Effects Of Drugs Research Articles

Can brain network connectivity facilitate the clinical development of disease-modifying anti-Alzheimer drugs?

Abstract The preclinical phase of Alzheimer’s disease represents a crucial time window for therapeutic intervention but requires the identification of clinically relevant biomarkers that are sensitive to the effects of disease-modifying drugs. Amyloid peptide and tau proteins, the main histological hallmarks of Alzheimer’s disease, have been widely used as biomarkers of anti-amyloid and anti-tau drugs. However, these biomarkers do not fully capture the multiple biological pathways of the brain. Indeed, robust amyloid-target engagement by anti-amyloid monoclonal antibodies has recently translated into modest cognitive and clinical benefits in Alzheimer’s disease patients, albeit with potentially life-threatening side effects. Moreover, targeting the tau pathway has yet to result in any positive clinical outcomes. Findings from computational neuroscience have demonstrated that brain regions do not work in isolation but are interconnected within complex network structures. Brain connectivity studies suggest that misfolded proteins can spread through these connections, leading to the hypothesis that Alzheimer’s disease is a pathology of network dysconnectivity. Based on these assumptions, here we discuss how incorporating brain connectivity outcomes could better capture the global brain functionality and, in conjunction with traditional Alzheimer’s disease biomarkers, could facilitate the clinical development of new disease-modifying anti-Alzheimer’s disease drugs.

Cost-Effective Bioimpedance Spectroscopy System for Monitoring Syncytialization In Vitro: Experimental and Numerical Validation of BeWo Cell Fusion

The placenta plays a critical role in nutrient and oxygen exchange during pregnancy, yet the effects of medicinal drugs on this selective barrier remain poorly understood. To overcome this, this study presents a cost-effective bioimpedance spectroscopy (BIS) system to assess tight junction integrity and monolayer formation in BeWo b30 cells, a widely used model of the multinucleated maternal–fetal exchange surface of the placental barrier. Cells were cultured on collagen-coated porous membranes and treated with forskolin to induce controlled syncytialization. Electrical impedance was measured using an entry level impedance analyzer, while immunofluorescence staining was used to confirm monolayer formation and syncytialization. The measurements and staining confirmed the formation of a confluent monolayer on day 4. In fact, the electrical resistance tripled for treated samples indicating a more electrically restrictive barrier. This resistance remained constant for treated samples reflecting the intact barrier’s integrity over the next 3 days. The measurements show that, on day 4, the electrical capacitance of the cells decreased for the treated samples as opposed to the untreated samples. This reflects that the surface area of the BeWo b30 cells decreased when the samples were treated with forskolin. Finally, a COMSOL model was developed to explore the effects of electrode positioning, depth, and distance on TEER measurements, explaining discrepancies in the literature. In fact, there was a substantial 97% and 39.4% difference in the obtained TEER values. This study demonstrates the AD2 device’s feasibility for monitoring placental barrier integrity and emphasizes the need for standardized setups for comparable results. The system can hence be used to analyze drug effects and nutrient transfer across the placental barrier.

Tannic acid reactivates HIV-1 latency by mediating CBX4 degradation.

