Inhibitor Drugs Research Articles

Therapeutic Potential of RAS Inhibitors in the Management of Diabetes

The global prevalence of diabetes is on the rise, with its pathogenesis closely related to the renin-angiotensin system (RAS) that includes the classical antagonistic pathway and the ACE2-Ang-(1-7)-Mas axis. Despite its well-documented role in cardiovascular health, the potential mechanisms by which RAS is associated with diabetes require further study. RAS interacts with metabolic regulatory factors such as obesity and autophagy. Excessive activation of the Ang II-AT1 receptor pathway can contribute to insulin resistance and diabetic complications. This review elucidates the mechanisms by which RAS contributes to diabetes development and discusses both clinical applications and future directions for RAS inhibitory drugs in managing diabetes. And it concludes that RAS inhibitors hold significant promise for treating diabetes and its associated complications, warranting deeper exploration into their future roles within this field. The results indicate the intricate relationship between RAS and diabetes, alongside the therapeutic potential offered by RAS inhibitors.

High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia.

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified SMAC mimetics as potent enhancers of NK cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK cell transition to an activated state and suppressed the expression of IFN-γ by NK cells, thus preventing IFN-γ mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML.

Ezetimibe Loaded Nanostructured Lipid Carriers Tablets: Response Surface Methodology, In-vitro Characterization, and Pharmacokinetics Study in Rats

PurposeThe present study aims to overcome the poor oral bioavailability of ezetimibe (EZ), a selective Biopharmaceutics Classification System (BCS) Class II cholesterol absorption inhibitor drug. EZ-loaded nanostructured lipid carriers (EZ-NLCs) were dried by lyophilization and incorporated in a convenient oral solid dosage form to enhance its dissolution, and absorption and increase patient compliance. Response surface methodology (RSM) was employed to systematically optimize formulation variables, improving the efficiency of disintegration and drug release characteristics.MethodsRSM was adopted to study the effects of (A) increasing the amount of the super-disintegrant, crosscarmelose sodium, (CCS), and (B) varying the ratio between the used drying excipients Avicel and mannitol (A: M) on the disintegration time (R1), and the percentage drug released after 24 h (R2). Thirteen EZ-NLCs tablets were prepared and subjected to pre-compression and post-compression evaluation. Furthermore, a bioequivalence study was conducted by administering EZ-NLCs and ezetrol® tablets to Sprague Dawley male rats.ResultsThe optimized EZ-NLCs tablet (prepared with the ratio of Avicel: mannitol (7.5:0) using 30 mg CCS), revealed a disintegration time of 3.85 ± 0.03 min, and 98 ± 3.09% of the drug were released at the end of the 24 h. EZ-NLCs tablet displayed a maximum concentration (Cmax) of 3.57 ± 0.27 ng/mL and an area under the curve (AUC0− 24) of 22.44 ± 2.68 ng.hr/mL, while those of ezetrol® were 2.79 ± 0.15 ng/mL and 15.36 ± 0.86 ng.hr/mL, respectively.ConclusionThe assessed relative bioavailability demonstrated the superiority of EZ-NLCs tablet over ezetrol® with 1.5 fold improvement which proves that EZ-NLCs tablet could be a good candidate to enhance the oral bioavailability of EZ.Graphical

Paroxetine alleviates ulcerative colitis in mice via restoring intestinal microbiota homeostasis and metabolism.

Ulcerative colitis (UC) is an inflammatory bowel disease and psychological factors may be one of its pathogeneses. Selective serotonin reuptake inhibitor drug such as paroxetine with an effective anti-depression ability may be a new option for UC treatment. To evaluate the therapeutic effect of paroxetine on the exacerbation of UC symptoms caused by depression, a dual model of C57BL/6 mice was established using dextran sulphate sodium and chronic unpredictable mild stress (CUMS). Behavioural experiments, H&E staining and the level of 5-hydroxytryptamine (5-HT) in the brain were used to demonstrate successful replication of the CUMS model. The levels of 5-HT, TNF-α and IL-1β in the colon and the activity of MPO in the serum were determined by ELISA kits. The levels of some gut microbiota in the faeces were measured by qPCR and faecal differential metabolites were analysed by 1H NMR. The results indicate that CUMS can exacerbate UC symptoms in mice by exacerbating inflammation, and UC+CUMS can disrupt gut microbiota and fatty acid metabolism. Paroxetine can improve the mental state of mice, reduce serum MPO activity, but increase TNF-α and IL-1β levels in the colon. In addition, paroxetine also can restore the intestinal flora of mice and improve intestinal absorption and metabolic function of amino acids and short-chain fatty acids.

