98) and coronary revascularization (RR: 0.89, 95% CI: 0.81-0.97) compared with NPC1L1 inhibitor. Although no regimen prolonged survival, colchicine had the lowest rank at non-cardiovascular death and the worse performance on all-cause mortality. Conclusions In patients with ASCVD receiving statins, inflammation-inhibiting with colchicine seems to be superior to intensive LDL-C lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor in cardiovascular prevention. However, using colchicine as an alternative to intensive lipid-lowering therapy may need to be weighed against the greater cardiovascular benefits and the potential harms of higher non-cardiovascular death. Given the worse performance of colchicine on survival based on current evidence, colchicine may be more appropriate for patients who have been treated with intensive LDL-C-lowering agents but still have recurrent cardiovascular events.Forest plots of included agentsRadar plot of treatments based on SUCRA

The novel role of complement 3 in Wnt5a-mediated vascular smooth muscle cell calcification

Abstract Background Although vascular calcification (VC) is a risk factor for cardiovascular and all-cause mortality, a therapy is not yet available. VC involves the transdifferentiation of vascular smooth muscle cells (VSMC) towards an osteochondrogenic lineage that results in calcium phosphate salts deposition in the arterial wall. We have previously shown an association between plasma WNT5A levels and new onset and progression of coronary artery calcification. Purpose We aimed to study the poorly understood role of Wnt5a in VSMC calcification. Methods Study 1 included 18 patients with coronary artery disease (CAD) undergoing cardiac surgery; VSMC were isolated from their saphenous veins to perform in vitro assays and microarrays. Study 2 included 11 patients with CAD; IMA were treated ex vivo with Wnt5a recombinant protein (rWnt5a) to perform western blot (WB) analyses. Study 3 included 647 patients with CAD; RNA sequencing was performed on samples from their internal mammary arteries (IMA), IMA perivascular adipose (PVAT), and thoracic adipose tissue (ThAT). VSMC and human aortic smooth muscle cells (HASMC) from healthy donors were grown in osteogenic medium in the presence or absence of rWnt5a with or without specific protein inhibitors. Calcium deposition and expression of VC markers (i.e. RUNX2, BMP2, and MSX2) were assessed with a colorimetric assay and by RT-qPCR, respectively. Phosphorylation/activation of non-canonical Wnt pathway effectors was evaluated by WB analyses. Results rWnt5a treatment significantly increased calcium deposition in both VSMC and HASMC at a concentration that activates both JNK and CaMKII, that are effectors of the non-canonical planar cell polarity pathway and the calcium-dependent pathway, respectively. Inhibition of either JNK or CaMKII could not counteract rWnt5a-mediated increase in VSMC calcium deposition; whereas, inhibition of both non-canonical pathway effectors (JNK-i and CaMKII-i) prevented rWnt5a-mediated increase in calcium deposition by VSMC (A) and HASMC. Inhibition of JNK and CaMKII also prevented rWnt5a-induced gene expression of VC markers, such as RUNX2 (B). rWnt5a treatment in IMA increased the activation of JNK and CaMKII. Patients with higher WNT5A levels in IMA had significantly higher RUNX2 levels. By intersecting RNA sequencing and microarray data complement 3 (C3) resulted as the most upregulated gene in rWnt5a-treated VSMC among those genes whose levels positively correlated in IMA with both WNT5A and RUNX2 expression (C). Patients with higher WNT5A levels in IMA, their PVAT, and ThAT had significantly higher C3 levels (D), and patients with higher levels of C3AR1, that is the gene coding for the C3a receptor, had higher VC markers expression. C3 inhibition (C3-i) with a C3AR1 antagonist counteracted Wnt5a-induced VSMC calcium deposition (E). Conclusions Non-canonical Wnt signalling promotes VSMC calcification through C3. Wnt5a may be a therapeutic target in VC.Abstract Figure

Valvular and myocardial fibroblast activation in aortic stenosis: a prospective positron emission tomography study