HIV-1 can integrate viral DNA into host cell chromosomes and establish a long-term stable latent viral reservoir, a major obstacle in curing HIV-1 infection. The reactivation of latent proviruses with latency-reversing agents (LRAs) is a prerequisite for the eradication of viral reservoirs. Previous reports have shown that tannic acid (TA) exerts several biological functions, including antioxidant and antitumor activities. Here, we identified a novel function of TA as a reactivator of HIV-1 latency. TA showed similar features to the HIV-1 transactivator of transcription (Tat) and was able to reactivate a larger number of proviruses from various integration sites. TA also showed a strong synergistic effect with other LRAs acting on different signaling pathways. Further studies revealed that the polycomb repressive complex 1 component, chromobox protein homolog 4 (CBX4), is specifically degraded by TA through ubiquitination. CBX4 is associated with the tri-methylation at lysine 27 of histone H3 (H3K27me3) which was enriched on HIV-1 long terminal repeat regions. The TA-induced CBX4 degradation decreased the H3K27me3 enrichment and subsequently enhanced the transcriptional activity of the integrated proviruses. These results suggest that TA is an efficient LRA aiming to a new target for HIV-1 latency, which could be developed to eradicate latent proviruses.IMPORTANCEHIV-1 remains a global health challenge, with its ability to integrate into the host genome and evade the effects of drugs. To overcome this obstacle, the "shock and kill" strategy was proposed, targeting the reactivation of latent HIV-1 for subsequent eradication through antiretroviral medication and immune system reinforcement. Here, we found a new reactivator for HIV-1 latency, tannic acid (TA), which can reactivate HIV-1 latency widely and deeply. Moreover, we demonstrated that TA could promote the interaction between the polycomb repressive complex 1 component CBX4 and the E3 ubiquitin ligase cullin 4A (CUL4A), resulting in CBX4 degradation through the ubiquitin-proteasome system. These events reduce H3K27me3 enrichment in the HIV-1 long terminal repeat region, thereby promoting HIV-1 transcription and ultimately reactivating HIV-1 latent infection. Our work may facilitate the identification of new latency-reversing agents and provide more theoretical evidence for the molecular mechanism of HIV-1 latency.

Single-Cell RNA Sequencing, Cell Communication, and Network Pharmacology Reveal the Potential Mechanism of Senecio scandens Buch.-Ham in Hepatocellular Carcinoma Inhibition

Background: Hepatocellular carcinoma (HCC), a prevalent form of primary liver malignancy, arises from liver-specific hepatocytes. Senecio scandens Buch.-Ham(Climbing senecio) is a bitter-tasting plant of the Compositae family with anti-tumor properties. This study aims to identify the molecular targets and pathways through which Climbing senecio regulates HCC. Methods: Active ingredients of Climbing senecio were collected from four online databases and mapped to relevant target databases to obtain predicted targets. After recognizing the key pathways through which Climbing senecio acts in HCC. Gene expression data from GSE54238 Underwent differential expression and weighted gene correlation network analyses to identify HCC-related genes. The “Climbing senecio-Hepatocellular Carcinoma Targets” network was constructed using Cytoscape 3.10.1 software, followed by topology analysis to identify core genes. The expression and distribution of key targets were evaluated, and the differential expression of each key target between normal and diseased samples was calculated. Moreover, single-cell data from the Gene Expression Omnibus (GSE202642) were used to assess the distribution of Climbing senecio’s bioactive targets within major HCC clusters. An intersection analysis of these clusters with pharmacological targets and HCC-related genes identified Climbing senecio’s primary targets for this disease. Cell communication, receiver operating characteristic (ROC)analysis, survival analysis, immune filtration analysis, and molecular docking studies were conducted for detailed characterization. Results: Eleven components of Climbing senecio were identified, along with 520 relevant targets, 300 differentially expressed genes, and 3765 co-expression module genes associated with HCC. AKR1B1, CA2, FOS, CXCL2, SRC, ABCC1, and PLIN1 were identified within the intersection of HCC-related genes and Climbing senecio targets. TGFβ, IL-1, VEGF, and CXCL were identified as significant factors in the onset and progression of HCC. These findings underscore the anti-HCC potential and mode of action of Climbing senecio, providing insights into multi-targeted treatment approaches for HCC. Conclusions: This study revealed that Climbing senecio may target multiple pathways and genes in the process of regulating HCC and exert potential drug effects through a multi-target mechanism, which provides a new idea for the treatment of HCC. However, the research is predicated on network database analysis and bioinformatics, offering insights into HCC therapeutic potential while emphasizing the need for further validation.

