Development Of New Drugs Research Articles

1,3,4-Oxadiazole: An Emerging Scaffold to Inhibit the Thymidine Phosphorylase as an Anticancer Agent.

Thymidine phosphorylase (TP), also referred to as "platelet-derived endothelial cell growth factor" is crucial to the pyrimidine salvage pathway. TP reversibly transforms thymidine into thymine and 2-deoxy-D-ribose-1-phosphate (dRib-1-P), which further degraded to 2-Deoxy-D-ribose (2DDR), which has both angiogenic and chemotactic activity. In several types of human cancer such as breast and colorectal malignancies, TP is abundantly expressed in response to biological disturbances like hypoxia, acidosis, chemotherapy, and radiation therapy. TP overexpression is highly associated with angiogenic factors such as vascular endothelial growth factor (VEGF), interleukins (ILs), matrix metalloproteases (MMPs), etc., which accelerate tumorigenesis, invasion, metastasis, immune response evasion, and resistant to apoptosis. Hence, TP is recognized as a key target for the development of new anticancer drugs. Heterocycles are the primary structural element of most chemotherapeutics. Even 75% of nitrogen-containing heterocyclic compounds are contributing to the pharmaceutical world. To create the bioactive molecule, medicinal chemists are concentrating on nitrogen-containing heterocyclic compounds such as pyrrole, pyrrolidine, pyridine, imidazole, pyrimidines, pyrazole, indole, quinoline, oxadiazole, benzimidazole, etc. The Oxadiazole motif stands out among all of them due to its enormous significance in medicinal chemistry. The main thrust area of this review is to explore the synthesis, SAR, and the significant role of 1,3,4-oxadiazole derivatives as a TP inhibitor for their chemotherapeutic effects.

Isoliquiritigenin alleviates SLC7A11-mediated efferocytosis inhibition to promote wounds healing in diabetes

The healing process of chronic wounds often progresses slowly and is fraught with challenges, imposing increasing economic burdens and physical suffering on patients. Managing persistent wound inflammation and stimulating angiogenesis are crucial elements in promoting wound healing. Plants have been playing a key role in traditional medicine, and their abundant bioactive components continually inspire the development and innovation of new drugs. Isoliquiritigenin (ISL), a flavonoid compound derived from licorice roots known as chalcone, has demonstrated multifaceted pharmacological potential. However, its effects on diabetic wounds and the detailed mechanisms remain to be investigated. Through in-depth exploration using network pharmacology, we successfully predicted potential therapeutic targets of ISL for ischemic diseases. The revealed mechanisms primarily focused on the critical pathway of efferocytosis. Subsequent in vivo experiments demonstrated that ISL significantly enhanced the efferocytosis of dendritic cells (DC), improving the functional behaviors of endothelial cells. Further research indicated that ISL promoted DC efferocytosis by regulating SLC7A11-mediated glycolysis. Notably, the overexpression of SLC7A11 diminished the positive effects of ISL, suggesting a potential antagonistic role of SLC7A11 in the regulatory process. In the wounds of diabetic mice, we observed that ISL accelerated DC efferocytosis and angiogenesis, resulting in faster wound closure and better tissue repair. In summary, this study not only demonstrates the broad potential of ISL in managing diabetic wounds but also delves deeply into its mechanisms, laying a solid theoretical foundation for future clinical applications.

GJA4 gene inhibition may represent a potential target for novel antithrombotic therapies