In silico study of RNA polymerase inhibitor drugs for Rift Valley fever virus using RdRp protein as the target

Context: Rift Valley fever (RVF) is a disease caused by the RVF virus (RVFV), concentrated mostly in Africa. The virus, usually found in animals, can infect humans through contact with infected animals or mosquito vectors. No established treatment exists, as infections are typically mild and self-resolving. However, in 1% of cases, the disease progresses to a more severe form, prompting further research on effective medication. Recently, favipiravir demonstrated the ability to alleviate RVFV symptoms by hindering replication by inhibiting the RdRp protein. This insight opens the door to drug repurposing efforts, focusing on RNA polymerase inhibitors as potential treatment options for RVF. Aims: To evaluate known RdRp inhibitors for the RVFV’s RdRp protein to halt viral replication. Methods: RNA polymerase inhibitors were selected from databases and reference papers using ADME values and toxicity levels followed by structural bioinformatics analysis of four best candidates and control. Results: Molecular docking showed the four candidates having equal or higher binding affinities than the control, favipiravir, across various binding pockets. Further molecular dynamics simulation shows a stable protein-ligand interaction based on the fluctuation plot. Hydrophobic interaction and hydrogen bonds from the 2D and 3D visualization indicate ribavirin has the strongest hydrogen bond, and molnupiravir has the most amino acids contributing to hydrophobic interactions. Conclusions: ADMETox, molecular docking, molecular dynamics simulations, and bond force analysis indicate the possibility of favipiravir, molnupiravir, galidesivir, ribavirin, and tenofovir as promising candidates as inhibitors for the RVFV’s RdRp protein to halt viral replication.

Dysregulated Signaling Pathways in Canine Mammary Tumor and Human Triple Negative Breast Cancer: Advances and Potential Therapeutic Targets.

In 2022, human breast cancer (HBC) and canine mammary tumors (CMTs) remained the most prevalent malignant tumors worldwide, with high recurrence and lethality rates, posing a significant threat to human and dog health. The development of breast cancer involves multiple signaling pathways, highlighting the need for effective inhibitory drugs that target key proteins in these pathways. This article reviews the dysregulation of the EGFR, PI3K/AKT/mTOR, Hippo, pyroptosis, and PD-1/PD-L1 signaling pathways in HBC and CMT, as well as the corresponding drugs used to inhibit tumor growth, with the aim of providing theoretical support for the development of more efficient drugs.

Virologic failure and emergent integrase strand transfer inhibitor drug resistance with long acting cabotegravir for HIV treatment: A meta-analysis.

The long-acting injectable regimen of cabotegravir plus rilpivirine (CAB/RPV) emerged as an alternative to oral standard of care integrase strand transfer inhibitor (INSTI)-based regimens for individuals with adherence challenges or preference for reduced dosing schedules. Although oral INSTI regimens have a high barrier to emergent resistance, less is known about the potency and durability of CAB/RPV. We reviewed clinical trial registries, PubMed, EMBASE, and conference abstract databases to identify published reports of CAB/RPV for HIV therapy. We abstracted data on virologic failure (VF) and treatment-emergent INSTI resistance at 48 weeks (range 24-52 weeks). We used single-proportion meta-analysis to summarize outcomes in three populations: 1) antiretroviral (ART)-naïve individuals initiating CAB/RPV following suppression on oral ART, 2) ART-experienced individuals switched to CAB/RPV with virologic suppression, and 3) ART-experienced individuals switched to CAB/RPV with detectable viremia. Cochrane's RoB2.0 and ROBINS-1 tools assessed risk of bias. PROSPERO registration CRD42024543919. Thirty-three studies (N=9224) reported VF prevalence. Nineteen studies (N=5662) reported resistance data. VF prevalence was 1% (95% confidence intervals [CI] 1-3%) in induction-maintenance studies, 1% (CI 1-2%) in switch-suppressed studies, and 5% (CI 3-10%) in switch-viraemic studies. INSTI resistance prevalence among successfully genotyped participants at failure was 71% (CI 25-95%), 61% (CI 44-75%), and 41% (CI 20-65%) respectively. Dolutegravir cross-resistance was common (64% of those with emergent resistance). Although VF rates with CAB/RPV were low, INSTI resistance emerged in approximately 40-70% of individuals experiencing VF. These rates are significantly higher than those for oral INSTI-based regimens. Both individual-level and broader resistance surveillance may be warranted in individuals and populations with expanding CAB/RPV use.