Depression and anxiety levels in patients with hypertension and relationship with blood pressure control: A review of study design for psychiatric intervention protocol

Arterial hypertension, anxiety, and depression are common in Western and Eastern medicines, with each offering therapeutic instructions and proposals. Arterial hypertension has been identified as a harmful factor that causing cardiovascular diseases and increasing global mortality. Depression affects over 322 million people worldwide, with an overall incidence of 4.4%. In cases of hypertension, depression is observed in approximately 30% of patients when assessed using questionnaires and in approximately 21% when assessed psychiatrically. Anxiety and depression are risk factors for arterial hypertension. On the contrary, hypertension has been considered to cause anxiety and depressive symptoms. This could be attributed to the direct effects of high blood pressure (BP), side effects of antihypertensive drugs, or psychological reactions to the diagnosis of hypertension. An unhealthy lifestyle increases stress and BP levels. Therefore, controlling stress is a complementary therapy for hypertension. In this context, this study presents a protocol aimed at evaluating stress/depression levels as well as the quality of life in patients with hypertension and examining their correlation with BP control and target organ damage. In addition, we will assess the effect of subsequent psychiatric interventions in hypertensive patients with increased levels of depression/stress on BP control, treatment compliance, and quality of life after a follow-up period of 1 year.

A sex-specific effect of M4 muscarinic cholinergic autoreceptor deletion on locomotor stimulation by cocaine and scopolamine

ObjectiveAcetylcholine modulates the activity of the direct and indirect pathways within the striatum through interaction with muscarinic M4 and M1 receptors. M4 receptors are uniquely positioned to regulate plasticity within the direct pathway and play a substantial role in reward and addiction-related behaviors. However, the role of M4 receptors on cholinergic neurons has been less explored. This study aims to fill this gap by addressing the role of M4 receptors on cholinergic neurons in these behaviors.MethodsTo investigate the significance of M4-dependent inhibitory signaling in cholinergic neurons we created mutant mice that lack M4 receptors on cholinergic neurons. Cholinergic neuron-specific depletion was confirmed using in situ hybridization. We aimed to untangle the possible contribution of M4 autoreceptors to the effects of the global M4 knockout by examining aspects of basal locomotion and dose-dependent reactivity to the psychostimulant and rewarding properties of cocaine, haloperidol-induced catalepsy, and examined both the anti-cataleptic and locomotion-inducing effects of the non-selective anticholinergic drug scopolamine.ResultsBasal phenotype assessment revealed no developmental deficits in knockout mice. Cocaine stimulated locomotion in both genotypes, with no differences observed at lower doses. However, at the highest cocaine dose tested, male knockout mice displayed significantly less activity compared to wild type littermates (p = 0.0084). Behavioral sensitization to cocaine was similar between knockout and wild type mice. Conditioned place preference tests indicated no differences in the rewarding effects of cocaine between genotypes. In food-reinforced operant tasks knockout and wild type mice successfully acquired the tasks with comparable performance results. M4 receptor depletion did not affect haloperidol-induced catalepsy and scopolamine reversal of catalepsy but attenuated scopolamine-induced locomotion in females (p = 0.04). Our results show that M4 receptor depletion attenuated the locomotor response to high doses of cocaine in males and scopolamine in females, suggesting sex-specific regulation of cholinergic activity.ConclusionDepletion of M4 receptors on cholinergic neurons does not significantly impact basal behavior or cocaine-induced hyperactivity but may modulate the response to high doses of cocaine in male mice and the response to scopolamine in female mice. Overall, our findings suggest that M4-dependent autoregulation plays a minor but delicate role in modulating specific behavioral responses to pharmacological challenges, possibly in a sex-dependent manner.