Abstract The GJA4 gene encodes a protein called connexin 37, a component of gap junctions in vascular endothelial cells, crucial in regulating endothelial function and influencing inflammation, platelet adhesion and thrombus formation. This gene deletion in mice diminished thrombus formation in vitro in human blood. In these circumstances, connexin inhibition with pharmacological agents may represent potential avenues for developing novel antithrombotic agents. Aim To investigate whether the GJA4 rs618675 T>C variant is a risk factor for progressing atherosclerosis and cardiovascular (CV) events in an asymptomatic free of apparent CAD from a Portuguese population. Methods A prospective study was performed with 1421 individuals without apparent CV disease (73.6% male, aged 52.2±8.3 years) followed during an extended period of 7.2±5.1 years). GJA4 rs618675 T>C variant was genotyped by TaqMan real-time PCR technique (Applied Biosystems). Conventional, anthropometric, biochemical and clinical risk factors were studied. Bivariate analysis and multivariate Cox regression adjusted for age, gender, traditional risk factors, biochemical markers, and the genotypes under study was performed to determine which variables were, significantly and independently, associated with CV events. Kaplan-Meier's estimate assessed the prognosis. Results Bivariate analysis showed that 50.6% of wild genotype (TT) carriers had CV events vs. 66.2% without events. Of the risk genotype (CC) carriers, 10.1% had CV events, and 3.4% did not. After the Kaplan-Meier analysis, the TT carriers had 90% CV event-free survival time and the CC risk carriers had only 64% of event-free survival. Finally, after adjustment, CC genotype remained in the equation with an HR of 3.1 (p=0.003) and CT heterozygous with HR of 1.6 (p=0.043), together with Hypertension (HR 3.0; p<0.0001), Smoking habits (HR 2.3; p=0.001) and Diabetes (HR 1.9; p=0.015). Conclusion: The CC risk genotype of the GJA4 rs618675 represented an independent risk factor for progressing atherosclerosis and CV events in a Portuguese Population. Thrombus formation often begins with the adhesion of platelets to the endothelium, and connexin 37 may influence this process. The inhibition of connexin 37 emerges as a promising candidate for future cardiovascular prevention as well as for the development of new antithrombotic drugs.

Prostate Cancer, Pathophysiology and Recent Developments in Management: A Narrative Review.

Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis. Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

Synthesis, Characterizationand Antibacterial Activity Studyof Para-substituted Derivatives of N -benzyl-3-methylbuten-2-enamides.

In order to deeply explorethe effect of para-substituentson the antibacterial activity ofN-benzyl-3-methylbuten-2-enamidederivatives,we elaborately synthesizedthreesuchpara-substituted derivatives(compounda: N-(4-hydroxybenzyl)-3-methylbut 2-enamide;compoundb:N-(4-isobutoxybenzyl)-3-methylbut-2-enamide;compoundc:N-(4-isopropoxybenzyl)-3-methylbut-2-enamide),of which thestructures were determined by ways of single crystal X-ray diffraction data analysis mainly. The antibacterial performance experiments showed thatcompounds a, band cwere evaluated for their antibacterial (Escherichia coli, Staphylococcus aureus,andEnterobacter aerogenes)activities.Among them, compounds a, band chavean effective antibacterial reagents forE.coliexhibiting MIC values of 0.01,0.01 and0.01g/mL, respectively, but inactive for E. aerogenes.In addition, compounds band chave better activity than compounda against S. aureuswithMIC values of 0.01 and0.02g/mL.These results provide an important basis for further study of the antibacterial properties and structure-activity relationship of these compounds, and are expected to provide valuable reference for the development of new antibacterial drugs.

Modern Russian drugs for the treatment of neurodegenerative diseases

Neurodegenerative diseases are characterized by progressive death of nerve cells of certain types with concomitant atrophy of the corresponding parts of the spinal cord or brain, which is symptomatically manifested by severe neurological and cognitive impairment. These diseases can manifest at any age and be caused by both genetic predisposition and inflammatory and autoimmune processes. Diseases of this group are a common cause of disability and mortality. Thus, the development of new effective domestic drugs for their treatment is an important task for the healthcare system of the Russian Federation. In this review is devoted to the analysis of Russian original and bioanalog organic and genetically engineered drugs for the treatment of neurodegenerative diseases that have been registered in recent years or are currently undergoing clinical trials in Russia.

Impairing protein-protein interactions in an essential tRNA modification complex: An innovative antimicrobial strategy against Pseudomonas aeruginosa.

Protein-protein interactions (PPIs) have been recognized as a promising target for the development of new drugs, as proved by the growing number of PPI modulators reaching clinical trials. In this context, peptides represent a valid alternative to small molecules, owing to their unique ability to mimic the target protein structure and interact with wider surface areas. Among the possible fields of interest, bacterial PPIs represent an attractive target to face the urgent necessity to fight antibiotic resistance. Growing attention has been paid to the YgjD/YeaZ/YjeE complex responsible for the essential t6A37 tRNA modification in bacteria. We previously identified an α-helix on the surface of Pseudomonas aeruginosa YeaZ, crucial for the YeaZ-YeaZ homodimer formation and the conserved YeaZ-YgjD interactions. Herein, we present our studies for impairing the PPIs involved in the formation of the YeaZ dimers through synthetic peptide derivatives of this helical moiety, both in vitro with purified components and on P. aeruginosa cells. Our results proved the possibility of targeting those PPIs which are usually essential for protein functioning and thus are refractory to mutational changes and antibiotic resistance development.