Current Updates on Nanotechnology-based Drug Delivery Platforms for Treating Alzheimer’s with Herbal Drugs

Abstract: Alzheimer's disease (AD) is an irreversible brain disorder that led to memory loss and disrupts daily life. Earlier strategies to treat AD such as acetylcholinesterase inhibitor (AChEI) drugs are not showing effectiveness due to the inability to cross the blood-brain barrier. Moreover, traditional AChEI provides limited efficacy in terms of bioavailability and solubility for treating AD treatment. Many of the current drugs such as donepezil taken to treat the disease exhibited harmful side effects. Hence, researchers are keen to find the alternative effective therapeutic agents for treating AD. This review summarizes the recent advancement in nanotechnology-based drug delivery systems of herbal drugs such as Curcumin, Ginkgo biloba, Salvia officinalis, etc for the prevention and cure of AD. Herbal drugs proved useful in treating neuronal disorders such as AD but exhibited some limitations like low bioavailability via oral drug delivery. Such limitations were overcome by tagging these drugs by nanoparticles which enables them to cross the blood-brain barrier and offer the delivery of greater concentration of herbal drugs to the brain. Inorganic nanoparticle-based drugdelivery systems such as gold nanoparticles and magnetic nanoparticles, organic nanoparticulate systems like polymeric micelles and dendrimers, and solid polymeric nanoparticles were some of the effective methods that have earlier shown potential for enhancing the delivery of herbal drugs to the brain. Long-term repeated injection of drugs loaded on nanomaterials can lead to the accumulation of nanomaterials in the body without timely and effective degradation which can cause serious issues to the brain. Hence, nanotechnology-based strategies should involve the formulation of nontoxic nanoparticles in such a way that they can significantly transport the drugs across the BBB followed by effective degradation of nanoparticles.

Integrating structure-guided and fragment-based inhibitor design to combat bedaquiline resistant Mycobacterium tuberculosis: a molecular dynamics study.

The first FDA approved, MDR-TB inhibitory drug bedaquiline (BDQ), entraps the c-ring of the proton-translocating F0 region of enzyme ATP synthase of Mycobacterium tuberculosis, thus obstructing successive ATP production. Present-day BDQ-resistance has been associated with cardiotoxicity and mutation(s) in the atpE gene encoding the c subunit of ATP synthase (ATPc) generating five distinct ATPc mutants: Ala63→Pro, Ile66→Met, Asp28→Gly, Asp28→Val and Glu61→Asp. We created three discrete libraries, first by repurposing bedaquiline via scaffold hopping approach, second one having natural plant compounds and the third being experimentally derived analogues of BDQ to identify one drug candidate that can inhibit ATPc activity more efficiently with less toxic properties. For this purpose, we adopted techniques like molecular dynamics simulation, virtual screening, PCA, DCCM, binding affinity analysis to gauge structure-function relationship of the L136-ATPc complexes. L136 was found to induce a distinguishable conformational change in the bound ATPc which captivated the c9 rotor ring. L136 displays a binding free energy of -57.294, -59.027, -57.273, -58.726, -55.889 and -58.651 kcal/mol for ATPc_WT and the five respective mutants. The pIC50 value for the L136 ligand for the same proteins was unveiled to be 6.760, 7.285, 6.898, 7.222, 6.987 and 7.687. Moreover, L136 exhibited a strong ADMET profile. Furthermore, we discovered that the change in the hydrophobic platform in ATPc mutants hinders BDQ binding, which is overcome by L136, ensuring efficient binding and providing an assessment of L136's mechanism of ATPc inhibition. L136 provides a scope for invivo test for future clinical drug trials.

