Effective Drug Therapy Research Articles

Xuanbai Chengqi Decoction alleviates acute lung injury by inhibiting NLRP3 inflammasome

Ethnopharmacological relevanceAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a prevalent critical respiratory disorder caused mostly by infection and other factors. However, effective drug therapies are currently lacking. Xuanbai Chengqi Decoction (XCD), a traditional Chinese medicine (TCM) prescription, is commonly employed to treat lung diseases. It has been recommended by Chinese health authorities as one of the TCM prescriptions for COVID-19. Nonetheless, its underlying mechanism for the treatment of ALI has not been fully understood. Aim of the studyThe study aims to investigate the therapeutic effect of XCD on lipopolysaccharide (LPS) -induced ALI in mice and explore its anti-inflammatory mechanism involving pyroptosis. Materials and methodsUltra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was employed to identify the active compounds of XCD, and quantitative analysis of the main compounds was conducted. Male C57BL/6J mice were given different doses of XCD (4.5 and 9.0 g/kg/day) or dexamethasone (5 mg/kg/day) by oral gavage for 5 consecutive days. Subsequently, ALI was induced by injecting LPS (20 mg/kg) intraperitoneally 2 h after the last administration, and serum and lung tissues were collected 8 h later. J774A.1 cells were pretreated with different doses of XCD (100, 200, 400 μg/ml) for 12 h, then incubated with LPS (1 μg/ml) for 4 h and ATP (1 mM) for 2 h to induce pyroptosis. Supernatant and cells were collected. Moreover, J774A.1 cells were transfected with an NLRP3 overexpression plasmid for 24 h, followed by subsequent experiments with XCD (400 μg/ml). Lung histopathological changes were evaluated using hematoxylin and eosin (HE) staining. To assess the efficacy of XCD on ALI/ARDS, the levels of inflammatory factors, chemokines, and proteins associated with NLRP3 inflammasome signaling pathway were evaluated. ResultsXCD was found to ameliorate lung inflammation injury in ALI mice, and reduce the protein expression of TNF-α, IL-1β, and IL-6 in both mouse serum and J774A.1 cell supernatant. Meanwhile, XCD significantly decreased the mRNA levels of IL-1β, pro-IL-1β, CXCL1, CXCL10, TNF-α, NLRP3, NF-κB P65, and the protein expression of NLRP3, Cleaved-Caspase1, and GSDMD-N in the lung and J774A.1 cells. These effects were consistent with the NLRP3 inhibitor MCC950. Furthermore, overexpression of NLRP3 reversed the anti-inflammatory effect of XCD. ConclusionThe therapeutic mechanism of XCD in ALI treatment may involve alleviating inflammatory responses in lung tissues by inhibiting the activation of the NLRP3 inflammasome-mediated pyroptosis in macrophages.

Summary of drug therapy to treat cognitive impairment-induced obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a severe sleep disorder associated with intermittent hypoxia and sleep fragmentation. Cognitive impairment is a signifi- cant and common OSA complication often described in such patients. The most commonly utilized methods in clinical OSA treatment are oral appliances and continuous positive airway pressure (CPAP). However, the current therapeutic methods for improving cognitive function could not achieve the expected efficacy in same patients. Therefore, further understanding the molecular mechanism behind cognitive dysfunction in OSA disease will provide new treatment methods and targets. This review briefly summarized the clinical manifestations of cognitive impairment in OSA disease. Moreover, the pathophysiological molecular mechanism of OSA was outlined. Our study concluded that both SF and IH could induce cognitive impairment by multiple signaling pathways, such as oxidative stress activation, inflammation, and apoptosis. However, there is a lack of effective drug therapy for cognitive impairment in OSA. Finally, the therapeutic potential of some novel compounds and herbal medicine was evaluated on attenuating cognitive impairment based on certain preclinical studies.

Evaluation of the venting principle to reduce start-up delays in syringe infusion pumps used for microinfusions.

