Therapeutic Medicine Research Articles

Effects of toxin metalloproteinases from jellyfish Nemopilema nomurai nematocyst on the dermal toxicity and potential treatment of jellyfish dermatitis

Jellyfish dermatitis is a common medical problem in many countries due to the jellyfish envenomation. However, there are no specific and targeted medications for their treatment. Here we investigated the possible therapeutic effects of metalloproteinase inhibitors on the dermal toxicity of Nemopilema nomurai nematocyst venom (NnNV), a giant venomous jellyfish from China, using the jellyfish dermatitis model, focusing on inflammatory effector molecules during jellyfish envenomation. Metalloproteinase may further stimulate inflammation by promoting oxidative stress in the organism and play key roles by activating MAPK and NF-κB, in the pathogenesis of jellyfish dermatitis. And the metalloproteinase inhibitors batimastat and EDTA disodium salt may treat the Jellyfish dermatitis by inhibiting the metalloproteinase activity in NnNV. These observations suggest that the metalloproteinase components of NnNV make a considerable contribution to dermal toxicity as the inflammation effect molecular, and metalloproteinase inhibitors can be regarded as novel therapeutic medicines in jellyfish envenomation. This study contributes to understanding the mechanism of jellyfish dermatitis and suggests new targets and ideas for the treatment of jellyfish envenomation.

Antioxidative single atomic nanocatalysts facilitate orally administered probiotic inulin gels for acute colitis amelioration

Acute colitis is characterized by the microenvironment with a high level of inflammation, oxidative stress as well as a disordered microbiome. Sustained delivery of the therapeutic medicine into the colitis foci is limited due to the harsh condition of the gastric environment and fast excretion kinetics in the gut. Herein, we have designed an orally administrable probiotic inulin gel (igel) containing living Bacillus subtilis (B. subt) engineered with outperformed antioxidative single manganese atomic nanocatalyst (SAM NCs) for effective, sustained, and biocompatible therapeutics against acute colitis. Based on the multi-catalytic antioxidative activities (superoxide dismutase, glutathione peroxidase, and catalase) of the synthetic SAM NCs, these nanocatalysts are capable of eliminating the oxidative stresses both in vitro and in vivo. With further engineering onto the living Bacillus subtilis and subsequent in situ gelation inside the inulin, the as-formed probiotic igel(SAM NCs@B. subt) could effectively target and colonize inside the colon region, triggering the in vivo anti-inflammatory, anti-oxidative and gut microbiome modulation performance with high biocompatibility. The present study provides a promising probiotic gelation therapeutic strategy against acute colitis, shedding light on the exploration and clinical transformation of gastrointestinal disease.

Alpha-Emitting Radionuclides: Current Status and Future Perspectives.

The use of radionuclides for targeted endoradiotherapy is a rapidly growing field in oncology. In particular, the focus on the biological effects of different radiation qualities is an important factor in understanding and implementing new therapies. Together with the combined approach of imaging and therapy, therapeutic nuclear medicine has recently made great progress. A particular area of research is the use of alpha-emitting radionuclides, which have unique physical properties associated with outstanding advantages, e.g., for single tumor cell targeting. Here, recent results and open questions regarding the production of alpha-emitting isotopes as well as their chemical combination with carrier molecules and clinical experience from compassionate use reports and clinical trials are discussed.

Rapid and high recovery isolation of mRNA from in vitro transcription system by ammonium sulphate precipitation at room temperature

