Ammodaucus Leucotrichus Seed Extract as a Potential Therapy in Animal Models of Rheumatoid Arthritis Induced by Complete Freund Adjuvant and Chicken Cartilage Collagen.

This study assessed the efficacy of an Ammodaucus leucotrichus seed extract to treat rheumatoid arthritis in rat models of this disease. Rheumatoid arthritis was induced in rats using two methods: immunization with 100 µL of Complete Freund Adjuvant (CFA) and immunization with 100 µL of a 3 mg/ml solution of type II collagen (CII) from chicken cartilage. The therapeutic potential of the extract was assessed at different doses (150, 300, and 600 mg/kg/day for 21 days in the CII-induced arthritis model and for 14 days in the CFA-induced arthritis model) and compared with methotrexate (MTX; 0.2 mg/kg for the same periods), a commonly used drug for rheumatoid arthritis treatment in humans. In both models (CII-induced arthritis and CFA-induced arthritis), walking distance, step length, intra-step distance and footprint area were improved following treatment with the A. leucotrichus seed extract (all concentrations) and MTX compared with untreated animals. Both treatments increased the serum concentration of glutathione and reduced that of complement C3, malondialdehyde and myeloperoxidase. Radiographic data and histological analysis indicated that cartilage destruction was reduced already with the lowest dose of the extract (100 mg/kg/dose) in both models. These results show the substantial antiarthritic potential of the A. leucotrichus seed extract, even at the lowest dose, suggesting that it may be a promising alternative therapy for rheumatoid arthritis and joint inflammation. They also emphasize its efficacy at various doses, providing impetus for more research on this extract as a potential therapeutic agent for arthritis.

Insights into the Biological Activities and Substituent Effects of Pyrrole Derivatives: The Chemistry-Biology Connection.

Pyrrole, with its versatile heterocyclic ring structure, serves as a valuable template for generating a diverse range of lead compounds with various pharmacophores. Researchers and scientists globally are intrigued by pyrrole and its analogues for their broad pharmacological potential, prompting thorough investigations aimed at advancing human welfare. This comprehensive review delves into the diverse activities exhibited by pyrrole compounds, encompassing their synthesis, reactions, and pharmacological properties alongside their derivatives. In addition to detailing the characteristics of pyrrole and its derivatives within the context of green chemistry, the review also examines microwave-assisted reactions. It provides insights into their chemical structures, natural occurrences, and potential applications across various domains. Furthermore, the article investigates structural alterations of pyrrole compounds and their implications on their functionality, highlighting their versatility as foundational elements for both functional materials and bioactive compounds. Ultimately, the review underscores the imperative for continued research and development in the realm of pyrrole compounds to unearth novel activities and advantages.

Bioprinting in cardiovascular medicine: Possibilities, challenges, and future perspectives for low and middle-income countries.

Cardiovascular diseases (CVD) stemming from various factors significantly impact the quality of life (QoL) and are prevalent with high mortality rates in both developed and developing countries. In cases where pharmacotherapy proves insufficient and end-stage disease ensues, a heart transplant/surgical repair becomes the only feasible treatment option. However, challenges such as a limited supply of heart donors, complications associated with rejection, and issues related to medication compliance introduce an additional burden to healthcare services and adversely affect patient outcomes. The emergence of bioprinting has facilitated advancements in creating structures, including ventricles, valves, and blood vessels. Notably, the development of myocardial/cardiac patches through bioprinting has offered a promising avenue for revascularizing, strengthening, and regenerating ventricles. Employment loss in developing countries as a circumstance of disability or death can severely impact a family's well-being and means for sustainable living. Innovations by means of life sustaining treatment options can provide hope for the impoverished and help reduce disability burden on the economy of low- to middle-income countries (LMICs). Such developments can have a significant impact that can last for generations, especially in developing countries. In this review, the authors delve into various types of bioprinting techniques, exploring their possibilities, challenges, and potential future applications in treating various end-stage cardiovascular conditions in LMICs.

Flavonoids and Alzheimer's disease: reviewing the evidence for neuroprotective potential.