Start-up delays of syringe pump assemblies can impede the timely commencement of an effective drug therapy when using microinfusions in hemodynamically unstable patients. The application of the venting principle has been proposed to eliminate start-up delays in syringe pump assemblies. However, effectively delivered infusion volumes using this strategy have so far not been measured. This invitro study used two experimental setups to measure the effect of the venting principle compared to a standard non-venting approach on delivered start-up infusion volumes at various timepoints, backflow volumes, flow inversion and zero drug delivery times by means of liquid flow measurements at flow rates of 0.5, 1.0 and 2.0 mL/h. Measured delivered initial start-up volumes were negative with all flow rates in the vented and non-vented setup. Maximum backflow volumes were 1.8 [95% CI 1.6 to 2.3] times larger in the vented setup compared to the non-vented setup (p < 0.0001). Conversely, times until flow inversion were 1.5 [95% CI 1.1 to 2.9] times shorter in the vented setup (p < 0.002). This led to comparable zero drug delivery times between the two setups (p = 0.294). Start-up times as defined by the achievement of at least 90% of steady state flow rate were achieved faster with the vented setup (p < 0.0001), but this was counteracted by the increased backflow volumes. The application of the venting principle to the start-up of microinfusions does not improve the timely delivery of drugs to the patient since the faster start-up times are counteracted by higher backflow volumes when opening the three-way stopcock.

Outcome of initial lenvatinib treatment in patients with unresectable anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a very rare disease with a poor prognosis and with no established effective drug therapy. The present study aimed to report the outcomes of lenvatinib single-agent therapy as an initial drug treatment in ATC, and to investigate its safety and efficacy. This retrospective cohort study included 56 patients with unresectable primary ATC, of whom 36 were treated with lenvatinib and 12 with weekly paclitaxel, and 8 patients who refused any drug treatment who received palliative care. The average survival in the lenvatinib group was 5.8 months, which was significantly longer than 2.0 months in the paclitaxel group (P=0.005). The efficacy of lenvatinib in the 36 patients with ATC, whose primary tumors were unresectable, was evaluated. The response rate was 33% and the median overall survival time was 5.0 months. A safety review indicated that lenvatinib should be used under the careful observation of local findings. Two patients, who showed a reduction with lenvatinib, underwent conversion surgery, which prolonged the prognosis in terms of avoiding events, such as asphyxia, fistula and hemorrhage due to tumor growth; however, the surgical margins were positive, indicating that complete remission was impossible even if surgical resection was performed. Therefore, starting with lenvatinib treatment and identifying a therapeutic drug based on genomic analysis is an acceptable treatment strategy for ATC while halting the disease progression.

Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

Intestinal Pgc1α ablation protects from liver steatosis and fibrosis

The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis. We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet. In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann-Pick C1-like 1 (Npc1l1), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes. In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and de novo fatty acid accumulation in the liver. Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a loweraccumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.

Molecular Genetics of Retrovirus Replication

Despite the availability of effective anti-HIV drug therapy, according to UNAIDS estimates, 1 [...]

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity

Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine invitro and invivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3',5'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, and Ca2+ in cell lines and in invitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine invivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery.

Stress-induced mental health disorders are affecting many people around the world. However, effective drug therapy for curing psychiatric diseases does not occur sufficiently. Many neurotransmitters, hormones, and mechanisms are essential in regulating the body's stress response. One of the most critical components of the stress response system is the hypothalamus-pituitary-adrenal (HPA) axis. The FKBP prolyl isomerase 51 (FKBP51) protein is one of the main negative regulators of the HPA axis. FKBP51 negatively regulates the cortisol effects (the end product of the HPA axis) by inhibiting the interaction between glucocorticoid receptors (GRs) and cortisol, causing reduced transcription of downstream cortisol molecules. By regulating cortisol effects, the FKBP51 protein can indirectly regulate the sensitivity of the HPA axis to stressors. Previous studies have indicated the influence of FKBP5 gene mutations and epigenetic changes in different psychiatric diseases and drug responses and recommended the FKBP51 protein as a drug target and a biomarker for psychological disorders. In this review, we attempted to discuss the effects of the FKBP5 gene, its mutations on different psychiatric diseases, and drugs affecting the FKBP5 gene.