A Systematic Review and Meta-Analysis of an Angiotensin Receptor-Neprilysin Inhibitor in Patients Using a Durable Left Ventricular Assist Device.

Introduction: Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) drug used to treat patients with heart failure and has shown improvement in outcomes. Different studies reported the use of an ARNI in patients using left ventricular assist devices (LVADs). However, there are limited data on the use of ARNIs in this population. We aimed to assess the efficacy of ARNIs in LVAD patients. Methods: A systematic search was performed in PubMed, Scopus, Web of Science, Embase, and Cochrane from inception to November 2024. We used all relevant words for "ARNI" and "LVAD" to search, and we included studies that assessed ARNIs in patients with LVAD. Efficacy and safety outcomes were extracted from the included studies. R software version 4.4.2 was used for a meta-analysis. Results: Seven studies totaling 249 patients were included. The ARNI was found to be effective in improvements from baseline in the New York Heart Association (NYHA), B-type natriuretic peptide (BNP) (mean = -630.07 pg/mL, 95% CI [-1113.13, -147.01]), diuretic dose (furosemide equivalents) (mean= -76.05 mg/day, 95% CI [-145.11, -6.99]), left ventricular end-diastolic diameter (LVEED) (mean = -7.3 mm, 95% CI [-11.4, -3.1]), and left ventricular ejection fraction (LVEF) (mean =5, 95% CI [3.52, 6.48]). No improvement was found in the creatinine (Cr) level. However, a slight increase in the potassium level was noticed (mean= 0.17 mEq/L, 95% CI [0.02, 0.34]). The overall mortality in patients using the ARNI was 5%, 95% CI [0.00, 20], and discontinuation was found in 25%, 95% CI [0, 100]. Conclusions: The ARNI improved several cardiac structural and hemodynamic parameters in patients on LVAD support.

Evaluation of the MRX PT DOAC assay for detection of clinically relevant factor Xa inhibitor drug levels.

Although routine monitoring is not needed for DOACs, knowing if a clinically relevant DOAC level is present can be critical, especially in cases of severe bleeding or urgent surgery. Rapid assays to exclude these levels are necessary but not widely available. The MRX PT DOAC assay measures the functional effect of DOACs using the clot-time ratio; a ratio between DOAC-sensitive prothrombin time (PT) and DOAC-insensitive PT. We conducted a multi-center retrospective study of 152 samples from 151 patients with known DOAC levels to assess whether the MRX PT DOAC assay could exclude clinically relevant drug levels of >50 ng/mL, and whether test performance differed across coagulation analyzers. To assess generalizability, the assay was run on four coagulation analyzers: Werfen ACLTOP 750, Diagnostica Stago STACompact MAX, Sysmex CS2500, and Sysmex CN-6000. The MRX PT DOAC assay had a sensitivity of 100% with a confidence interval (CI) of 70-100% and negative predictive value (NPV) of 100% (CI:57-100%) for edoxaban drug levels >50 ng/mL. For rivaroxaban, sensitivity was 100% (CI:61-100%) and NPV was 100% (CI:5-100%). For apixaban, sensitivity ranged from 59% to 83% (CI:41-93%) and NPV ranged from 0% to 50% (CI:0-69%). The specificity of the assay ranged from 61% to 86% (CI:39-93%) for apixaban, 36% to 50% (CI:3-95%) for edoxaban, and 75% to 100% (CI:30-100%) for rivaroxaban. The MRX PT DOAC assay reliably excludes clinically relevant DOAC levels edoxaban and rivaroxaban, across multiple analyzers, but not for apixaban.

Pharmaceutical aspects of JAK inhibitors: a comparative review.