Optimising Paediatric HIV Treatment: Recent Developments and Future Directions.

Treatment options for children living with HIV have historically been less effective, less practical and more difficult to implement compared with those for adults, as the research and development of new drugs for children has lagged behind. Significant progress has been achieved in response to the paediatric HIV epidemic over the last decade. Several optimised paediatric antiretroviral formulations are currently available or in development, including fixed-dose combination tablets containing a complete World Health Organization-recommended regimen. Despite these advancements, virological suppression rates in children are generally lower than in adults. Even when oral fixed-dose combinations with the optimal target profiles are developed, for some children virological suppression is not achievable for reasons such as adherence challenges, intolerance, toxicity and genotypic resistance. New safe, effective, well-tolerated antiretroviral agents from existing and novel classes, as well as innovative administration strategies are essential. To achieve the UNAIDS target of virological suppression in 95% of children receiving antiretroviral therapy, concerted efforts are required. This includes identifying priority drugs in line with latest developments, focusing drug development studies on these priorities, ensuring a timely technical knowledge transfer between originator and generic companies, accelerating regulatory approvals and facilitating procurement and implementation in countries. Success in these efforts depends on collaboration among all stakeholders, including communities, researchers, pharmaceutical companies, guideline and policymakers, governments, funders, regulators and healthcare providers. This review outlines which paediatric antiretroviral therapies are currently available, those which are under development and the future directions of paediatric HIV treatment.

Biofilm Demolition by [AuIII(N^N)Cl(NHC)][PF6]2 Complexes Fastened with Bipyridine and Phenanthroline Ligands; Potent Antibacterial Agents Targeting Membrane Lipid.

The development of new antibacterial drugs is essential for staying ahead of evolving antibiotic resistant bacterial (ARB) threats, ensuring effective treatment options for bacterial infections, and protecting public health. Herein, we successfully designed and synthesized two novel gold(III)- NHC complexes, [Au(1)(bpy)Cl][PF6]2 (2) and [Au(1)(phen)Cl][PF6]2 (3) based on the proligand pyridyl[1,2-a]{2-pyridylimidazol}-3-ylidene hexafluorophosphate (1•HPF6) [bpy= 2,2'-bipyridine; phen= 1,10-phenanthroline]. The synthesized complexes were characterized spectroscopically; their geometries and structural arrangements were confirmed by single crystal XRD analysis. Complexes 2 and 3 showed photoluminescence properties at room temperature and the time-resolved fluorescence decay confirmed the fluorescence lifetimes of 0.54 and 0.62 ns respectively; which were used to demonstrate their direct interaction with bacterial cells. Among the two complexes, complex 3 was found to be more potent against the bacterial strains (Staphylococcus aureus, Gram-positive and Pseudomonas aeruginosa, Gram-negative bacteria) with the MIC values of 8 µg.mL-1 and 16 µg.mL-1 respectively. Studies revealed the binding of the complexes with the fundamental phospholipids present in the cell membrane of bacteria, which was found to be the leading cause of bacterial cell death. Cytotoxicity was evaluated using an MTT assay on 293T cell lines; emphasizing the potential therapeutic uses of the Au(III)-NHC complexes to control bacterial infections.

Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.

Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.

Acquired Bortezomib Resistance in Multiple Myeloma:From Mechanisms to Strategy.

Multiple myeloma (MM) is a heterogeneous plasma cell tumor with a survival period of several months to over ten years. Despite the development of various new drugs, MM is still incurable and recurs repeatedly. Bortezomib, a landmark event in the history of MM treatment, has dramatically improved the prognosis of patients with MM. Although proteasome inhibitors (PIs) represented by bortezomib, have greatly prolonged MM survival, unfortunately, almost all MM will develop bortezomib resistance, leading to relapse with a shorter survival. It has been reported that both the tumor microenvironment and myeloma cells drive bortezomib resistance. Multiple treatment methods have been attempted to overcome bortezomib resistance, but unfortunately, there has been no breakthrough. It is believed that the key resistance mechanism has not yet been discovered. A deeper understanding of the mechanism of bortezomib resistance and strategies to overcome it can help identify key resistance mechanisms and further improve the prognosis of MM.