ANG2 Blockade Diminishes Proangiogenic Cerebrovascular Defects Associated With Models of Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT. Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods. Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes. Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.

P184 TRANSESOPHAGEAL ELECTROPHYSIOLOGICAL STUDY FOR FOLLOW UP OF NEONATAL PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA

Abstract Introduction Paroxysmal supraventricular tachycardia (TPS) is the most common form of arrhythmia in neonatal age. The transesophageal electrophysiological study allows us to demonstrate the possible persistence of arrhythmia after the first year of age. Aim of the study: To evaluate the reliability of transesophageal electrophysiological study in the follow–up of these patients. Materials and methods: We retrospectively observed 8 patients who came to our observation in neonatal age for TPS. All patients underwent echocardiogram and Holter and were discharged to effective drug therapy for rhythm control (with one or two drugs). Afterwards, they carried out follow–up with Holter in drug therapy every 3 months. Within one year of age, antiarrhythmic therapy was discontinued and a transesophageal electrophysiological study was performed, including atrial stimulation at increasing frequencies and programmed atrial stimulation with single, double and triple extrastimulus. In case of TPS inducibility, therapy was resumed and the study was repeated after one year in wash out. Results We observed 8 patients who came for TPS in neonatal age. 7 of these had a structurally normal heart; one patient had aortic coarctation corrected with aortoplasty. After one year of therapy, 4 patients (50%), half of whom were in dual therapy (flecainide associated with beta–blocker and/or amiodarone) were non– inducible; these patients, who were permanently discontinued, no longer presented arrhythmic episodes in the follow–up. The remaining 4 resumed therapy (double in half of the cases) for another year and then repeated the study in wash out: one patient continued to present arrhythmias (patient with correct aortic coarctation); the other 3 were non–inducible. In the subsequent follow–up, 3 of these patients only one showed a recurrence of arrhythmia. Conclusions The transesophageal electrophysiological study is a simple, minimally invasive and reliable method to identify subjects at risk of TPS recurrence. The persistence of arrhythmia in our study is independent of the pharmacological treatment carried out in mono or dual therapy. We also observed that in case of positivity after one year of therapy, the study can be repeated later allowing therapy to be interrupted at a later time.

Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.

Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear. Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed. We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in β-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency. This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.

Analysis of mortality among patients suffering from heart failure, using the example of a megalopolis

The medical documentation (n = 146912) introduced into the system Regional fragment of the unified state information system in the field of healthcare of Saint Petersburg for 20192021 was analyzed. To evaluate the mortality of patients due to heart failure, all deceased patients from 2019 to 2021 in Saint Petersburg (n = 192133) were taken as a basis, and based on a thorough study of medical documentation, patients who died from cardiovascular diseases and because of heart failure were singled out separately. The total mortality from all causes in Saint Petersburg in 2019 was 53025 people; in 2020, 66468 people; and in 2021, 72640 people. The analysis of mortality due to cardiovascular diseases from 2019 to 2021 showed an upward trend of 20.1% over the 3-year period of data analysis. When analyzing the prevalence of heart failure among deceased patients, an increase of 129.4% was noted over this period. The obtained results of the prevalence, mortality, and mortality of patients due to heart failure on the example of a megalopolis are the most relevant at the current time; they indicate a steady increase in the number of patients suffering from heart failure with an increase in the burden on the citys healthcare system. Simultaneously, there is insufficient continuity in the provision of medical care to patients suffering from heart failure, which is because of not only a shortage of medical personnel at all stages of medical care but also insufficient compliance of patients who either do not want to be treated or cannot continue treatment. Moreover, a significant disconnect was found in the continuity of medical care at the stages of pre-hospital and hospital treatment, as well as further outpatient follow-up of patients suffering from heart failure in the metropolis. All this leads to a significant increase in the mortality and mortality of patients suffering from heart failure, despite all the existing modern effective drug therapies. It appears critical to create a unified register platform for recording patients with heart failure, which will allow for a more accurate understanding of epidemiological aspects, the solution of which will improve the quality of medical care, identify the need for the crucial medicines, and reduce mortality, and mortality rates due to heart failure.