Messenger RNA (mRNA) technologies have shown great potential in prophylactic vaccines and therapeutic medicines. Rapidly and effectively separating mRNA from in vitro transcription (IVT) products is important to reduce the accumulation of byproducts and avoid degradation of the mRNA. In this study, the salting out of mRNA encoding enhanced green fluorescent protein (EGFP) by ammonium sulfate (AS) that was widely employed in protein precipitation was examined. Effects of precipitation conditions, including AS concentration, pH, temperature, and time, on the precipitation rate and re-dissolution yield of mRNA were first investigated by the design of experiments (DOE) method, using LiCl-purified mRNA. The optimal condition was determined to be 2 M AS, pH 7.0, 20 °C, and 2 h of precipitation time, under which almost 100 % precipitation rate and nearly 100 % dissolution rate could be reached. This optimal condition was then applied to separate mRNA from IVT and co-transcriptional capping system, overall recovery of about 80 % of mRNA was obtained; meanwhile, more than 80 % DNA template and 99.0 % residual NTP were removed. In co-transcriptional capping system, >90 % dsRNA was removed. The mRNA purified by AS precipitation was transfected into HEK293T cells to successfully express EGFP with efficiency of 45.65 % which was similar to that by LiCl-purified mRNA (43.85 %). Though the removal rate for T7 polymerase was low (about 30 %) due to protein-mRNA interaction induced co-precipitation in 2 M AS, our results demonstrated significant advantages of AS precipitation over conventional LiCl precipitation in terms of biosafety and energy cost. Thus, the AS precipitation provides a cost-effective method to rapidly separate, concentrate, and store the mRNA from the IVT system, as well as during subsequent downstream processes.

Identification of diagnostic molecules and potential traditional Chinese medicine components for Alzheimer's disease by single cell RNA sequencing combined with a systematic framework for network pharmacology.

Single-cell RNA sequencing (scRNA-Seq) provides new perspectives and ideas to investigate the interactions between different cell types and organisms. By integrating scRNA-seq with new computational frameworks or specific technologies, better Alzheimer's disease (AD) treatments may be developed. The single-cell sequencing dataset GSE158234 was obtained from the GEO database. Preprocessing, quality control, dimensionality-reducing clustering, and annotation to identify cell types were performed on it. RNA-seq profiling dataset GSE238013 was used to determine the components of specific cell subpopulations in diverse samples. A set of genes included in the OMIM, Genecards, CTD, and DisGeNET databases were selected as highly plausible AD-related genes. Then, ROC curves were created to predict the diagnostic value using the significantly expressed genes in the KO group as hub genes. The genes mentioned above were mapped to the Coremine Medical database to forecast prospective therapeutic Chinese medicines, and a "Chinese medicine-ingredient-target" network was constructed to screen for potential therapeutic targets. The last step was to undertake Mendelian randomization research to determine the causal link between the critical gene IL1B and AD in the genome-wide association study. Using the scRNA-seq dataset, five unique cell clusters were discovered. These clusters were further subdivided into four distinct cell types using marker genes. The KO group showed a more substantial differential subgroup of macrophages than the WT group. By using the available datasets and PPI network analysis, 54 common genes were discovered. Four clusters were identified using the MCODE approach, and correlation analysis showed that seven genes in those four clusters had a significantly negative correlation with macrophages. Six genes in four sets had a significantly positive correlation. Five genes had different levels of expression in the WT and KO groups. The String database was used to identify the regulatory relationships between the four genes (IL10, CX3CR1, IL1B, and IL6) that were finally selected as AD hub genes. Screening identified potential traditional Chinese medicine to intervene in the transformation process of AD, including Radix Salviae, ginseng, Ganoderma, licorice, Coptidis Rhizoma, and Scutellariae Radix, in addition to promising therapeutic targets, such as PTGS1, PTGS2, and RXRA. Finally, it was shown that IL1B directly correlated with immune cell infiltration in AD. In inverse variance weighting, we found that IL1B was associated with a higher risk of AD, with an OR of 1.003 (95% CI = 1.001-1.006, p = 0.038). Our research combined network pharmacology and the scRNA-seq computational framework to uncover pertinent hub genes and prospective traditional Chinese medicine potential therapeutic targets for AD. These discoveries may aid in understanding the molecular processes behind AD genes and the development of novel medications to treat the condition.

Pluronic F68 Micelles as Carriers for an Anti-Inflammatory Drug: A Rheological and Scattering Investigation.