Janus kinase inhibitors (JAKIs) are a new class of drugs used in the treatment of a heterogeneous group of diseases, mainly inflammatory and autoimmune diseases. Janus kinase (JAK) is a family of non-receptor tyrosine kinases in cells that transduce cytokine-mediated signals. JAK, along with signal transducer and activator of transcription (STAT) protein, mediate important cellular processes such as immune response, carcinogenesis, cell differentiation, cell division, and cell death. Therefore, inhibitors of JAK-STAT signaling pathways could be useful in treating conditions mediated by the above-mentioned processes. JAK inhibitors mainly treat inflammatory and/or autoimmune diseases such as rheumatoid arthritis, psoriasis, and atopic dermatitis. In this review, we tried to focus on the discovery, pharmacology, and pharmaceutical aspects of JAK inhibitor drugs and their relative risks and benefits, especially focusing on the adverse effects of this class of drugs.

Trends in Proton Pump Inhibitor Use in Sweden by Sex and Age: A Drug Utilisation Study.

Proton pump inhibitors (PPIs) are among the most popular drugs worldwide. Yet, there are concerns on long-term safety and poor adherence to prescription guidelines. Off-label use in children and increasing maintenance use in older adults may be particularly worrisome. To assess differences in PPI use by age, sex calendar year and PPI type, and to explore potential underlying indications (ulcerogenic drugs, and indications) in Sweden. Proton pump inhibitor drug utilisation study based on the Swedish nationwide prescribed drug (2006-2023) and patient registries (2006-2022). Proton pump inhibitors were used by 14.4% (women) and 10.5% (men) of adults; and 1.0-1.5% of children and adolescents (aged < 20 years). Proton pump inhibitor use was higher in women in all age-groups except small children (aged < 5 years). Proton pump inhibitor use has increased in all age groups, especially in young children (aged < 10 years) and the oldest groups (aged > 65 years). Proton pump inhibitor users aged > 85 years filled most prescriptions with an annual average of 9.5 (men), 11.6 (women) prescriptions. Most prescriptions were for omeprazole and esomeprazole: 63.7% and 23.5% in adults; 23.5% and 44.7% in children (2023). Prescriptions for other drugs for peptic ulcers/reflux became rare, with 99% of prescriptions in this category being PPIs by 2023. Gastro-intestinal diagnoses were predominantly recorded in men, became less prevalent and only explained part of PPI use, while ulcerogenic drugs were common (particularly in women), suggesting PPIs are regularly used for gastroprotection. Proton pump inhibitor use has doubled in children and increased 50% in adults over the study period, in both sexes, while recorded gastrointestinal indications decreased. Alternative therapies were rarely prescribed in Sweden.

The Complement System: An Important New Therapeutic Target in IgA Nephropathy

Background: IgA nephropathy is the most common primary glomerular disease worldwide, and it is an important cause of end-stage kidney disease. Until recently, there were not any treatments of proven benefit, and care of patients with IgAN primarily involved supportive measures. Within the past few years, however, multiple new drugs have shown promise in clinical trials. Summary: Among the new drugs, several complement inhibitory drugs have demonstrated efficacy at reducing proteinuria, and there is a strong rationale for expecting that these agents will be effective at slowing progression of the disease. Furthermore, anticomplement drugs target a part of the immune system that is not directly blocked by other classes of immunosuppressive agents. One of the new drugs, iptacopan, is a selective inhibitor of the alternative pathway. Preliminary results from a phase 3 study of iptacopan in IgA nephropathy demonstrated that treatment is associated with a rapid reduction in proteinuria, and the drug recently received accelerated approval from the Food and Drug Administration. Additional drugs that have been tested in IgA nephropathy include agents that block the complement cascade at the levels of C3 and C5. Complement activation in the kidneys of IgA nephropathy patients generates biomarkers that can be detected in the blood, urine, and kidney biopsies. If multiple complement inhibitory drugs receive approval for IgA nephropathy, these biomarkers may be useful for selecting the most appropriate drug for an individual patient. Complement biomarkers may also be useful for monitoring a patient’s response to treatment. Key Messages: Several complement inhibitors are currently in clinical trials for IgAN. Iptacopan recently received accelerated approval for the indication and complement inhibitory drugs will likely become an integral part of the treatment for this disease in the near future. As these drugs become available in the clinic, it will be important to develop biomarkers that can guide clinicians to the best drug for an individual patient.

