Active Drug Research Articles

Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

Background:: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective:: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods:: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results:: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion:: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic profile.

A review on drug interaction

Drug interaction occur when the response of one drug is altered by the simultaneous or closely time administration of another drug. Polypharmacy involving the simultaneous use of multiple drugs, raise concern due to unpredictable and potential severe internation. While some drug interactions are intentionally utilized in therapeutics strategies, their severity can vary making prediction challenging. Prescribing multiple medications increases the risk of drug interactions, which can occur with other drugs, foods, beverages, and herbs, both inside and outside the body. Understanding in vitro interactions is crucial to prevent drug activity loss before administration. While not all theoretical drug interactions may occur in practice, they remain a significant cause of adverse events associated with drug administration. Drug-drug interactions (DDIs) represent a significant source of medication errors in developed nations, especially among the elderly who often take multiple medications simultaneously, leading to a prevalence of 20-40%. The complexity of managing therapy increases with poly-therapy, elevating the risk of clinically significant DDIs that can either trigger adverse drug reactions or diminish clinical efficacy. DDIs are typically categorized into two groups: pharmacokinetic and pharmacodynamic. In vivo interactions at pharmacokinetic level affect absorption, distribution, biotransformation or excretion of drugs. Induction or inhibition of cytochrome P450 (CYP450) enzymes forms a major basis of drug interactions. Induction of metabolism of a substrate drug leads to treatment failure.

Progress in experimental models to investigate the invivo and invitro antidiabetic activity of drugs.

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders, and it is a rapidly growing global public health issue. It is characterized by hyperglycemia, a condition involving a high blood glucose level brought on by deficiencies in insulin secretion, decreased activity of insulin, or both. Prolonged effects of diabetes include cardiovascular problems, retinopathy, neuropathy, nephropathy, and vascular alterations in both macro- and micro-blood vessels. Invivo and invitro models have always been important for investigating and characterizing disease pathogenesis, identifying targets, and reviewing novel treatment options and medications. Fully understanding these models is crucial for the researchers so this review summarizes the different experimental invivo and invitro model options used to study diabetes and its consequences. The most popular in vivo studies involves the small animal models, such as rodent models, chemically induced diabetogens like streptozotocin and alloxan, and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals. Other models include virally induced models, diet/nutrition induced diabetic animals, surgically induced models or pancreatectomy models, and non-obese models. Large animals or non-rodent models like porcine (pig), canine (dog), nonhuman primate, and Zebrafish models are also outlined. The invitro models discussed are murine and human beta-cell lines and pancreatic islets, human stem cells, and organoid cultures. The other enzymatic invitro tests to assess diabetes include assay of amylase inhibition and inhibition of α-glucosidase activity.

Use of Viscous medium to study anthelmintic drug action in Caenorhabditis elegans

Caenorhabditis elegans is an appealing tool for experimental evolution and for working with antiparasitic drugs, from understanding the molecular mechanisms of drug action and resistance to uncover new drug targets. We present a new methodology for studying the impact of antiparasitic drugs in C. elegans. Viscous medium was initially designed for C. elegans maintenance during long-term evolution experiments. Viscous medium provides a less structured environment than the standard nematode growth media agar, yet the bacteria food source remains suspended. Further, the Viscous medium offers the worm population enough support to move freely, mate, and reproduce at a rate comparable to standard agar cultures. Here, the Viscous medium was adapted for use in antiparasitic research. We observed a similar sensitivity of C. elegans to anthelmintic drugs as in standard liquid media and statistical difference to the standard agar media through a larval development assay. Using Viscous medium in C. elegans studies will considerably improve antiparasitic resistance research, and this medium could be used in studies aimed at understanding long-term multigenerational drug activity.

Recent Development of Transition Metal Complexes as Chemotherapeutic Hypoxia Activated Prodrug (HAP).