Age-long ambition of medical scientists has always been advancement in healthcare and therapeutic medicine. Biomedical research indeed claims paramount importance in nanomedicine and drug delivery, and the development of biocompatible storage structures for delivering drugs stands at the heart of emerging scientific works. The delivery of drugs into the human body is nevertheless a nontrivial and challenging task, and it is often addressed by using amphiphilic compounds as nanosized delivery vehicles. Pluronics belong to a peculiar class of biocompatible and thermosensitive nonionic amphiphilic copolymers, and their self-assemblies are employed as drug delivery excipients because of their unique properties. We herein report on the encapsulation of diclofenac sodium within Pluronic F68 self-assemblies in water, underpinning the impact of the drug on the rheological and microstructural evolution of pluronic-based systems. The self-assembly and thermoresponsive micellization were studied through isothermal steady rheological experiments at different temperatures on samples containing 45 wt % Pluronic F68 and different amounts of diclofenac sodium. The adoption of scattering techniques, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), allowed for the description of the system features at the nanometer length scale, providing information about the characteristic size of each part of the micellar structures as a function of temperature and drug concentration. Diclofenac sodium is not a good fellow for Pluronic F68. The triblock copolymer aids the encapsulation of the drug, highly improving its water solubility, whereas diclofenac sodium somehow hinders Pluronic self-assembly. By using a simple empirical model and no fitting parameters, the steady viscosity can be predicted, although qualitatively, through the volume fraction of the micelles extracted through scattering techniques and compared to the rheological one. A tunable control of the viscous behavior of such biomedical systems may be achieved through the suitable choice of their composition.

Use of nano-enabled approaches to advance acupuncture therapy for disease management.

Acupuncture is an ancient form of therapy, which has long been part of traditional Chinese medicine (TCM); however, its use has spread globally, to the point where it is currently practiced worldwide. Although metal needles continue to be used most commonly, through multidisciplinary research, novel technologies, including nanotechnology, have allowed acupuncture to evolve to the point of achieving greater efficiency and more sophisticated functions in clinical practice. We summarized recent advancements in the literature using nano-enabled strategies to create novel needles that enhance and expand their therapeutic effects and found that nanotechnology may help provide new evidence to verify acupuncture theory, improve the features of acupuncture needles and their clinical effects by combining with drug delivery, and even enable new therapeutic methods when combined with acupuncture needles. The use of nano-technology with acupuncture delivery looks very promising for potential clinical applications. We also envisage that with nanotechnology, innovations in acupuncture needles could generate a multi-functional toolbox for use in both diagnostic and therapeutic medicine. Such new types of acupuncture needles could be used at acupoints and data collected to guide the planning of clinical trials may be more consistent with acupuncture theory and traditional clinical applications of this therapeutic modality.

Implications of siRNA Therapy in Bone Health: Silencing Communicates.

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its 'bench-to-bedside' usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures.

The Need to Integrate Fundamental Radiology in Undergraduate Medicine Curriculum

Dear Editor, 
 Since its advent in the early Twentieth Century, Radiology beholds capital significance in diagnostic and therapeutic medicine. Imaging techniques of the likes of X – Ray, CAT scan, MRI and the positron emission tomography (PET) have taken the world by storm over the past 20 years so much so that they have become indispensable in Medical Investigation. There is a growing school of thought with the view that basic radiological knowledge of X – Rays and Ultrasound should be imparted to medical students from the get-go.1
 As a matter of fact, until recently an overwhelming majority of Medical Institutions in Pakistan have been adherent to the orthodox Non - Modular system which was essentially based on the then transformative Flexner Report of July 1910 where Abraham Flexner vehemently advocated learning basic biomedical sciences prior to clinical sciences; thereby preferring less practical theoretical knowledge to that of empirical importance to the clinician.2 Unfortunately, that is not how patients are to be treated.3 Recently, all Medical Colleges under University of Health Sciences have adopted the Integrated Modular system4 which endorses the studying of basic and clinical subjects side by side. In addition to this much needed step, the concerned authorities are exhorted to look into the need to include fundamental radiological techniques in the under graduate Medical curriculum in order to properly integrate the modular system.