The progress of Mycobacterium tuberculosis drug targets

Tuberculosis (TB) has been troubling humans for hundreds of years, is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, Mtb can infect almost all organs of the body and is one of the deadly infectious diseases in the world. At present, the first-line treatment regimen has a long treatment cycle and is prone to multiple drug resistance. Anti-tuberculosis drugs and latent tuberculosis infection (LTBI) resistance are increasing year by year, and new targets and new bioactive compounds are urgently needed to treat this disease. This review focuses on the latest reported anti-TB drug targets and related compounds in recent years, reviews the current TB drug regimen and major defects, outlines the key drug targets developed to date in Mtb, and the current situation of newly discovered anti-TB resistant forms of drugs. To provide a reference for the research and development of new anti-TB drugs and bring new treatment strategies for TB patients.

Antimicrobial, anticancer and photocatalytic dye degradation activities of silver nanoparticles phytosynthesized from Secamone emetica aqueous leaf extract

Secamone emetica (Family: Apocynaceae) is traditionally used for several ailments among indigenous people due to the bioactive components present in it. Nanomedicine has undergone impressive modifications and the development of new drugs with significant healthcare outcomes. The purpose of the present study was to green synthesize and characterize silver nanoparticles (Ag-NPs) using aqueous leaf extract of S. emetica, and to study their in vitro antimicrobial, anticancer and photocatalytic dye degradation activities. Various spectroscopic and microscopic analytical tools were used to characterize the Ag-NPs. Selective G+ve, G−ve bacteria and fungal species were used to test the Ag-NPs antibacterial and antifungal activity. Anticancer efficacy of the Ag-NPs was appraised by MTT test using MDA-MB 231 human breast cancer cells. Degradation of Rhodamine B dye by the Ag-NPs under visible light was assessed. The characterization studies confirmed the formation of Ag-NPs which were crystalline cubical symmetry with an average size of 26.69 nm. Dose dependent antimicrobial activity displayed a maximum zone of inhibition of 22.39 mm against E. coli followed by 21.28 mm against S. aureus at 100 µL/mL concentration of Ag-NPs. The IC50 value of synthesized Ag-NPs on MDA-MB 231 cell lines was 0.5 μg/mL. The Ag-NPs catalyst degraded 96 % of Rhodamine B dye in 150 min under visible light. Phytosynthesized Ag-NPs showed strong antimicrobial and anticancer properties and also revealed excellent dye degradation capacity. It is possible to further utilize the biosynthesized Ag-NPs as a possible source of antimicrobial, anticancer, and dye-degradation activities.

Genomic insights into Aspergillus tamarii TPD11: enhancing polyphyllin production and uncovering potential therapeutic applications.

The excavation and utilization of endophytic fungi from medicinal plants is highly important for the development of new drugs. The endophytic fungus Aspergillus tamarii TPD11, which was isolated and obtained by the authors in the previous stage, can produce a variety of polyphyllins with important potential applications in hemostasis, inflammation and antitumor activities; however, the genomic information of TPD11 is still unknown. In this study, we sequenced and assembled the whole genome of the endophytic fungus A. tamarii TPD11, resolved the genome evolutionary relationships of 24 Aspergillus strains, and phylogenetic analysis of the genomes of 16 strains revealed the evolutionary differences between Aspergillus and Penicillium and the mechanisms of genome expansion and contraction. CAZy annotation analysis revealed that TPD11 obtains nutrients mainly by ingesting starch from the host plant. TPD11 has a biosynthesis-related gene cluster for the synthesis of squalestatin S1, and the silencing of this biosynthesis-related gene cluster might increase the content of polyphyllin. Annotation of 11 UDP-glycosyltransferase genes helps to further reveal the biosynthetic pathway of polyphyllin. In addition, secondary metabolism gene cluster and CAZy analyses confirmed the potential probiotic, insecticidal and antimicrobial activities of TPD11 on host plants. This study reveals the intrinsic mechanism by which endophytic fungi increase the content of polyphyllin, which provides a basis for the synthetic synthesis of the natural product polyphyllin.