Hypoxia is a state characterized by low concentration of Oxygen. Hypoxic state is often found in the central region of solid tumors. Hypoxia is associated with abnormal neovascularization resulted in poor blood flow in tissues and increased proliferation of tumor cells, imbalance between O2 supply and O2 consumption in tumor cells, high concentration of proton and strong reducibility. And, these abnormalities enhance the survival potency of the hypoxic tumours and increase the resistance towards chemotherapy and radiotherapy. One of the approach for treating hypoxic region of tumour is to use reducing environment of hypoxic tumours for reducing a molecule (hypoxia activated prodrug, HAP) and as a result the active drug will be released in hypoxic region in a controlled manner from the prodrug and kill the hypoxic tumour. Co(III) and Pt(IV) complexes with monodentate active drug molecule in the axial position can be reduced to Co(II) and Pt(II) moieties and as a result, the axial ligands (active drug) could come out from the metal center and could show its anticancer activity. In this review we have highlighted the research articles where transition metal-based complexes are used as chemotherapeutic hypoxia activated prodrug molecules which are reported in last 5 years.

Selective Binding of Tannic Acid-Conjugated Lipid Nanovesicles to Proline-Rich Proteins Enhances Transdermal Lipophilic-Antioxidant Delivery.

Tannic acid (TA) possesses a notable ability to adhere to proline-rich proteins that make up skin cells and the extracellular matrix (ECM) in the skin tissue. Drug carriers with this specific adhesion ability exhibit improved drug delivery efficiency on the skin. Taking advantage of this, this study presents skin-adhesive TA-conjugated lipid nanovesicles (TANVs) for enhanced transdermal antioxidant delivery. We found that TANVs exhibited selective intermolecular interactions with keratinocyte proline-rich proteins (KPRPs) and collagen that makes up skin cells by hydrogen bonding and van der Waals interactions, further enabling the strong bonding to macroscopic skin itself and ECM. We used vitamin E (α-tocopherol), which is known to effectively reduce oxidative stress but has limited skin penetration, as a drug to verify improved in vitro delivery and therapeutic efficacy. The evaluation revealed that the antioxidant-loaded TANVs exerted excellent scavenging effects against reactive oxygen species induced by ultraviolet light or peroxides in the skin, thereby enabling the development of an active drug delivery system for dermal therapy.

MiR-26a is a Key Therapeutic Target with Enormous Potential in the Diagnosis and Prognosis of Human Disease.

MicroRNA-26a (miR-26a) belongs to small non-coding regulatory RNA molecules emerging as fundamental post-transcriptional regulators inhibiting gene expression that plays vital roles in various processes of human diseases such as depression, renal ischemia and reperfusion injury, liver injury and some refractory cancer. In this review, we expound on the results of studies about miR-26a with emphasis on its function in animal models or in vitro cell culture to simulate the most common human disease in the clinic. Furthermore, we also illustrate the underlying mechanisms of miR-26a in strengthening the antitumor activity of antineoplastic drugs. Importantly, dysregulation of miR-26a has been related to many chronic and malignant diseases, especially in neurological disorders in the brain such as depression and neurodegenerative diseases as well as cancers such as papillary thyroid carcinoma, hepatocellular carcinoma and so on. It follows that miR-26a has a strong possibility to be a potential therapeutic target for the treatment of neurological disorders and cancers. Although the research of miRNAs has made great progress in the last few decades, much is yet to be discovered, especially regarding their underlying mechanisms and roles in the complex diseases of humans. Consequently, miR-26a has been analyzed in chronic and malignant diseases, and we discuss the dysregulation of miR-26a and functional roles in the development and pathogenesis of these diseases, which is very helpful for understanding their mechanisms as new biomarkers for diagnosing and curing diseases in the near future.

A Review of Current Research on Traditional Medicines for the Treatment of Gastrointestinal and Biliary Disorders

Abstract: Gastrointestinal (GI) and biliary disorders are the most commonly known health issues for people in the present time as a consequence of modern lifestyle, eating habits, stress, and many other conditions. The usage of traditional substances has been phased out over time, resulting in an increase in the occurrence of numerous diseases and a decrease in immunity. Therefore, in the current scenario, traditional medicine is increasingly being used to treat and manage diseases worldwide. Traditional medical systems of India, China, and Africa are the most frequently used today. Indian medicinal system includes the Ayurveda, Siddha, and Unani systems of medicine. Ayurveda is the most antique system of medicine, which relies on the usage of plant-based formulations. Herbal medicines are used nowadays by up to half of the world's population. Phytomedicines isolated from plants contain a wide variety of bioactive components that can have both negative and positive effects. Many herbal plants, such as Acacia, Aloe, Carum, Rose, Funnel, etc., are proven to be effective as phytomedicines that are effective for the cure of gastrointestinal and biliary problems. The available pharmacological therapeutic drugs often have efficacy but are associated with many adverse effects. To minimize the adverse effects, the use of phytomedicines can be the best possible alternative. In this study, a review of some of the most frequently used traditional herbal medicine isolates with their proven pharmacological activity and novel drug delivery systems for the proper delivery of isolates is presented. Moreover, currently available herbal-marketed formulations are also highlighted.