Abstract Introduction In patients with aortic stenosis, fibrosis is a common pathophysiological feature of leaflet thickening as well as left ventricular decompensation as it transitions from hypertrophy to heart failure. Valvular fibrosis can be quantified by contrast-enhanced computed tomography, and myocardial fibrosis by late gadolinium enhancement on magnetic resonance imaging, but neither can detect the activity of fibrosis and extracellular matrix remodelling. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to activated fibroblasts, the key effector cell of fibrogenesis, and provides a measure of fibroblast activation and fibrosis activity. We aimed to measure fibrosis activity in the aortic valve and left ventricular myocardium of patients with aortic stenosis using 68Ga-FAPI uptake. Methods In a prospective observational cohort, patients with aortic stenosis and control subjects with normal aortic valves underwent transthoracic echocardiography, 68Ga-FAPI positron emission tomography, computed tomography, and magnetic resonance imaging. Valvular and myocardial 68Ga-FAPI uptake was quantified using the target-to-background ratio (TBRmax). Valvular non-calcific volume was quantified on computed tomography and replacement myocardial fibrosis was quantified by late gadolinium enhancement on magnetic resonance imaging. Results Fifty patients with aortic valve disease (9 with aortic sclerosis, and 7 with mild, 23 with moderate and 11 with severe aortic stenosis; 72±8 years, 70% male) and 4 control subjects (66±7 years, 50% male) participated. Increased 68Ga-FAPI uptake was observed in the aortic valves of patients with aortic sclerosis and stenosis and peaked in those with moderate disease (Figure 1). TBRmax of 68Ga-FAPI uptake correlated with the aortic valve non-calcific volume (r=0.354, p&amp;lt;0.05) on computed tomography. Thirty-one patients (62%) had myocardial 68Ga-FAPI uptake, of whom half (n=17; 34%) also had late gadolinium enhancement corresponding to the region of 68Ga-FAPI uptake (Figure 2). Myocardial 68Ga-FAPI uptake correlated with increased indexed left ventricular mass (r=0.333, p&amp;lt;0.05) and left ventricular wall thickness (r=0.385, p&amp;lt;0.05). Conclusions For the first time, we have identified both valvular and myocardial fibrosis activity in patients with aortic stenosis. Valvular fibroblast activation is increased in patients with aortic sclerosis and stenosis, peaking in patients with moderate disease and correlating with leaflet thickening. Myocardial fibroblast activation is seen in the majority of patients with aortic stenosis both in areas with and without established fibrosis, and is associated with indices of adverse left ventricular remodelling. Activated fibroblasts are thus an important potential treatment target in the valve and myocardium, with 68Ga-FAPI positron emission tomography holding major promise in better understanding the pathophysiology, progression and consequences of aortic stenosis.

Fibroblast activation in cardio-oncology

Abstract Introduction Carcinoid heart disease is a rare disease affecting the right sided heart valves (1) while anthracycline cardiotoxicity is a dreaded sequelae of a common chemotherapeutic agent that can occur early or even years after exposure (2). Activated fibroblasts, a key factor in these diseases, can be imaged with 68Gallium-fibroblast activation protein inhibitor (68Ga-FAPI). Method 12 patients with carcinoid syndrome, 12 patients with previous anthracycline exposure and 10 healthy volunteers underwent hybrid 68Ga-FAPI positron emission tomography and magnetic resonance imaging. Areas of fibroblast activation were quantified as mean and maximum target-to-background ratios (TBRmean and TBRmax). Results Carcinoid syndrome: 2 of the 12 patients had carcinoid heart disease [mean age 70, 50% female] (CHD) (Figure 1A). 68Ga-FAPI uptake was seen in the liver lesions of all patients with known carcinoid liver tumours. Of the 10 patients without cardiac involvement, 6 had significant tricuspid valve 68Ga-FAPI uptake (CHD- FAPI+) (Figure 1B) and 4 did not (CHD- FAPI-). Median tricuspid TBRmax was significantly higher in CHD + [2.38 (IQR 2.35-2.42)], than CHD- patients [CHD- FAPI+: 1.68 (IQR 1.65-1.73), CHD- FAPI-: 1.55 (IQR 1.53-1.65)], although this was higher than healthy volunteers [1.45 (IQR 1.43- 1.61; p&amp;lt;0.05). CHD- FAPI+ patients had significantly elevated urinary 5-HIAA levels compared to CHD- FAPI- patients [Median =188 mg/24hr (IQR 151-196) in CHD- FAPI+ vs 32mg/24hr ( IQR 12-73); p=0.03]. Anthracycline chemotherapy: 3 of the 12 patients had cardiotoxicity [mean age 61, 67% female]. Anthracycline patients had higher left ventricular myocardial 68Ga-FAPI uptake than healthy volunteers with cardiotoxicity patients having the highest. [TBRmean: Cardiotoxicity 1.46 (IQR 1.36- 1.53), No cardiotoxicity 1.37 (IQR 1.19- 1.49), Healthy volunteers 0.73 (IQR 0.66 - 0.81); p&amp;lt;0.01 (Figure 1E). Across the cohort a moderate negative correlation was observed between Left ventricular ejection fraction and 68Ga-FAPI activity (LV TBRmean r =-0.46 and TBRmax (r= -0.66) Discussion 68 Ga-FAPI provides us the ability to assess fibroblast activation and for the first time demonstrated the key role of these cells in both these cardio-oncology conditions. Increased fibroblast activation is observed around the tricuspid valve in patients with carcinoid syndrome both in those with and without overt clinical disease. Similarly increased myocardial fibroblast activation is observed in patients exposed to anthracyclines even many years after exposure and where there is no overt evidence of cardiotoxicity. Conclusion 68Ga-FAPI imaging holds promise in evaluating the role of activated fibroblasts in the pathology of both carcinoid heart disease and cardiotoxicity, providing information beyond the current resolution of current clinical approaches.