Factors influencing the development and implementation of new entomoceutical drugs in veterinary medicine

Recently, the use of insects in various directions has been increasing, and the field of veterinary pharmacology has not become an exception. Biologically active substances from insects have become the object of increasingly intensive research, due to their unique properties, wide variety and potential in humane as well as veterinary medicine. Scientific research is published annually, which examines a variety of options for the use of chemical compounds of insects for therapeutic and preventive purposes. But despite this, there are no mass-produced drugs recognized by the consumer. The phenomenon in which the number of scientific studies is not proportional to the products sold can be considered a natural process when unprofitable projects are eliminated, but, compared with other studies of sources of medicinal raw materials, an incomparable percentage of insect products "does not reach" mass sales. The identified causes slowing the development of entomoceutics can partially identify the shortcomings of modern humane and veterinary pharmacology and expand general knowledge about the subtle moment of transition from the initial idea to the products being sold by the example of insect medicines. Neural networks can make a significant contribution to the development of veterinary entomoceutics, allowing to accelerate the process of developing new drugs from insects, improve the selection of effective therapy for specific patients, taking into account genetic predispositions on which the activity of the body's enzymatic systems depends, as well as the presence or absence of idiosyncratic reactions in animals, and optimize ways to predict the activity of substances in a particular organism. With proper research, description of methods for the isolation and purification of active substances, centralized regulation, the use of neural networks and the necessary financing, entomoceutics is able to fill the market with high-quality veterinary pharmacological preparations, which, with less financial and time costs, will not yield pharmacokinetic and pharmacodynamic properties to medicinal substances obtained in a traditional longer-term way, which will allow in a short time to withdraw veterinary medicine pharmacology to a new qualitative level.

Mirror-Image RNA: A Right-Handed Z-Form RNA and Its Ligand Complex

Until now, Z-form RNAs were believed to only adopt a left-handed double-helix structure. In this study, we describe the first observation of a right-handed Z-form RNA in NMR solution formed by L-nucleic acid RNA and present the first resolution of structure of the complex between a right-handed Z-form RNA and a curaxin ligand. These results provide a platform for the design of topology specific to Z-form-targeting compounds and are valuable for the development of new potent anticancer drugs.

Peptide Activator Stabilizes DJ-1 Structure and Enhances Its Activity

DJ-1 is a vital enzyme involved in the maintenance of mitochondrial health, and its mutation has been associated with an increased risk of Parkinson’s disease (PD). Effective regulation of DJ-1 activity is essential for the well-being of mitochondria, and DJ-1 is thus a potential target for PD drug development. In this study, two peptides (15EEMETIIPVDVMRRA29 and 47SRDVVICPDA56) were utilized with the aim of enhancing the activity of DJ-1. The mechanisms underlying the activity enhancement by these two peptides were investigated using hydrogen/deuterium exchange mass spectrometry (HDXMS). The HDXMS results revealed distinct mechanisms. Peptide 1 obstructs the access of solvent to the dimer interface and stabilizes the α/β hydrolase structure, facilitating substrate binding to a stabilized active site. Conversely, peptide 2 induces a destabilization of the α/β hydrolase core, enhancing substrate accessibility and subsequently increasing DJ-1 activity. The binding of these two peptides optimizes the activity site within the dimeric structure. These findings offer valuable insights into the mechanisms underlying the activity enhancement of DJ-1 by the two peptides, potentially aiding the development of new drugs that can enhance the activity of DJ-1 and, consequently, advance PD treatment.

Oroxylin A suppressed colorectal cancer metastasis by inhibiting the activation of the TGF-β/SMAD signal pathway

Metastatic colorectal cancer continues to have a high fatality rate, with approximately only 14% of patients surviving more than 5 years. To improve the survival rate of these patients, the development of new therapeutic drugs is a priority. In this study, we investigated the effects of Oroxylin A on the metastasis of human colorectal cancer cells and its potential molecular mechanism. This study utilised CCK8 assay, transwell assay, flow cytometry, western blot analysis, molecular docking, HE staining, immunofluorescence staining, and xenograft models. The proliferation, migration, and invasion of colon cancer cells were effectively suppressed by Oroxylin A in a dose-dependent manner. Oroxylin A has the potential to inhibit the process of epithelial‒mesenchymal transition (EMT) by upregulating the expression of E-cadherin, a marker associated with epithelial cells, while downregulating the levels of N-cadherin, Snail, vimentin, and slug, which are markers associated with mesenchymal cells. In addition, 200 mg/kg of Oroxylin A inhibited the growth of colorectal tumours. Molecular docking technology revealed that Oroxylin A can bind to TGFβ and inhibit the activation of the TGFβ-smad signalling pathway. The overexpression of TGFβ weakened the inhibitory effect of Oroxylin A on the proliferation, migration, and invasion of human colorectal cancer cells, as well as the promoting effect on apoptosis. Oroxylin A inhibited the activation of the TGF-smad signalling pathway and the EMT process, thereby suppressing the migration and invasion of human colorectal cancer cells.