Effect of childhood epilepsy and antiepileptic drugs on visual evoked potential response and optical coherence tomography

BackgroundEpileptic seizures arise from an excessively synchronous and sustained discharge of a group of neurons. The single feature of all epileptic syndromes is a persistent increase of neuronal excitability. Visual affection in epileptic children could be attributed to the disease itself or the use of anti-epileptic drugs, these changes may involve abnormal electro-physiological response. This biphasic study, conducted at the neuro-pediatric clinic at neurology department, aimed to investigate effect of idiopathic childhood epilepsy per se on (1) visual evoked potential and (2) optical coherence tomography and effect of selected two antiepileptic medications on them. All subjects were exposed to visual evoked potential and only cooperative subjects exposed to ocular coherence tomography before and after anti-epileptic drugs and were followed up over 2 years.ResultsThe study included 50 newly diagnosed epileptic children and 50 healthy controls, the mean P100 latency in the right eyes of the control group was 110.4 ± 3.76ms, while in the patients group was 114.94 ± 12.81ms that showed significant difference between the two groups with p value (0.020). After 2 years of treatment by levetiracetam and valproate, the mean P100 latency of the right and left eyes in the valproate group was 112.34 ± 7.05 ms and 112.59 ± 5.2 ms, respectively, and it was 114.85 ± 10.39 ms and 116.14 ± 9.84 ms, respectively, in the valproate group, which showed insignificant difference between the two groups. The mean average of retinal nerve fiber layer thickness between patients and controls was significant in both right and left eyes with p value 0.002 and < 0.001, respectively. After 1 year of treatment by levetiracetam in the first group and valproate in the second group, there was no significant difference between the two groups neither regarding retinal nerve fiber layer thickness nor ganglion cell complex in both eyes.ConclusionsThere was prolonged latency in the epileptic children before starting anti-epileptic drugs more than the control group; also there was thinning of the retinal nerve fiber layer thickness and average part of the ganglion cell complex thickness more in the epileptic children than in the healthy controls.

Assessment of the Anticancer Effects of Simvastatin on Human Osteosarcoma and Colorectal Cancer Cell Lines

Background: Colorectal cancer (CRC) and osteosarcoma (OS) and all other cancers represents one of the most challenger issues to the humanity for long time, due to their associated sever health lesions, emotional and psychological hardships, and significant economic encumbrances. Adding to that, the poor curing fate achieved with current therapeutic strategies of cancer. The invention of new drugs for cancer treatment required long time reaching to years as well as consuming the huge money budget, so that the focusing on the aspect of the repositioning of conventional drugs (like simvastatin) has gradually take a large consideration as they can participate in the alleviation of cancer treatment burden in view of this work promising results and preceding hopeful findings and conclusions have been obtained from the studies conducted in this field. The Aim: assessment of the cytotoxic effects of a lipid lowering drug, simvastatin, in human CRC and OS cells. Methods: SW480 (CRC) and MG-63 (OS) cell lines were utilized in this work and have been treated with various doses of simvastatin, then its cytotoxic effects have been evaluated by MTT assay. Thereafter, the VEGF and GDF-15 suppression effects of simvastatin have been measured in SW480 and MG-63 cells. Results: exposure of CRC and OS cells to simvastatin resulted in significant cellular growth inhibition, and VEGF and GDF-15 suppression effects. Conclusions: Simvastatin has a promising antineoplastic potential and its role in cancer therapy cannot be underestimated, and encourage the utilization and surveying of other preexisting drugs in cancer treatment path.

Leveraging Evolutionary Immunology in Interleukin-6 and Interleukin-17 Signaling for Lung Cancer Therapeutics.