Lipid-based Nanocarrier Drug Delivery Approach for Biomedical Application

Abstract: The development of nanosized drug-carrier systems has been investigated over the past few decades using various techniques. The two main categories of these systems are polymeric nanoparticles and lipid nanoparticles (LNPs). The toxicological risk associated with lipid nanoparticles is significantly lower than the danger associated with polymeric nanoparticles due to the materials' natural and biological origins. Lipid-based drug delivery systems like Nanostructured lipid carriers (NLCs) and Solid Lipid Nanoparticles (SLNs) are well-established nanotechnology systems for preparing all major pharmaceuticals. These delivery systems can be scaled up with easy manufacturing procedures and are biocompatible. NLCs are the second generation of lipid-based nanocarriers (SLNs), formed by combining solid and liquid biocompatible lipids to form an unstructured matrix that provides high entrapment efficiency of active constituents. LNPs can promote the distribution of active pharmaceutical ingredients to the target site. Increasing the active drug concentration to target organ LNPs enhances the therapeutic effectiveness and reduces the side effects. This paper reviews the structure of SLNs and different NLCs, various steps involved in manufacturing lipid nanoparticles, excipients used in the formulation, and applications for targeted drug delivery.

Dermal Delivery of Hypericum perforatum (L.)Loaded Nanogel: Formulation to Preclinical Psoriasis Assessment.

Nanophytosomes represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. The goal of the current study was to investigate the potential benefits of using Hypericum perforatum extract nanogel as a means of improving skin penetration and prolonging skin deposition in dermatitis similar to psoriasis. Nanophytosomes (NPs) were developed, optimised and thoroughly characterised. The optimised NPs were then placed in a Carbopol gel base matrix and tested ex-vivo (skin penetration and dermatokinetic) and in-vivo (antipsoriatic activity in an Imiquimod-induced psoriatic rat model). The optimised NPs had a spherical form and entrapment efficiency of 69.68% with a nanosized and zeta potential of 168nm and -10.37mV, respectively. XRD spectra and transmission electron microscopy tests confirmed the plant botanical encapsulation in the NPs. Following 60 days of storage at 40 ± 2°C/75 ± 5% RH, the optimised formula remained relatively stable. As compared to extract gel, nano-gel showed a much-improved ex vivo permeability profile and considerable drug deposition in the viable epidermal-dermal layers. When developed nano-gel was applied topically to a rat model of psoriasis, it demonstrated distinct in vivo anti-psoriatic efficacy in terms of drug activity and reduction of epidermal thickness in comparison to other formulations and the control. ELISA and histopathologic studies also demonstrated that nano-organogel had improved skin integrity and downregulated inflammatory markers (IL-17, IL-6, IFN-γ and MCP-1). Findings suggest that a developed plant botanicals-based nanogel has a potential for the treatment of psoriasis-like dermatitis with better skin retention and effectiveness.

Enhancing cisplatin drug sensitivity through PARP3 inhibition: The influence on PDGF and G-coupled signal pathways in cancer