Successful treatment of a severe Takotsubo syndrome case complicated by liver abscess

The main manifestations of Takotsubo syndrome (TTS) are a spherical expansion of the left ventricle or near the apex and decreased systolic function. TTS is mostly thought to be induced by emotional stress, and the induction of TTS by severe infection is not often reported. A 72-year-old female patient with liver abscess reported herein was admitted due to repeated fever with a history of hypertension and impaired glucose tolerance. Her severe infection caused TTS, and her blood pressure dropped to 80/40 mmHg. IABP treatment was performed immediately and continued for 10 days, and comprehensive medication was administered. Based on her disease course and her smooth recovery, general insights and learnings may be: Adding to mental and other pathological stress reaction, serious infections from pathogenic microorganism could be of great important causation of stress reaction leading to TTS, while basic diseases such as coronary heart disease, hypertension, and diabetes were be of promoting factors; In addition to effective drug therapies for TTS, the importance of the timely using of IABP should be emphasized.

How Can We Prevent Mother-to-Child Transmission of HTLV-1?

The perception of human T-cell leukemia virus type 1 (HTlV-1) infection as a "silent disease" has recently given way to concern that its presence may be having a variety of effects. HTLV-1 is known to cause adult T-cell leukemia (ATL), an aggressive cancer of peripheral CD4 T cells; however, it is also responsible for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Most patients develop ATL as a result of HTLV-1 mother-to-child transmission. The primary route of mother-to-child transmission is through the mother's milk. In the absence of effective drug therapy, total artificial nutrition such as exclusive formula feeding is a reliable means of preventing mother-to-child transmission after birth, except for a small percentage of prenatal infections. A recent study found that the rate of mother-to-child transmission with short-term breastfeeding (within 90 days) did not exceed that of total artificial nutrition. Because these preventive measures are in exchange for the benefits of breastfeeding, clinical applications of antiretroviral drugs and immunotherapy with vaccines and neutralizing antibodies are urgently needed.

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski’s rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of −8.22, −7.52, −6.98, −6.61 and −6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of −8.03, −6.42, −6.82, −5.84 and −5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of −8.16, −6.4, −7.46, −6.92, and −6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively. Communicated by Ramaswamy H. Sarma

A Drosophila chemical screen reveals synergistic effect of MEK and DGKα inhibition in Ras-driven cancer.

Elevated Ras signalling is highly prevalent in human cancer; however, targeting Ras-driven cancers with Ras pathway inhibitors often leads to undesirable side effects and to drug resistance. Thus, identifying compounds that synergise with Ras pathway inhibitors would enable lower doses of the Ras pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a specialised chemical screen using a Drosophila model of Ras-driven cancer, we have identified compounds that reduce tumour size by synergising with sub-therapeutic doses of the Ras pathway inhibitor trametinib, which targets MEK, the mitogen-activated protein kinase kinase, in this pathway. Analysis of one of the hits, ritanserin, and related compounds revealed that diacyl glycerol kinase α (DGKα, Dgk in Drosophila) was the critical target required for synergism with trametinib. Human epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene SCRIB were also sensitive to treatment with trametinib and DGKα inhibitors. Mechanistically, DGKα inhibition synergises with trametinib by increasing the P38 stress-response signalling pathway in H-RASG12V SCRIBRNAi cells, which could lead to cell quiescence. Our results reveal that targeting Ras-driven human cancers with Ras pathway and DGKα inhibitors should be an effective combination drug therapy.

Meta-Analysis of Exploring the Effect of Curcumin Supplementation with or without Other Advice on Biochemical and Anthropometric Parameters in Patients with Metabolic-Associated Fatty Liver Disease (MAFLD).