Antioxidant Activity and Cytotoxicity of Cyanthilium Cinereum and Cinnamon-in Vitro Study

Introduction: Cyanthillium cinereum is a native of tropical Africa and Asia (India, Indochina, Indonesia) and is used as a smoking cessation drug and relief for cold. Leaves act as an abortifacient and blood purifier and have diuretic, antiviral, analgesic, antipyretic, and anti-inflammatory properties. Cinnamon is the inner bark of cinnamon cassia found on the west coast of India, Sri Lanka, and Indonesia. It is a forest evergreen tree that has antioxidant, anti-inflammatory, anti-diabetic, and anti-microbial properties, treats bronchitis, diabetes and has traces of Vitamin B & K. Hence, we aimed to study the antioxidant activity and cytotoxicity in the herbal synergy of cinnamon and cyanthillium cinereum. Materials and Methods: An in vitro study was conducted, and the polar aqueous extract of this combination of herbs cinnamon \ and cyanthilium cinereum was prepared and tested for DPPH assay assay to study its antioxidant properties and the absorbance value was evaluated. Brine Shrimp Assay with viable nauplii cell lines was used for cytotoxicity assessment. Results: Antioxidant activity of the aqueous extract of Cyanthillium cinereum and Cinnamon revealed that there was a decrease in the antioxidant activity with an increase in the concentration of the aqueous extract. Cytotoxicity of the aqueous extract of Cyanthillium cinereum and Cinnamon reported an increase in the cytotoxic activity with a rise in the concentration of the aqueous extract. Conclusion: This research showed that aqueous extract of cinnamon and cyanthillium cinereum has good antioxidant activity, is less cytotoxic, and can be used as a therapeutic and preventive medicine.

연령대별 복합요인과 신체활동량의 변화가 만성질환의 수준과 의료비에 미치는 영향

Objective : The purpose of this study was to confirm the relationship between the disease degree and the lifestyle in the cases.
 Methods : Using Korean Health Panel Survey Data ver. 1.71 to determine the risk of chronic disease by age group, the complex factors, longitudinal study analysis was conducted for the data was extracted from the participants who participated in the 4 years questionnaire(n=7,184). Results : First, Age(50-64) and Age(over 65) group PA decreased from simple chronic disease to complex chronic disease compared to the normal group. Age(over 65) showed PA decrease in the group above the average medical expenditure. Second, compared to the normal group, the Sit time of the elderly increased from simple chronic disease to complex chronic disease. Third, in complex factor the risk increased of Hypertension and Diabetes odds in the high-risk group compared to the low-risk group, and the risk of Cerebrovascular Disease odds in the high sit grop compared to the low-risk group. Cardiovascular risk increased in all groups compared to low-risk group. Conclusion : Along with data-based therapeutic medicine, a preventive medicine-level approach is needed.

Development and Characterization of Polyherbal Anti-acne face gel using Liquorice and Palash extract

Anti-acne herbal formulations are used to treat acne vulgaris and also have the added benefit of not having any side effects, unlike synthetic medications. Acne is a bacterial-induced inflammatory skin disease caused by blockages in the pilosebaceous and inflammation. Antibiotics, both topical and systemic, are always used to treat acne, however antibiotic resistance can impair the success rate of acne treatment. The creation of effective therapeutic medicines relies heavily on medicinal plants. So, natural medicines are more acceptable because they are believed to be safer and have fewer adverse effects than manufactured ones. In the global market, herbal formulations are in high demand. The goal of this study is to produce and characterise herbal anti-acne face gel that contains neem (Azdirachta indica) extract, liquorice root (Glycyrrhiza glabra) extract, orange peel (Citrus aurantium var. sinensis) extract, and palash (Butea monosperma) flower extract. Although there are a variety of topical herbal formulations for acne on the market, we recommend creating a polyherbal formulation using a variety of herbal and synthetic ingredients. The plant has been found to have antimicrobial and anti-inflammatory properties in the literature. The prepared extract was screened to identify the presence or absence of various active principles like phenolic compounds, carbohydrates, flavanoids, glycosides, saponins, alkaloids, protein and amino acid. Polymers in various proportions were used to create several formulations ranging from F1 to F8. Colour, appearance, consistency, washability, pH, and spreadability and stability of prepared formulations (F1 to F8) were all examined.