Drug resistance poses a significant challenge in cancer treatment despite the clinical efficacy of cisplatin. Identifying and targeting biomarkers open new ways to improve therapeutic outcomes. In this study, comprehensive bioinformatic analyses were employed, including a comparative analysis of multiple datasets, to evaluate overall survival and mutation hotspots in 27 base excision repair (BER) genes of more than 7,500 tumors across 23 cancer types.By using various parameters influencing patient survival, revealing that the overexpression of 15 distinct BER genes, particularly PARP3, NEIL3, and TDG, consistently correlated with poorer survival across multiple factors such as race, gender, and metastasis. Single nucleotide polymorphism (SNP) analyses within protein-coding regions highlighted the potential deleterious effects of mutations on protein structure and function. The investigation of mutation hotspots in BER proteins identified PARP3 due to its high mutation frequency.Moving from bioinformatics to wet lab experiments, cytotoxic experiments demonstrated that the absence of PARP3 by CRISPR/Cas9-mediated knockdown in MDA-MB-231 breast cancer cells increased drug activity towards cisplatin, carboplatin, and doxorubicin. Pathway analyses indicated the impact of PARP3 absence on the platelet-derived growth factor (PDGF) and G-coupled signal pathways on cisplatin exposure.PDGF, a critical regulator of various cellular functions, was downregulated in the absence of PARP3, suggesting a role in cancer progression. Moreover, the influence of PARP3 knockdown on G protein-coupled receptors (GPCRs) affects their function in the presence of cisplatin.In conclusion, the study demonstrated a synthetic lethal interaction between GPCRs, PDGF signaling pathways, and PARP3 gene silencing. PARP3 emerged as a promising target.

The influence of cholesterol and calcium ions on the interaction of cryoprotectors with a biological membrane model

In this work, we studied the effects of three cryoprotectors – ethylene glycol, dimethyl sulfoxide and sucrose – on the compression isotherms of egg yolk Langmuir monolayers both in the presence and in the absence of cholesterol in the monolayer. The influence of calcium ions from the subphase affecting the effectiveness of cryoprotection on π-A isotherms is also examined. In addition, the elastic properties of the obtained monolayers are investigated by calculation and comparison the compression modulus of the monolayer. The scientific novelty of the work is in consideration of a complex biosimilar system (an egg yolk monolayer, cholesterol and their mixtures) on the surface of the aqueous solution of the nutrient mixture and obtaining information about the specific interaction of different cryoprotectors with lipid membranes. We found that when calcium ions and cryoprotectors are simultaneously added to the subphase, they block each other's influence on the lipid monolayer and reduce the effectiveness of cryoprotection. Cholesterol in the yolk in a ratio of 1:50 m m−1 changes the properties of the monolayer, which leads to increased action of cryoprotectors. Also, for the first time, the effect of a significant increase in surface pressure (by ∼20 mN m−1) was detected when cryoprotectors were added to the system under consideration. This effect can serve as an indicator of the effectiveness of membrane dehydration by cryoprotectors and can be used to find the most effective and safe cryoprotector compositions. The obtained data can provide important recommendations for the development of cryoprotective media for cell freezing. Since the study of the mechanisms of calcium interaction (the most important signaling cation) with biological membrane and membrane-like systems is important for understanding the various effects caused by medicinal and biologically active drugs at the cellular level, the study is of interest for various fields of biophysics and biomedicine.

Synthesis, structural characterization, fukui functions, DFT calculations, molecular docking and biological efficiency of some novel heterocyclic systems

The electron deficient centers in α,β-unsaturated ketone 3 are C-2 and C=O of chromone moieties as well as C=O and H-β of α,β-unsaturated ketone segment. To investigate the reactivity of various electron deficient centers and to synthesize some heterocyclic systems, compound 3 was allowed to react with some binucleophilic reagents. The antimicrobial activity of some compounds showed a notable inhibitory effect on the microorganisms that were being studied. The synthesized compounds were verified by spectral and analytical data. The structure of the prepared compounds were optimized at the DFT/B3LYP level of theory employing 6-311G(d,p). Density Functional Theory (DFT) was used to compute the chemical reactivity descriptors. Compound 9 is more stable and less reactive than other compounds. MEP mapping was applied at the same computational level to identify the favored locations for electrophilic and nucleophilic assault, providing additional insight into the regioselectivity in the desired reaction. Moreover, the most reactive sites of compound 3 were investigated by Fukui function descriptor using Mulliken charges. The 13C and 1H-NMR spectra of the prepared compound were measured experimentally in DMSO, and correlated with the theoretical calculations that performed by 6-311G(d,p) of DFT-B3LYP method. All compounds met Veber's and Lipinski's requirements according to in silico predictions made with the SwissADME online server, suggesting the possibility for usage as oral active drugs. The synthesized compounds were also subjected to molecular docking studies to investigate their binding pattern and affinity for the CDKs active site and correlated with antimicrobial data.