Lung cancer is among the most common instances of cancer subtypes and is associated with high mortality rates. Due to the availability of fewer therapies and delayed clinical investigations, the number of cancer incidences is rising dramatically. This is possibly an effect of immune modulations and chemotherapeutic drugs that raises cancer resistance. Among the list, IL-6 and IL-17 are host-derived paradoxical effectors that attune immune responses in malignant lung cells. Their excessive release in the cytokine milieu stabilizes immunosuppressive phenotypes, resulting in cellular perturbations. During tumor development, the significance of these molecules is reflected in their potential to regulate oncogenesis by initiating a myriad of signaling events that influence tumor growth and the metastatic ability of benign cancer cells. Moreover, their transactivation contributes to antiapoptotic mechanisms and favors cancer cell survival via constitutive expression of immunoregulatory molecules. Co-evolution and gene duplication events could be the major drivers behind cytokine evolution, which have prompted generic changes and, hence, the additive effect. The evolutionary model and statistical analysis provide evidence about the cytokines ancestral relationships and site-specific conservation, which is more convincing as both cytokines share cysteine-knot-like structures important in maintaining structural integrity. Funneling through the findings could help find residues that serve a catalytic role in immune functioning. Designing peptides or subunit vaccine formulations against those conserved residues could aid in combating lung cancer pathogenesis.

Carbohydrate polymer-based nanoparticles with cell membrane camouflage for cancer therapy: A review.

Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.

Prooxidant state in anticancer drugs and prospect use of mitochondrial cofactors and anti-inflammatory agents in cancer prevention.

An extensive body of literature has associated cancer with redox imbalance and inflammatory conditions. Thus, several studies and current clinical practice have relied on the use of anticancer drugs known to be associated with prooxidant state. On the other hand, a number of studies have reported on the effects of several antioxidants, anti-inflammatory agents and of mitochondrial cofactors (also termed mitochondrial nutrients, MNs) in counteracting or slowing carcinogenesis, or in controlling cancer growth. In the available literature, a body of evidence points on the roles of anti-inflammatory agents and of individual MNs against carcinogenesis or in controlling cancer cell proliferation, but only a few reports on the combined use of two or the effect of three MNs. These combinations are proposed as potentially successful tools to counteract carcinogenesis in prospective animal model studies or in adjuvant cancer treatment strategies. A "triad" of MNs are suggested to restore redox balance, mitigate side effects of prooxidative anticancer drugs, or aid in cancer prevention and/or adjuvant therapy. By elucidating their mechanistic underpinnings and appraising their clinical efficacy, we aim to contribute with a comprehensive understanding of these therapeutic modalities.

Nutrient conditions affect antimicrobial pharmacodynamics in Pseudomonas aeruginosa.

The infectious microenvironment in chronic respiratory tract infections is characterized by substantial variability in nutrient conditions, which may impact colonization and treatment response of pathogens. Metabolic adaptation of the cystic fibrosis (CF)-associated pathogen Pseudomonas aeruginosa has been shown to lead to changes in antibiotic sensitivity. The impact of specific nutrients on the response to antibiotics is, however, poorly characterized. Here, we investigated how different carbon sources impact the antimicrobial pharmacodynamic responses in P. aeruginosa. We evaluated the effect of six antibiotics (aztreonam, ceftazidime, ciprofloxacin, colistin, imipenem, and tobramycin) on P. aeruginosa cultured in a basal medium enriched for seven different carbon sources (alanine, arginine, aspartate, glucose, glutamate, lactate, and proline). Pharmacodynamic responses were characterized by measuring time-kill profiles for a bioluminescent P. aeruginosa PAO1 Xen41 strain. We show that single-nutrient modifications minimally affected bacterial growth rate. For specific nutrient-antibiotic combinations, we find relevant alterations in antibiotic sensitivity (i.e., EC50) and the maximum drug effect (Emax), in particular for ciprofloxacin, colistin, imipenem, and tobramycin. The most pronounced effect was observed for tobramycin, where glucose was found to reduce the EC50 (0.5-fold), whereas lactate-enriched conditions led to a 4.3-fold increase in EC50. Using pharmacokinetic-pharmacodynamic simulations, we illustrate that the magnitude of the nutrient-driven pharmacodynamic changes impact treatment for clinical dosing strategies of tobramycin. In summary, this study underscores the impact of nutrient composition on antimicrobial pharmacodynamics, which could potentially contribute to observed variability of antimicrobial treatment responses in CF patients.IMPORTANCEChronic respiratory tract infections in cystic fibrosis patients present significant challenges for antibiotic treatment due to the complexity of the respiratory environment. This study investigated how variations in nutrient levels, altered during chronic infections, affect pathogen response to antibiotics in an experimental setting. By simulating different nutrient conditions, we aimed to uncover interactions between nutrient availability and antibiotic sensitivity. Our findings provide critical insights that could lead to more effective treatment strategies for managing chronic respiratory tract infections in cystic fibrosis patients while also guiding future research in improving treatment methodologies.