68Ga]Ga-FAPI04 Outperforms [18F]FDG PET/CT for Detecting Nodal Metastasis of Head and Neck Squamous Cell Carcinoma: A Single-Center Experience.

This study assesses fibroblast activated protein inhibitor (FAPI) targeted PET/CT imaging against [18F]FDG PET/CT (FDG PET) for detecting nodal involvement in head and neck squamous cell carcinoma (HNSCC), intending to improve diagnostic precision for metastatic lymph nodes and lay the groundwork for future investigations. Methods: Patients diagnosed with HNSCC were retrospectively enrolled. All patients underwent [68Ga]Ga-FAPI04 PET/CT (FAPI PET) and FDG PET within 6 d. Primary tumor, lymph nodes, and tracer uptake were visually and quantitatively compared. The metastatic lymph nodes were evaluated using patient-and lesion-based analyses, with biopsy or postoperative histopathological examination as the reference. Results: The cohort includes 24 patients (17 men, 7 women; mean age 60 ± 11.8 years) who underwent FDG and FAPI PET for preoperative diagnostic workup or restaging due to known recurrence of HNSCC. Lesions included 24 primary tumors, 54 cervical lymph nodes, and 5 metastases. Primary tumors exhibited significant uptake on both PET modalities (median maximum standardized uptake value [SUVmax]: FDG 19.4 ± 11.6, FAPI 16.9 ± 4.6), with no statistically significant difference (p > 0.5). For lymph nodes, FAPI and FDG PET showed median SUVmax of 9.18 ± 6.77 and 9.67 ± 6.5, respectively. The patient-based analysis found FDG PET sensitivity at 88.2% and FAPI PET at 94.1%, with FAPI PET specificity significantly higher (85.7% vs. 42.8% for FDG PET). Lesion-based analysis revealed FAPI PET sensitivity and specificity at 84.2% and 93.7%, respectively, contrasting FDG PET's at 81.5% and 25%, respectively. Conclusion: This study underscores the efficacy of FAPI PET in detecting primary tumors in HNSCC. Furthermore, FAPI PET shows improved specificity over FDG PET for metastatic lymph nodes advocating further investigations for integrating FAPI PET into HNSCC clinical protocols for its enhanced precision in detecting metastatic lymph nodes.

Same-Day Positron Emission Tomography/Computed Tomography with 68Ga-Radiolabeled Fibroblast Activation Protein Inhibitors and 18F-Fluorodeoxyglucose Imaging for Gastrointestinal Cancers.

Objective: We investigated the clinical practicability of same-day 68Ga-radiolabeled fibroblast activation protein inhibitors (68Ga-FAPI)-first and 18F-fluorodeoxyglucose (18F-FDG) imaging and compared it with same-day 18F-FDG-first or 2-day procedures in diagnosing gastrointestinal cancers. Materials and Methods: Sixty-five patients with confirmed gastrointestinal cancers were divided into same-day 68Ga-FAPI-first group (Group A), same-day 18F-FDG-first group (Group B), and 2-day group (Group C). Low-dose CT and low injection activity were performed on 68Ga-FAPI positron emission tomography/computed tomography (PET/CT). Interval times, radiation dose, diagnostic performance, and detectability were assessed among groups. Additionally, the uptake, tumor-to-liver ratio (TLR), diagnostic efficacy, and TNM stage were compared between the two modalities. Results: The total waiting time for Group C was significantly longer than that for Group A or B (both p < 0.001). The total dose-length product and effective dose decreased in all groups. There were comparable detectability and diagnostic performance among groups (all p > 0.05). The within-group analysis in Group B indicated that 68Ga-FAPI PET/CT had higher uptake in the primary and recurrent lesions than 18F-FDG without differences in TLR, due to higher liver background on 68Ga-FAPI PET than Group A or C (both p < 0.001).68Ga-FAPI PET/CT possessed higher accuracy than 18F-FDG and changed staging in 14 patients (14/65, 21.54%). Conclusions: The same-day 68Ga-FAPI-first and 18F-FDG imaging reduced examination waiting time without increased radiation dose, simultaneously achieving excellent diagnostic performance and improving clinical staging in diagnosing gastrointestinal cancers.