Evaluation of the inhibition performance of pyrrole derivatives against CYP450 isoforms

Cytochrome P450 is a heme-containing superfamily accountable for the oxidation of various pharmacologically active drugs. The aim of this study was to conduct in silico and in vitro activity assessments of recently synthesized pyrrole-based compounds against three major CYP450 isoforms – CYP1A2, CYP2D6 and CYP3A4. The in vitro study contained specific cytochrome P450 isoform inhibitors and substrates (for CYP1A2, CYP2D6, and CYP3A4) to determine the inhibition performance of the tile compounds at 1 µM concentration. The in vitro data showed that none of the implemented molecules (MI_a-e and MII_a-e) are capable of inhibiting neither of the CYP isoforms. In addition, the potential interactions of the title compounds and the evaluated CYP isoforms were displayed after molecular docking with Glide (Schrödinger). Induced-fit simulations and binding free energy (MM/GBSA) calculations were applied to elucidate the accessibility in each CYP isoform. None of the pyrrole-based compounds exerted significant inhibition towards the applied isoenzymes. Two of the best scored compounds were visualized in the active site of CYP3A4 (PDB: 2V0M). Overall, good correlation between the in vitro results and the free binding MM/GBSA recalculations was observed.

Isoniazid-Induced Cerebellitis in a Chronic Kidney Disease Patient

Abstract The bacterial disease tuberculosis (TB), when it affects organs of the body other than the lungs, is called extrapulmonary TB. The treatment regimen includes the drugs isoniazid, rifampicin, pyrazinamide, and ethambutol, of which isoniazid is known to be the most active drug. Adverse drug reactions commonly include immunological as well as drug toxicity effects, with the latter being particularly important in renally impaired patients because of high risk of drug accumulation. Cerebellitis, which is an inflammatory condition that results in cerebellar dysfunction, is a rare complication of isoniazid use. Diagnosis is made after excluding all other possibilities. In the case described here, the extrapulmonary TB patient was a known case of chronic kidney disease (G4). He presented with slurred speech and sedation; magnetic resonance imaging scan showed bilateral fluid-attenuated inversion recovery hyperintensities in the dentate nuclei, indicative of cerebellitis. Dramatic improvement was seen upon replacing Isoniazid with levofloxacin and administration of antioxidants and pyridoxine supplements, which confirmed the diagnosis of isoniazid-induced cerebellitis.

The Catechol O-MethyltransferaseInhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phaseIII clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

Suitably Incorporated Hydrophobic, Redox-Active Drug in Poly Lactic Acid-Graphene Nanoplatelet Composite Generates 3D-Printed Medicinal Patch for Electrostimulatory Therapeutics.

Polymer carbon composites have been reported for improved mechanical, thermal and electrical properties to provide reduced side effect by 3D printing personalized biomedical drug delivery devices. But control on homogeneity in loading and release of dopants like carbon allotropes and drugs, respectively, in the bulk and on the surface has always been a challenge. Herein, we are reporting a methodological cascade to achieve a model, customizable, 3D printed, homogeneously layered and electrically stimulatory, PLA-Graphene nanoplatelet (hl-PLGR) based drug delivery device, called 3D-est-MediPatch. The medicinal patch has been prepared by 3D-printing a Nic-hl-PLGR composite obtained by incorporating a redox active model drug, niclosamide (Nic) in hl-PLGR. The composite of Nic-hl-PLGR was characterized in three sequentially complex forms─composite film, hot melt extruded (HME) filament, and 3D printed (3DP) patches to understand the effect of filament extrusion and 3D-printing processes on Nic-hl-PLGR composite and overall drug incorporation efficiency and control. The incorporation of graphene was found to improve the homogeneity of the drug, and the hot melt extrusion improved the dispersion of drug and graphene fillers in the composite. The electroresponsive drug release from the Nic-hl-PLGR composite was found to be controllably accelerated compared to the drug release by diffusion, in simulated buffer condition. The released drug concentration was found to reach within the IC50 range for malignant melanoma cell (A375) and showed in vitro selectively, with reduced effects in noncancerous, fibroblast cells (NIH3T3). Further, the feasibility of application for this system was assessed in generating personalized 3D-est-MediPatch for skin, liver and spleen tissues in ex-vivo scenario. It showed excellent feasibility and efficacy of the 3D-est-MediPatch in controlled and personalized release of drugs during electrostimulation. Thus, a model platform, 3D-est-MediPatch, could be achieved by suitably incorporating a hydrophobic, redox-active drug (niclosamide) in poly lactic acid-graphene nanoplatelet composite for electrostimulatory therapeutics with reduced side effects.