Suicidality and use of psychotropic medications in patients with schizophrenia: a prospective cohort study.

The lifetime prevalence of suicide is around 5% in patients with schizophrenia. Non-adherence to antipsychotic medication is an important risk factor, but prospective studies investigating joint effects of antipsychotic drugs, antidepressants, and benzodiazepines on suicidality are scarce. We aimed to investigate how use and non-use of psychotropic medications are associated with suicidality in schizophrenia. An open cohort study followed all patients consecutively admitted to a psychiatric acute unit during a 10-year period with a diagnosis of schizophrenia (n = 696). Cox multiple regression analyses were conducted with use of antipsychotics, antidepressants, and benzodiazepines as time-dependent variables. Adjustments were made for age, gender, depressive mood, agitated behavior, and use of alcohol and illicit substances. A total of 32 (4.6%) suicide events were registered during follow-up. Of these, 9 (28%) were completed suicides and 23 (72%) were attempted suicides. A total of 59 (8.5%) patients were readmitted with suicidal plans during the follow-up. Compared to non-use, use of antipsychotics was associated with 70% lower risk of attempted or completed suicide (adjusted hazard ratio [AHR] = 0.30, p < 0.01, CI 0.14-0.65) and 69% reduced risk of readmission with suicidal plans (AHR = 0.31, p < 0.01, CI 0.18-0.55). Use of prescribed benzodiazepines was associated with 126% increased risk of readmission with suicidal plans (AHR = 2.26, p = 0.01, CI 1.24-4.13). Adherence to antipsychotic medication is strongly associated with reduced suicidal risk in schizophrenia. The use of prescribed benzodiazepines was identified as a significant risk factor for being readmitted with suicidal plans.

A pilot study of tofacitinib citrate with 308-nm excimer laser for the treatment of vitiligo.

Vitiligo is a clinically prevalent acquired skin disorder characterized by depigmentation. Currently, the therapeutic options for vitiligo are restricted, and numerous issues exist, such as a prolonged treatment course, unsatisfactory therapeutic efficacy, adverse reactions, and a high propensity for recurrence after treatment cessation. To assess the safety and efficacy of combined treatment involving oral tofacitinib citrate (TC) and a 308-nm excimer laser (EL), with the aim of discovering a rapid and effective treatment approach to minimize the side effects of various drugs. A total of 63 patients with progressive vitiligo and a Vitiligo Disease Activity Score (VIDA) score of four from January 2022 to January 2024 were enrolled and divided into three groups. The three groups were the TC combined with 308-nm EL and methylprednisolone treatment group, the TC and 308-nm EL treatment group, and the methylprednisolone treatment alone group. The treatment was continued for 24 weeks. Finally, assessment of therapy outcomes was performed. When TC was combined with 308-nm EL and methylprednisolone treatment, the effect was more rapid. When TC was combined with 308-nm EL, it had a more favorable treatment effect than that of methylprednisolone alone, despite having a slower effect onset. After 24 weeks of treatment, there was no significant difference between the two groups in terms of the total response rate or significant efficiency. However, when only methylprednisolone treatment was applied, the effect is relatively slow and inefficient. This study confirmed the rapid and efficient treatment of vitiligo through the combination of TC and 308-nm EL, and no serious adverse reactions were reported, which could offer an optimal treatment plan for patients with vitiligo.