STRAP Knockdown Inhibits Migration and Growth of Non-Small Cell Lung Cancer.

Serine-threonine kinase receptor-associated protein (STRAP) regulates cell proliferation and apoptosis by binding to many target proteins and plays an important regulatory role in tumor development. We studied the effects of STRAP on non-small cell lung cancer (NSCLC) in vivo and in vitro in order to elucidate possible mechanisms underlying the regulatory effects of this protein. The levels of STRAP in NSCLC tissues and cells were determined by quantitative reverse transcription PCR, immunohistochemical staining, and Western blotting. In in vitro experiments, A549 and HCC827 cells were transfected with small interfering RNA (siRNA) to knockdown STRAP (si-STRAP) or with negative control sequence; cell migration and invasion were detected by scratch and Transwell assays, respectively. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), caspase-3, and caspase-9 were determined by Western blotting. In addition, we analyzed changes of tumor volume in a nude mouse NSCLC model. STRAP was highly expressed in NSCLC tissues and cells, but its expression was significantly suppressed in A549 and HCC827 cells transfected with si-STRAP. STRAP knockdown resulted in a significant inhibition of migration and invasion of A549 and HCC827 cells. It also significantly reduced the expression of XIAP and elevated expression of caspase-3 and caspase-9. In nude mice with tumor originated from transplanted A549 cells, inhibition of STRAP expression retarded the tumor growth. Overall, these findings indicate that STRAP is overexpressed in NSCLC, while knockdown of STRAP gene inhibits the growth of NSCLC.

Cationic Surface Charge Engineering of Recombinant Transthyretin Remarkably Increases the Inhibitory Potency Against Amyloid β-Protein Fibrillogenesis.

The deposition of amyloid β-protein (Aβ) in the brain is the main pathogenesis of Alzheimer's disease (AD). The development of potent inhibitors against Aβ aggregation is one of the effective strategies to combat AD. Endogenous transthyretin (TTR) can inhibit Aβ fibrillization via hydrophobic interactions, but its weak inhibitory potency hinders its application in AD therapy. Here, different recombinant TTRs were designed by cationic surface charge engineering. Compared with TTR, all positively charged recombinant TTRs showed enhanced capability in inhibiting Aβ aggregation, especially the recombinant protein obtained by mutating the acidic amino acid in TTR to arginine (TTR-nR) exhibited excellent inhibitory effect. Among them, TTR-7R remarkably increased the inhibitory potency against Aβ, which could effectively inhibit Aβ40 fibrillization at a very low concentration (0.5 μM). In addition, TTR-7R increased cultured cell viability from 62% to 89%, scavenged amyloid plaques in AD nematodes, and prolonged nematode lifespan by 5 d at 2 μM. Thermodynamic studies demonstrated that TTR-7R, enriching in positive charges, presented hydrophobic interactions and enhanced electrostatic interactions with Aβ40, leading to a significantly enhanced inhibitory capacity of TTR-7R. The research provided insights into the development of efficient recombinant protein inhibitors for AD treatment.

A Rare Case of Orbital Metastasis from Invasive Lobular Carcinoma: Challenges of 18F-FDG PET/CT and the Search for Consensus on Imaging.

Invasive lobular carcinoma (ILC) frequently underlies orbital metastasis. A 74-y-old woman, who was current with mammograms and had no cancer history, presented to her ophthalmologist with visual complaints and was found to have metastatic ILC. MRI was contraindicated, and an 18F-FDG PET/CT scan revealed a mildly hypermetabolic right orbital mass and low uptake in the left subareolar breast, suggestive of metastatic ILC. Small studies have found that in ILC, 16α-18F-fluoroestradiol and fibroblast activation protein inhibitors are more avid than 18F-FDG. There is currently no consensus regarding imaging for ILC. Many people have contraindications to MRI, and the higher rate of false-negative findings on mammography for ILC than for other breast cancers makes this patient population more vulnerable to inaccurate staging, incorrect assessment of tumor burden, and, consequently, insufficient treatment. We provide this interesting case to highlight the potential of 18F-fluoroestradiol PET/CT and fibroblast activation protein inhibitors over 18F-FDG in this breast cancer subtype.