Revealing Local Structure of Angiotensin Receptor-Neprilysin Inhibitor (S086) Drug Cocrystal by Linear and Nonlinear Infrared Spectroscopies.

Structurally knowing the active sites of a drug is important for understanding its therapeutic functions. S086 is a novel angiotensin receptor-neprilysin inhibitor that consists of the molecular moieties of EXP3174 (the active metabolite of the angiotensin receptor blocker losartan) and sacubitril (a neprilysin inhibitor prodrug) in a 1:1 molar ratio. There are two forms of cocrystals of S086, namely, ξ-crystal and α-crystal, which were formed both via intermolecular coordination bonding to calcium ions, with the aid of internal water. The binding state of multiple carboxyl anions (COO-) to Ca2+ of EXP3174 and sacubitril was examined in this study using infrared (IR) absorption spectroscopy, in which the asymmetric stretching (as) and symmetric stretching (ss) modes of the COO- groups were used as IR probes. Ultrafast two-dimensional (2D) IR spectroscopy was utilized for spectrally assigning the origin of multiple COO- groups by the presence or absence of interchromophore vibrational coupling. Key structural variation between the two crystal forms was found: in the unit cell of ξ-crystal, the ratio of "bridging" and "bidentate" types of COO- binding to Ca2+ for four EXP3174 molecules is 2:2, while the ratio is predicted to be 3:1 in the case of α-crystal. However, in both crystals, four sacubitril molecules are believed to similarly form a "trident" type of COO- binding to Ca2+. Our study demonstrates that linear and nonlinear IR spectroscopies can be used to characterize local crystal structures of drugs and reveal subtle difference between similar crystal structures.

Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates inflammation and autophagy in mice hindlimb ischemia–reperfusion injury

BackgroundIschemia-reperfusion injury (I/R) for skeletal muscle usually results from vascular injuries or trauma. Sitagliptin (STG) is an effective member of the dipeptidyl peptidase-4 (DPP-4) inhibitors drug family that plays roles in oxidative stress regulation, inflammation, and autophagy control. In this study, we evaluated the protective roles of STG against I/R of gastrocnemius muscle and the underlying mechanisms.Materials and methodsForty-eight mice were randomly allocated into three groups: Group I (n = 24): control group which was subdivided equally into subgroup IA; negative control, subgroup IB; sitagliptin (STG), Group II (n = 12): ischemia–reperfusion injury (I/R), and Group III (n = 12): sitagliptin pretreatment (300 mg/kg/ day; p.o.) for two weeks followed by ischemia–reperfusion injury (STG + I/R). We measured SOD activity and MDA level to assess oxidative stress. Moreover, GLP-1/p-PI3K/ p-AKT expression levels were investigated. Autophagy was estimated by assessing lncRNA H19, Beclin-1 and ATG7 expression by RT-qPCR analysis. Inflammatory markers were assessed by iNOS and NF‐κB expression using immunohistochemistry.ResultsOur results revealed that STG pretreatment significantly attenuated oxidative stress and inflammation and upregulated GLP-1, p-PI3K, and p-AKT protein levels. Also, LnRNA H19, Becline-1, and ATG7 mRNA expression were downregulated as well as decrease the expression of the inflammatory markers iNOS and NF‐κB with STG pretreatment.ConclusionOur results highlighted the useful effects of Sitagliptin during hind limb I/R that could be mediated by antioxidant, anti-inflammatory effects, and attenuation of excessive autophagy.

Clodronic Acid has Strong Inhibitory Interactions with the Urease Enzyme of Helicobacter pylori: Computer-aided Design and in vitro Confirmation.