The impact of surgery with general anesthesia on cognitive function and putamen volume: a cross-sectional study among older adults

BackgroundPrevious studies have shown that surgery under general anesthesia may diminish cognitive function; however, the proposed mechanisms need further elucidation. The purpose of the current study was twofold: (1) to compare overall and domain-specific differences in cognitive function between the surgery under general anesthesia group and the control group, and (2) to investigate the possible mechanisms of surgery under general anesthesia affecting cognitive function, using T1-structural magnetic resonance imaging.MethodsA total of 194 older adults were included in this study. Patients were divided into a surgery under general anesthesia group (n = 92) and a control group (n = 104). The two groups were matched for age, sex, and educational level. All participants underwent clinical evaluation, neuropsychological testing, blood biochemistry analysis, and T1 phase structural magnetic resonance imaging.ResultsWe found that older adults with a history of surgery under general anesthesia had lower Montreal Cognitive Assessment (MoCA) scores and smaller right putamen volumes (p &amp;lt; 0.05). Linear regression analysis (mediation model) indicated that surgery under general anesthesia affected MoCA scores by diminishing the volume of the right putamen (B = 1.360, p = 0.030).ConclusionWe found evidence that older adults who underwent surgery under general anesthesia had poorer cognitive function, which may have been caused by an apoptotic or otherwise toxic effect of anesthetic drugs on the volume of the right putamen.

The role of hypoxia-inducible factors 1 and 2 in the pathogenesis of diabetic kidney disease

AbstractAccording to the 10th edition of the IDF Diabetes Atlas, 537 million people suffered from diabetes in 2021, and this number will increase by 47% by 2045. It is estimated that even 30–40% of these individuals may develop diabetic kidney disease (DKD) in the course of diabetes. DKD is one of the most important complications of diabetes, both in terms of impact and magnitude. It leads to high morbidity and mortality, which subsequently impacts on quality of life, and it carries a high financial burden. Diabetic kidney disease is considered a complex and heterogeneous entity involving disturbances in vascular, glomerular, podocyte, and tubular function. It would appear that hypoxia-inducible factors (HIF)-1 and HIF-2 may be important players in the pathogenesis of this disease. However, their exact role is still not fully investigated. In this article, we summarize the current knowledge about HIF signaling and its role in DKD. In addition, we focus on the possible effects of nephroprotective drugs on HIF expression and activity in various tissues. Graphical abstract

Prospects for applying the chronic social conflict model in medical and biological research

Long-term studies (1987–2023) have shown that the model of chronic social conflict with the original name «sensory contact model» can be used to model various pathological conditions that develop in mice under the influence of chronic social stress, which makes it possible to study neurophysiological and neuromolecular mechanisms at different stages of disease development, in particular, increased anxiety, depression-like and psychosis-like states in mice of the C57BL/6 strain under repeated agonistic interactions. In pharmacological experiments in mice with different pathological symptoms, it becomes possible to study: the therapeutic and protective effects of drugs at different stages of disease development, the effectiveness of treatment, and methods for prevention of relapses of the disease. The model makes it possible to develop approaches to pharmacogenomic therapy, as well as search for peripheral markers of pathological conditions.

Gut microbiota profiles of patients with idiopathic pulmonary fibrosis.