“Healing is having faith in Allah, the healer, and the medicine": An exploratory qualitative study of Islamic-based healing practices in Northern Ghana

Faith-based healing practices are becoming widespread in Ghana. Charismatic churches, traditional healers, and Islamic faith healers provide healthcare services for multitudes nationwide. However, Islamic faith-based healers' medical perspectives and healing practices are less known. This descriptive exploratory qualitative study explores Islamic-based healing practices among the Dagomba and how Dagbon culture influences Islamic-based healing. Data were collected from six Islamic-based healers through participant observations and in-depth individual interviews using a semi-structured interview guide. Thematic analysis was employed, and results are reported narratively. The study discovered that Islamic-based healing is important in Dagbon, with healers providing healing services for diverse illnesses. Practitioners of Islamic-based healing among the Dagomba observe that having faith in Allah and trust in His healing powers is the foundation of health. Islamic principles of faith and the Dagomba worldviews of health and illness affect these healers’ medical knowledge and healing practices. The study found that rituals and sacrifices are significant healing practices with unique gendered perspectives. Spirituality is perceived as both an illness-causal factor and a healing tool. We invite further research to identify the prospects, constraints, and therapeutic possibilities Islamic medicine and healing hold for Ghana’s integrative medical system_._

Fibromyalgia Animal Models Using Intermittent Cold and Psychological Stress.

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR1) knock-out mice or by LPAR1 antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR1 antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer's disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome.

Pyruvate Dehydrogenase Complex in Neonatal Hypoxic-Ischemic Brain Injury.

The disruption of cerebral energy metabolism in relation to brain damage has been the subject of extensive research. However, the pyruvate dehydrogenase complex (PDHC), which is primarily characterized by poor cerebral energy metabolism following brain trauma, has received relatively little study in comparison to newborn hypoxic-ischemic brain injury. Mitochondrial PDHC, a multienzyme complex that functions as a crucial hub in energy metabolism and acts as a central metabolic node to mediate pyruvate oxidation after glycolysis and fuel the Krebs cycle to meet energy demands, has been reported to be one cause of energy metabolism dysfunction according to recent studies. Here we assess the potential mechanisms of neonatal hypoxic-ischemic brain injury-related brain dysfunction mediated by PDHC and further discuss the neuroprotective effects of therapeutic medicines that target PDHC activation. We also provide a summary of recent research on medicines that target PDHC in neonates with hypoxic-ischemic brain damage. Through an understanding of the mechanisms by which it is modulated and an investigation of the neuroprotective techniques available to activate brain PDHC and improve neonatal hypoxic-ischemic impairment, our review emphasizes the significance of PDHC impairment in neonatal hypoxic-ischemic brain injury.

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives.

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.

Pharmacological Activities of Dioscorea spp.: A Narrative Review

Pharmacological research has become essential for the development of nature-based drugs to support the claimed therapeutic properties of medicinal plants. Dioscorea species are medicinal plants found to have an impressive pharmacological profile. This review aims to compile the pharmacological properties of three Dioscorea species, D. hispida, D. alata and D. bulbifera and their derived compounds through scientific findings, mainly focusing on the biological activities. Relevant clinical and preclinical studies on the pharmacological properties of these plants were identified, screened, and analysed. A systematic search using predetermined keywords on electronic databases (Scopus, Springer and ScienceDirect) was conducted. This review found these Dioscorea species to possess various pharmacological activities such as anti-inflammatory, antimicrobial, anticancer, antioxidant, anti-diabetic, antihypertensive and estrogenic effects. The plant tubers contain active compounds such as diosgenin that is responsible for anti-inflammatory and anti-diabetic activities in D. alata and D. bulbifera, respectively. Other compounds like dioscorine, phenolic, flavonoid and terpenoid elucidated from the yam tubers were found to be antimicrobial and showed prominent free radical scavenging effects. The plants demonstrated various pharmacological activities although data on their mechanisms of action is very limited. Therefore, further research is needed to explore the full potential of these plants as future therapeutic medicines.