Ni-modified boron nitride nanocones as nonlinear optical active drug carriers, a DFT study

Ni-modified boron nitride nanocones as nonlinear optical active drug carriers, a DFT study

Emergence of extensive drug resistance and high prevalence of multidrug resistance among clinical Proteus mirabilis isolates in Egypt

BackgroundProteus mirabilis is an opportunistic pathogen that has been held responsible for numerous nosocomial and community-acquired infections which are difficult to be controlled because of its diverse antimicrobial resistance mechanisms.MethodsAntimicrobial susceptibility patterns of P. mirabilis isolates collected from different clinical sources in Mansoura University Hospitals, Egypt was determined. Moreover, the underlying resistance mechanisms and genetic relatedness between isolates were investigated.ResultsAntimicrobial susceptibility testing indicated elevated levels of resistance to different classes of antimicrobials among the tested P. mirabilis clinical isolates (n = 66). ERIC-PCR showed great diversity among the tested isolates. Six isolates (9.1%) were XDR while all the remaining isolates were MDR. ESBLs and AmpCs were detected in 57.6% and 21.2% of the isolates, respectively, where blaTEM, blaSHV, blaCTX−M, blaCIT−M and blaAmpC were detected. Carbapenemases and MBLs were detected in 10.6 and 9.1% of the isolates, respectively, where blaOXA−48 and blaNDM−1 genes were detected. Quinolone resistant isolates (75.8%) harbored acc(6')-Ib-cr, qnrD, qnrA, and qnrS genes. Resistance to aminoglycosides, trimethoprim-sulfamethoxazole and chloramphenicol exceeded 80%. Fosfomycin was the most active drug against the tested isolates as only 22.7% were resistant. Class I or II integrons were detected in 86.4% of the isolates. Among class I integron positive isolates, four different gene cassette arrays (dfrA17- aadA5, aadB-aadA2, aadA2-lnuF, and dfrA14-arr-3-blaOXA−10-aadA15) and two gene cassettes (dfrA7 and aadA1) were detected. While class II integron positive isolates carried four different gene cassette arrays (dfrA1-sat1-aadA1, estXVr-sat2-aadA1, lnuF- dfrA1-aadA1, and dfrA1-sat2).ConclusionP. Mirabilis ability to acquire resistance determinants via integrons may be held responsible for the elevated rates of antimicrobial resistance and emergence of XDR or even PDR strains limiting the available therapeutic options for management of infections caused by those strains.

Harnessing endocytic pH gradients for cascaded formation of intracellular condensates to inhibit autophagy: A pathway to cancer therapy

Cancer cells rely on autophagy to degrade damaged organelles and survive in the harsh environment for progression and metastasis. Autophagy inhibition can improve the efficacy of anticancer therapy because many anticancer drugs can induce protective autophagy in cancer cells. However, current clinically available autophagy inhibitors are rare and have adverse effects with limited selectivity. This work develops an intracellular biomolecular condensate for autophagy inhibition to kill cancer without apparent side effects. A modularly designed amphiphilic peptide (PNP) can self-assemble to form toxic nanofibrous condensates successively from nanoparticles with the pH changes of the endocytic pathway. Mechanistic studies by CLSM and FRAP demonstrate that the PNP finally forms solid nanofibrous condensates in the lysosome after cell endocytosis. Bio-EM and cell transfection with adenovirus expressing mCherry-GFP-LC3B fusion protein (autophagy marker) experiments indicate the autophagy inhibition by PNP nanofibrous condensates. In vitro experiments show that PNP can significantly boost the activity of the clinical drug by 150-fold against drug-resistant lung cancer cells by inducing G2/M phase arrest of the cell cycle. Furthermore, PNPs demonstrate effective tumor targeting and permeability in vivo, inhibiting tumor growth and reducing the side effects of clinical chemotherapy drugs. Overall, this work provides a simple and feasible strategy for designing intracellular condensates to inhibit autophagy for cancer therapy.