Computational approach for decoding malaria drug targets from single-cell transcriptomics and finding potential drug molecule

Malaria is a deadly disease caused by Plasmodium parasites. While potent drugs are available in the market for malaria treatment, over the years, Plasmodium parasites have successfully developed resistance against many, if not all, front-line drugs. This poses a serious threat to global malaria eradication efforts, and the continued discovery of new drugs is necessary to tackle this debilitating disease. With recent unprecedented progress in machine learning techniques, single-cell transcriptomic in Plasmodium offers a powerful tool for identifying crucial proteins as a drug target and subsequent computational prediction of potential drugs. In this study, We have implemented a mutual-information-based feature reduction algorithm with a classification algorithm to select important proteins from transcriptomic datasets (sexual and asexual stages) for Plasmodium falciparum and then constructed the protein-protein interaction (PPI) networks of the proteins. The analysis of this PPI network revealed key proteins vital for the survival of Plasmodium falciparum. Based on the function and identification of a few strong binding sites on a couple of these key proteins, we computationally predicted a set of potential drug molecules using a deep learning-based technique. Lead drug molecules that satisfy ADMET and drug-likeliness properties are finally reported out of the generated drugs. The study offers a general computational pipeline to identify crucial proteins using scRNA-seq data sets and further development of potential new drugs.

Opportunities to rehabilitation of multimorbid patients with asthma and obesity

BACKGROUND: The challenges of rehabilitation and achieving asthma control in patients with multimorbid conditions remain relevant despite advances in asthma treatment. Improving therapeutic approaches requires not only the development of new drugs, but also the creation of comprehensive individualized rehabilitation programs. AIM: To develop complex rehabilitation programs for patients with asthma and multimorbid diseases (obesity, osteoarthritis) and assess their impact on asthma and comorbid conditions. MATERIALS AND METHODS: 70 patients with asthma and obesity were divided into two groups: a rehabilitation group and a control group. The study evaluated external respiration functions, quality of life using Asthma Quality of Life Questionnaire (standardized), asthma control with Asthma Control Questionnaire-5 (ACQ-5), multimorbid pathology with Cumulative Illness Rating Scale (CIRS), Lequesne index, exercise capacity via 6-minute walk test, physical activity using questionnaire ODA23+, and levels of interleukin-6, interleukin-4, tumor necrosis factor alpha, leptin. RESULTS: Both groups were comparable across all assessed parameters, with most participants presenting moderate to severe asthma. Physical activity levels were low to moderate. The CIRS index was 10.0 ± 1.1 in group 1 and 9.2 ± 1.1 in group 2 (p 0.05), while the Lequesne index was 9.70 ± 1.47 and 8.80 ± 1 (p = 0.3900), respectively. After rehabilitation program, the Lequesne index in the group 1 decreased by 2.37 ± 0.60 (р 0,05), which correlated with improved exercise tolerance (6-minute walk test) and increased physical activity by 6.57 ± 2.00 (р 0.05), and increased asthma control (with ACQ-5 decreasing by 0.74 ± 0.20 points; р 0.05) and quality of life with Asthma Quality of Life Questionnaire (standardized) 3.8 ± 0.4 to 4.5 ± 0.3 (р 0.05). In group 2, no significant changes were observed in the Lequesne index, physical activity, asthma control, or quality of life (p 0.05). Proinflammatory cytokines, including interleukin-6, tumor necrosis factor alpha, and leptin, decreased significantly in group 1, while the control group showed no significant changes. CONCLUSIONS: Multicomponent rehabilitation programs tailored to the individual characteristics of patients with multimorbid conditions contribute to better management of both asthma and comorbidities. Rehabilitation improves asthma control, quality of life, and exercise tolerance. It also helps to reduce pain syndrome, increase physical activity, and decrease proinflammatory cytokines and leptin levels.