Helicobacter pylori (HP) infection could lead to various gastrointestinal diseases. Urease is the most important virulence factor of HP. It protects the bacterium against gastric acid. Therefore, we aimed to design urease inhibitors as drugs against HP infection. The DrugBank-approved library was assigned with 3D conformations and the structure of the urease was prepared. Using a re-docking strategy, the proper settings were determined for docking by PyRx and GOLD software. Virtual screening was performed to select the best inhibitory drugs based on binding affinity, FitnessScore, and binding orientation to critical amino acids of the active site. The best inhibitory drug was then evaluated by IC50 and the diameter of the zone of inhibition for bacterial growth. The structures of prepared drugs were screened against urease structure using the determined settings. Clodronic acid was determined to be the best-identified drug, due to higher PyRx binding energy, better GOLD FitnessScore, and interaction with critical amino acids of urease. In vitro results were also in line with the computational data. IC50 values of Clodronic acid and Acetohydroxamic Acid (AHA) were 29.78 ± 1.13 and 47.29 ± 2.06 μg/ml, respectively. Diameters of the zones of inhibition were 18 and 15 mm for Clodronic acid and AHA, respectively. Clodronic acid has better HP urease inhibition potential than AHA. Given its approved status, the development of a repurposed drug based on Clodronic acid would require less time and cost. Further, in vivo studies would unveil the efficacy of Clodronic acid as a urease inhibitor.

Effects of catechins, resveratrol, silymarin components and some of their conjugates on xanthine oxidase-catalyzed xanthine and 6-mercaptopurine oxidation.

Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies. Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect. 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Erlotinib Improves the Response of Glioblastoma Cells Resistant to Photodynamic Therapy.

Background: Glioblastoma (GBM) is the most common and deadly type of brain cancer in adults. Dysregulation of receptor tyrosine kinase pathways, such as the epidermal growth factor receptor (EGFR), contributes to therapeutic resistance. Drugs that inhibit tyrosine kinase activity and monoclonal antibodies against EGFR are strategies used in clinical trials. Photodynamic therapy (PDT) is a tumor treatment that involves the administration of a photosensitizing drug, followed by its activation with visible light, which causes cell death due to oxidative stress. Although PDT helps prolong median survival in patients with GBM, complete remission has not been achieved. Populations of GBM cells have been obtained from the T98G line resistant to PDT with methyl-5-aminolevulinic acid (Me-ALA) for characterization, comparing them with the original parental population. Objective: The objective of this work was to evaluate the general response of T98G GBM cells resistant to PDT when EGFR activity is inhibited with the drug erlotinib. Methods and Results: It has been observed that the administration of the EGFR inhibitor drug in combination with PDT reduced viability (MTT) in resistant populations compared to PDT alone. Furthermore, the PpIX content (flow cytometry) was increased in the resistant population when cells were incubated with Me-ALA and erlotinib. Erlotinib prevented cell proliferation of parental and resistant spheroids. Wound closure was reduced in both parental and PDT-resistant populations. Conclusions: Our results indicate that EGFR activation would be relevant in the resistance of GBM cells to PDT.

Raddeanin A Inhibits Colorectal Cancer Growth and Ameliorates Oxaliplatin Resistance Through the WNT/β-Catenin Signaling Pathway.

Background: Chemotherapy based on oxaliplatin (OXA) is the first-line treatment for advanced colorectal cancer (CRC), and acquired resistance to OXA is the main reason for clinical treatment failure in CRC. Methods: To search for compounds that can reverse OXA resistance, we screened a small molecule inhibitor drug library and identified a drug, Raddeanin A (RA), that enhanced the anticancer effect of OXA. Using human CRC cell lines, CRC organoid models, and invivo subcutaneous tumorigenic studies, we determined that RA inhibits the proliferation of CRC cells by promoting apoptosis and inducing cell cycle arrest. Results: We constructed OXA-resistant CRC cell lines and demonstrated that RA enhances the sensitivity of these cells to OXA. Further experiments showed that the mechanism by which RA enhanced the anticancer effects of OXA in CRC was by inhibiting the activation of the WNT/β-catenin signaling pathway. Conclusions: Because RA has been shown to be biocompatible in animal models, there is a possibility that RA could be developed as a sensitizer for resistant cancer cells or as a novel lead compound to enhance the therapeutic efficacy of OXA in resistant CRCs.