Repurposing of Oxicam Derivatives to Inhibit NDM-1: Molecular Docking and Molecular Dynamic Simulation Studies

The New Delhi Metallo-β-lactamase-1 (NDM-1) causes hydrolysis of broad spectrum β-lactam antibiotics, such as carbapenems, resulting in the development of antimicrobial resistance. Still, there are not any approved NDM-1 inhibitors, globally. Therefore, repositioning approved medicines as NDM-1 inhibitors to combine with carbapenems may be a crucial strategy to combat resistant pathogens. This study repurposes. Oxicam derivatives as inhibitors of bacterial NDM-1. The two-dimensional structures were obtained from the PubChem database. Twenty derivatives of oxicam were assessed computationally to realize their NDM-1 inhibition capability. To identify potential inhibitors of the NDM-1 target protein, a molecular docking protocol was used. In addition, drug-likeness and pharmacokinetic properties were predicted for the designed molecules. Three compounds with the most negative ΔGbinding results were chosen for additional study using molecular dynamic (MD) simulations. The compounds M010, M013, and M016 possessed a significantly more negative binding free energy than the positive control and other designed molecules, had stable MD simulations (Root-mean-square deviation &lt; 0.5 Å), passed Lipinski's rule of five, and possessed favourable physicochemical and pharmacokinetic properties. The findings can inform In vitro studies of the promising compounds.

Lomitapide: navigating cardiovascular challenges with innovative therapies.

Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs) Secondary dyslipidemia: its treatments and association with atherosclerosis. Glob Health Med, Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies. The current treatment strategies for managing dyslipidemia focus on reducing low-density lipoprotein cholesterol (LDL-C) to minimize the risks of atherosclerosis and myocardial infarction (MI). Homozygous Familial Hypercholesterolemia (HoFH) is an inherited autosomal dominant disease caused by a mutation in the LDL receptor (LDLr), which can lead to extremely high levels of LDL-C The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) Mice with Obesity, The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Although statin therapy has been the primary treatment for dyslipidemia, HoFH patients do not respond well to statins, requiring alternative therapies. Microsomal triglyceride transfer protein (MTP) inhibition has emerged as a potential therapeutic target for treating HoFH. MTP is primarily responsible for transferring triglyceride and other lipids into apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver. Lomitapide, an inhibitor of MTP, has been approved for treatingof HoFH adults. Unlike statins, lomitapide does not act on the LDLr to reduce cholesterol. Instead, lomitapide lowers the levels of ApoB-containing proteins, primarily VLDL, eventually decreasing LDL-C levels. Studies have shown that lomitapide can reduce LDL-C levels by more than 50% in patients with HoFH who have failed to respond adequately to other treatments. Lowering LDL-C levels is important for preventing atherosclerosis, reducing cardiovascular risk, improving endothelial function, and promoting overall cardiovascular health, especially for patients with HoFH Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. This review paper focuses on research findings regarding the therapeutic benefits of lomitapide, highlighting its effectiveness in lowering cholesterol levels and reducing the risk of CVDs The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity.

Fibroblast activation protein inhibitor PET/CT as an emerging diagnostic modality in interstitial lung disease and other fibrotic conditions.

Interstitial lung diseases (ILD) encompass a wide range of disorders characterized by alveolar inflammation and fibrotic tissue remodeling, marked by significant morbidity and mortality. Systemic sclerosis (SSc), among other connective tissue diseases, is a frequent cause of ILD. Assessment of pulmonary fibrosis is frequently constrained by the delayed manifestations of profibrotic activation of fibroblasts, which results in late macroscopic alterations detectable by standard imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) scans. 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI [fibroblast activation protein inhibitor]) are novel radionuclides used in the selective positron emission tomography/computed tomography (PET/CT) detection of profibrotic fibroblasts, a key player in fibrotic tissue remodeling. Application of 68Ga-FAPI in different target organs undergoing fibrosis, such as lung and heart, highlights its efficacy in detecting ongoing fibrotic processes, since FAPI tracer uptake has been correlated with clinical disease progression markers in SSc-ILD. This feature could enable physicians to detect subclinical fibrotic activity and tailor an individualised therapy plan on a case by case basis. The use of 68Ga-FAPI in ILD and other fibrotic conditions may emerge as a novel tool in future clinical practice for both activity monitoring and treatment optimisation. Other tracers tested in ILD of different etiologies have shown promising results and may in future also be considered for potential application in SSc-ILD.

Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy.

Geldanamycin, an ansa-macrolide composed of a rigid benzoquinone ring and an aliphatic ansa-bridge, was isolated from Streptomyces hygroscopicus. Geldanamycin is a potent heat shock protein inhibitor with remarkable antiproliferative activity. However, it shows pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties. Four geldanamycin analogs have progressed through various phases of clinical trials, but none have yet completed clinical evaluation or received FDA approval. To enhance the efficacy of these Hsp90 inhibitors, strategies such as prodrug approaches or nanocarrier delivery systems could be employed to minimize systemic and organ toxicity. Furthermore, exploring new drug combinations may help overcome resistance, potentially improving therapeutic outcomes. This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate its toxicity and maximize its clinical efficacy. The main focus is on those derivatives that have progressed to clinical trials or that have shown important in vivo activity in preclinical models.

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

Diammonium glycyrrhizinate ameliorates alcohol-induced liver injury by reducing oxidative stress, steatosis, and inflammation

Alcohol-induced liver injury (ALI) is a serious global health issue. Diammonium glycyrrhizinate (DG), a pharmaceutical form of glycyrrhizic acid, has been reported to have anti-inflammatory and anti-oxidative stress properties. We investigated the potential hepatoprotective effects of DG against ALI and explored the mechanisms of it. In vivo, C57BL/6J mice were used to investigate the protective effect of DG on ALI induced by chronic plus binge alcohol exposure. In vitro, AML-12 cells were applied to evaluate the role of DDX5 in the hepatic protection of DG and explore the possible mechanism of STAT1 activation regulated by DDX5. The results showed that DG significantly alleviated liver injury, inflammation, and lipid deposition in hepatocytes. It also beneficially influenced oxidative stress dysregulation. RNA-seq expression in mouse liver tissue indicated that Dead-box helicase 5 (DDX5) might be a potential target of DG. Compared with the control group, the expression of DDX5 decreased significantly in the ethanol-fed group, while DDX5 was restored in the DG treatment group. In addition, the protective effects of DG against ALI were impaired by DDX5 deficiency. DDX5 inhibited the phosphorylation of signal transducer and activator of transcription 1 (STAT1) by recruiting the protein inhibitor of activated STAT1 (PIAS1) to STAT1. The protective effect of DG against ALI associated with oxidative stress, steatosis, and inflammation was probably via regulating the DDX5/STAT1 axis.

Computational identification of Vernonia cinerea-derived phytochemicals as potential inhibitors of nonstructural protein 1 (NSP1) in dengue virus serotype-2.

Dengue virus (DENV) infection, spread by Aedes aegypti mosquitoes, is a significant public health concern in tropical and subtropical regions. Among the four distinct serotypes of DENV (DENV-1 to DENV-4), DENV-2 is associated with the highest number of fatalities worldwide. However, there is no specific treatment available for dengue patients caused by DENV-2. This study aimed to identify inhibitory phytocompounds in silico in Vernonia cinerea (V. cinerea), a widely used traditional medicinal plant, for treating DENV-2 associated illnesses. The chemical structures of 17 compounds from V. cinerea were sourced from the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) database. These compounds underwent geometry optimization, were screened against nonstructural protein 1 (NSP1) of DENV-2, and further validated through molecular dynamics simulations (MDS). Baicalein, an established drug against DENV-2, was used for validation in molecular screening, MDS, and MM-GBSA analyses. Among these compounds, Beta-amyrin, Beta-amyrin acetate, Chrysoeriol, Isoorientin, and Luteolin showed promising potential as inhibitors of the NSP1 of DENV-2, supported by the results of thermodynamic properties, molecular orbitals, electrostatic potentials, spectral data and molecular screening. Besides, these compounds adhered to the Lipinski's "rule of 5", showing no hepatotoxicity/cytotoxicity, with mixed mutagenicity, immunotoxicity, and carcinogenicity. Furthermore, final validation through MDS confirmed their potential, demonstrating stable tendencies with significant inhibitory activities against NSP1 of DENV-2 over the control drug Baicalein. Among the screened compounds, Chrysoeriol emerged as the most promising inhibitor of NSP1 of DENV-2, followed by Luteolin and Isoorientin. Taken together, our results suggest that Chrysoeriol is the best inhibitor of NSP1 of DENV-2, which could be evaluated as a therapeutic agent or a lead compound to treat and manage DENV-2 infections.