Metabolic (dysfunction)-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common chronic liver disease. MAFLD is characterized by the excessive presence of lipids in liver cells and metabolic diseases/dysfunctions, e.g., obesity, diabetes, pre-diabetes, or hypertension. Due to the current lack of effective drug therapy, the potential for non-pharmacological treatments such as diet, supplementation, physical activity, or lifestyle changes is being explored. For the mentioned reason, we reviewed databases to identify studies that used curcumin supplementation or curcumin supplementation together with the use of the aforementioned non-pharmacological therapies. Fourteen papers were included in this meta-analysis. The results indicate that the use of curcumin supplementation or curcumin supplementation together with changes in diet, lifestyle, and/or physical activity led to statistically significant positive changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood insulin (FBI), homeostasis model assessment of insulin resistance (HOMA-IR), total triglycerides (TG), total cholesterol (TC), and waist circumference (WC). It appears that these therapeutic approaches may be effective in alleviating MAFLD, but more thorough, better designed studies are needed to confirm this.

Advancing Precision Medicine in Paediatrics: Past, present and future.

Precision Medicine is an approach to disease treatment and prevention taking into account individual genetic, environmental, therapeutic and lifestyle variability for each person. This holistic approach to therapeutics is intended to enhance drug efficacy and safety not only across healthcare systems but for individual patients. While weight and to some extent gestational age have been considered in determining drug dosing in children, historically other factors including genetic variability have not been factored into therapeutic decision making. As our knowledge of the role of ontogeny and genetics in determining drug efficacy and safety has expanded, these insights have provided new opportunities to apply principles of Precision Medicine to the care of infants, children and youth. These opportunities are most likely to be achieved first in select sub-groups of children. While there are many challenges to the successful implementation of Precision Medicine in children including the need to ensure that Precision Medicine enhances rather than reduces equity in children's health care rather, there are many more opportunities. Research, advocacy, planning and teamwork are required to move Precision Medicine forward in children in pursuit of the common goal of safe and effective drug therapy.

Опыт применения препарата Актитропил при хронической ишемии головного мозга: результаты наблюдательной клинической программы

Background: chronic cerebral ischemia (CCI) is one of the most common diseases in modern medical practice. The possibility of using effective drug therapy is the research subject. Aim: to study the efficacy and safety of Actitropil in patients with CCI in clinical practice. Patients and Methods: 30 patients with CCI were examined within the framework of the program. The diagnosis was established on the basis of generally accepted clinical practice guidelines with verification of changes in brain structures during imaging diagnostics. During follow- up (before and after the treatment course), changes in the parameters of the MoCA Test, the EQ-5D, MFI-20 scales, the Rivermead Mobility Index, and the neurologic symptom severity were evaluated. To assess the safety of the studied drug, adverse events (AE) were recorded. Results: by the time the treatment was completed, a significant improvement was obtained with normalization of cognitive functions: the number of points scored in the MoCA Test increased statistically significantly from 25 (24;25) to 28 (27;28.5), p=0.000004. There was a significant increase in the values on the EQ-5D scale by the 2nd visit from 45 (37;53) to 86 (79;90) points, p&lt;0.0001. Less marked, but statistically significant results were also achieved when assessing neurological manifestations according to the Rivermead Mobility Index (p=0.002). According to the results of comprehensive testing, there was a statistically significant decrease in the asthenia severity on the MFI-20 scale (total score) from 44 (37;47) to 22 (20;25), p=0.000002. The subjective severity scoring of neurological symptoms showed a decrease from 4 (3;5) (submaximal) to 2 (1;2) (minimum) points, p=0.000002. During therapy with the studied drug, AE which required dose reduction or drug withdrawal, as well as serious adverse events were not registered. Conclusions: therapy with Actitropil in a daily dose of 200 mg (divided into two doses), for 30 days led to a significant regression in the severity of CCI clinical manifestations: cognitive, motor and asthenic. The studied drug has a favorable safety profile. KEYWORDS: chronic cerebral ischemia, cognitive functions, life quality, Rivermead Mobility Index, nootropics. FOR CITATION: Andreyev V.V. Experience of using Actitropil in chronic cerebral ischemia: clinical follow-up results. Russian Medical Inquiry. 2023;7(10):620–624 (in Russ.). DOI: 10.32364/2587-6821-2023-7-10-2.