Purpose/Aim: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia. Multiple genetic factors, environmental exposures, micro-aspirations secondary to gastroesophageal reflux, age, sex, smoking habit, and infections contribute to its etiology; consequently, its pathogenesis remains unclear. The homeostasis of gut microbiota, including bacteria, archaea, and fungi, can influence the functions of both the intestine and remote organs. There are still many unknowns regarding the effects and mechanisms of gut microbiota dysbiosis on the development of IPF. In this study, we aimed to characterize the gut microbiota of patients with IPF compared with that of healthy controls. Furthermore, we assessed the effects of antifibrotic drugs on gut dysbiosis. Materials and Methods: This study involved 12 patients with IPF receiving antifibrotic drug therapy, 12 patients with IPF not receiving antifibrotic drug therapy, and 8 healthy controls. The clinical parameters of the patients were recorded, and DNA extracted from stool samples was subjected to 16S ribosomal RNA gene sequencing of the V1-V9 hypervariable regions. Results: Campylobacterota species were detected in the patient groups but not in the control group. Staphylococcales and Gemellaceae species were not detected in the IPF groups; however, a significant relationship was observed in the control group. In the IPF groups, Actinobacteria, Bifidobacteriales, Burkholderiales, Bacteroidaceae, Dorea, Fusicatenibacter, and Ruminococcus -gauvreauii abundance was low and Enterobacterales, Erysipelotrichaceae, Holdemanella, and Alloprevotella abundance was high compared with those in the control group. When the IPF group using antifibrotic drugs and that not using antifibrotic drugs were compared, only Lachnospiraceae UCG 004 abundance was found to be lower in the patient group receiving antifibrotic drugs. Conclusions: Patients with IPF exhibit higher or lower abundance of certain taxa compared to healthy controls, providing novel perspectives on the pathogenesis and treatment of various illnesses. Examining changes in intestinal microbiota during treatment may guide the clinical strategy for managing adverse effects.

Long-term effects of treatment of acute lymphoblastic leukemia in childhood on the part of the musculoskeletal system

Effective treatment of leukemia in children has improved both the five-year and long-term survival of patients. An increase in life expectancy requires an assessment of the long-term effects of treatment. The use of antitumor drugs such as mercaptopurin, methotrexate, tyrosine kinase inhibitors, as well as glucocorticosteroids often negatively affect the musculoskeletal system, including bone mineralization, which can lead to fractures, necrosis, arthropathy and other lesions of the musculoskeletal system, Side effects of anticancer drugs, glucocorticosteroids on bone tissue are especially important in childhood, when the skeleton is being formed and their long-term negative effect on the musculoskeletal system is no less important. The assessment of long-term consequences will make it possible to develop timely preventive measures. KEYWORDS: bone tissue, antitumor therapy, leukemia, long-term effects of treatment.

Translational population target binding model for the anti-FcRn fragment antibody efgartigimod

Efgartigimod is a human IgG1 antibody Fc-fragment that lowers IgG levels through blockade of the neonatal Fc receptor (FcRn) and is being evaluated for the treatment of patients with severe autoimmune diseases mediated by pathogenic IgG autoantibodies. Engineered for increased FcRn affinity at both acidic and physiological pH, efgartigimod can outcompete endogenous IgG binding, preventing FcRn-mediated recycling of IgGs and resulting in increased lysosomal degradation. A population pharmacokinetic-pharmacodynamic (PKPD) model including FcRn binding was developed based on data from two healthy volunteer studies after single and repeated administration of efgartigimod. This model was able to simultaneously describe the serum efgartigimod and total IgG profiles across dose groups, using drug-induced FcRn receptor occupancy as driver of total IgG suppression. The model was expanded to describe the PKPD of efgartigimod in cynomolgus monkeys, rabbits, rats and mice. Most species differences were explainable by including the species-specific in vitro affinity for FcRn binding at pH 7.4 and by allometric scaling of the physiological parameters. In vitro-in vivo scaling proved crucial for translation success: the drug effect was over/underpredicted in rabbits/mice when ignoring the lower/higher binding affinity of efgartigimod for these species versus human, respectively. Given the successful model prediction of the PK and total IgG dynamics across species, it was concluded that the PKPD of efgartigimod can be characterized by target binding. From the model, it is suggested that the initial fast decrease of measurable unbound efgartigimod following dosing is the result of combined clearance of free drug and high affinity target binding, while the relatively slow terminal PK phase reflects release of bound drug from the receptor. High affinity target binding protects the drug from elimination and results in a sustained PD effect characterized by an increase in the IgG degradation rate constant with increasing target receptor occupancy.