Alzheimer’s disease genetics and real‐world patient data fuel target and drug discovery in European and African American ancestries

AbstractBackgroundTranslation of massive genetic and genomic data into Alzheimer’s target and drug discovery has not materialized. One challenge in this process is ethnicity‐based differences in the field of Alzheimer’s disease (AD). For example, African Americans (AAs) and European Americans (EAs) differ in AD prevalence, risk factors, and symptomatic presentation, and AAs have historically been less frequently enrolled in AD clinical trials.MethodWe conducted ancestry genetic‐specific target and drug discovery by gathering large genetic data from a diverse population with real‐world patient data to boost the likelihood of identifying disease‐modifying drug targets and treatments for AD. We analyzed genetic data from 275,540 AD cases and 1.55 million controls across 7 AD genome‐wide association studies (GWAS) datasets for both EA and AA ancestries, using Mendelian randomization. We utilized the genetic instruments from 9 expression quantitative trait loci (eQTL) and 3 protein quantitative trait loci (pQTL) datasets from three large human brain biobanks: a) Mount Sinai Brain Bank (MSBB), b) Mayo clinic (Mayo), and c) Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP) (ROS/MAP).ResultWe identified 25 drug targets in EAs and 6 new drug targets in AAs among 1,176 investigated druggable targets. Notably, the inflammatory target of epoxide hydrolase 2 (EPHX2) emerged as a potent AD target in EAs, and treatment of transgenic TgF344‐AD rats with an EPHX2 inhibitor was therapeutic. Among 6 AA‐specific targets, we identified that TRPV3 is a potent drug target for AA individuals with AD, and further replicated our finding in AA‐specific eQTL data. We additionally identified 23 candidate drugs associated with reduced risk of AD in mild cognitive impairment (MCI) patients after analysis of ∼80 million electronic health records. Using a propensity score‐matched design, we identified that usage of either apixaban (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.69 – 0.80) or amlodipine (HR = 0.91, 95% CI 0.88 – 0.94) were both significantly associated with reduced progression to AD in people with MCI.ConclusionCombining genetics and real‐world patient data has identified ancestry‐specific therapeutic targets and medicines for AD.

HPR65 Pricing and Reimbursement Mechanisms for Advanced Therapeutic Medicinal Products in 20 Countries

HPR65 Pricing and Reimbursement Mechanisms for Advanced Therapeutic Medicinal Products in 20 Countries

Bioinformatics-Based Analysis and Verification of Chromatin Regulators and the Mechanism of Immune Infiltration Associated with Myocardial Infarction.

Recent studies have shown that dysfunction in chromatin regulators (CRs) may be an important mechanism of myocardial infarction (MI). They are thus expected to become a new target in the diagnosis and treatment of MI. However, the diagnostic value of CRs in MI and the mechanisms are not clear. CRs-related differentially expressed genes (DEGs) were screened between healthy controls and patients with MI via GSE48060, GSE60993, and GSE66360 datasets. DEGs were further analyzed for enrichment analysis. Hub genes were screened by least absolute shrinkage and selection operator (LASSO) regression and weighted gene co-expression network analysis (WGCNA). GSE61144 datasets were further used to validate hub genes. RT-qPCR examined peripheral blood mononuclear cells (PBMCs) to verify expressions of hub genes. In addition, a correlation between hub genes and immune cell infiltration was identified by CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Finally, we constructed a diagnostic nomogram and ceRNA network and found possible therapeutic medicines which were based on hub genes. Firstly, 16 CR-related DEGs were identified. Next, Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and transcriptional regulator Jun dimerization protein 2 (JDP2) were selected as hub genes by LASSO and WGCNA. Receiver operating characteristic curves in the training and test data sets verified the reliability of hub genes. Results of RT-qPCR confirmed the upregulation of hub genes in MI. Subsequently, the immune infiltration analysis indicated that DUSP1, GADD45A, and JDP2 were correlated with plasmacytoid dendritic cells, natural killer cells, eosinophils, effector memory CD4 T cells, central memory CD4 T cells, activated dendritic cells, and activated CD8 T cells. Furthermore, a nomogram that included DUSP1, GADD45A, and JDP2 was created. The calibration curve, decision curve analysis, and the clinical impact curve indicated that the nomogram could predict the occurrence of MI with high efficacy. The results of the ceRNA network suggest that hub genes may be cross-regulated by various lncRNAs and miRNAs. In addition, 10 drugs, including 2H-1-benzopyran, Nifuroxazide, and Bepridil, were predicted to be potential therapeutic agents for MI. Our study identifies three promising genes associated with the progression of chromatin regulators (CRs)-related myocardial infarction (MI) and immune cell infiltration, including Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and Jun dimerization protein 2 (JDP2), which might be worthy of further study.