Neurodegeneration, which manifests as several chronic and incurable diseases, is an age-related condition that affects the central nervous system (CNS) and poses a significant threat to the public's health for the elderly. Recent decades have experienced an alarming increase in the incidence of neurodegenerative disorders (NDDs), a severe public health issue due to the ongoing development of people living in modern civilizations. Alzheimer's disease (AD) is a leading trigger of age-related dementia. Currently, there are no efficient therapeutics to delay, stop, or reverse the disease's course development. Several studies found that dietary bioactive phytochemicals, primarily flavonoids, influence the pathophysiological processes underlying AD. Flavonoids work well as a supplement to manufactured therapies for NDDs. Flavonoids are effective in complementing synthetic approaches to treat NDDs. They are biologically active phytochemicals with promising pharmacological activities, for instance, antiviral, anti-allergic, antiplatelet, anti-inflammatory, antitumor, anti-apoptotic, and antioxidant effects. The production of nitric oxide (NO), tumor necrosis factor (TNF-α), and oxidative stress (OS) are downregulated by flavonoids, which slow the course of AD. Hence, this research turned from preclinical evidence to feasible clinical applications to develop newer therapeutics, focusing on the therapeutic potential of flavonoids against AD.

Human olfactory neurosphere-derived cells: A unified tool for neurological disease modelling and neurotherapeutic applications.

As one of the leading causes of global mortality and morbidity, various neurological diseases cause social and economic burdens. Despite significant advances in the treatment of neurological diseases, establishing a proper disease model, especially for degenerative and infectious diseases, remains a major challenging issue. For long, mice were the model of choice but suffered from serious drawbacks of differences in anatomical and functional aspects of the nervous system. Furthermore, the collection of post-mortem brain tissues limits their usage in cultured cell lines. Overcoming such limitations has prompted the usage of stem cells derived from the peripheral nervous system, such as the cells of the olfactory mucosa as a preferred choice. These cells can be easily cultured in vitro and retain the receptors of neuronal cells life-long. Such cells have various advantages over embryonic or induced stem cells, including homology, and ease of culture and can be conveniently obtained from diseased individuals through either biopsies or exfoliation. They have continuously helped in understanding the genetic and developmental mechanisms of degenerative diseases like Alzheimer's and Parkinson's disease. Moreover, the mode of infection of various viruses that can lead to post-viral olfactory dysfunction, such as the Zika virus can be monitored through these cells in vitro and their therapeutic development can be fastened.

Prevalence and knowledge of polycystic ovary syndrome (PCOS) and health-related practices among women of Syria: a cross-sectional study.

Polycystic Ovarian Syndrome (PCOS) is a prevalent metabolic and hormonal disorder affecting women of reproductive age. Limited data exists on Syrian women's PCOS awareness and health behaviors. This study aimed to gauge PCOS prevalence, knowledge, awareness, and health-related practices among Syrian women. A cross-sectional online survey was conducted from 11 February to 27 October 2022, targeting Syrian women aged 18-45. Collaborators from specific medical universities distributed a questionnaire adapted from a Malaysian paper through social media platforms. Out of 1840 surveyed Syrian women, 64.2% were aged 21-29, and 69.6% held bachelor's degrees. Those with a bachelor's degree exhibited the highest mean knowledge score (12.86), and women previously diagnosed with PCOS had a higher mean knowledge score (13.74) than those without. Approximately 27.4% were confirmed PCOS cases, and 38.9% had possible cases. Women with PCOS were 3.41 times more likely to possess knowledge about the condition. The findings suggest a moderate level of PCOS knowledge and health-related practices among Syrian women, emphasizing the need for increased awareness. Consistent local PCOS screening programs, in collaboration with obstetrics and gynecology professionals, are crucial for improving understanding and clinical symptom recognition of this condition among Syrian women.

Correction: Chakraborty et al. Bromelain a Potential Bioactive Compound: A Comprehensive Overview from a Pharmacological Perspective. Life 2021, 11, 317.

The authors were not aware of errors made in one small subsection (Section 6.17. Antidiarrheal Effect, including the data in the table of effects) of this paper [...].

Hepatoprotective and cardioprotective effect of Artemisia nilagirica leaf extract on E. coli challenged broiler chicken.

Artemisia nilagirica is an important medicinal plant found to exhibit several medicinal properties but the use of its leaves for combating E. coli infection has not been scientifically validated in poultry. The present study was conducted to evaluate the protective effects of methanol leaf extract of A. nilagirica (ANE) on E. coli challenged broiler chickens. Three hundred and thirty, day-old broiler chickens, were divided into 6 groups of 55 each, with group EX infected intraperitoneally (I/P) with LD50 dose of 1 × 107 cfu/ml of E. coli; group(s) EA1, EA2 and EA3 infected I/P with 1 × 107 cfu/ml of E. coli and supplemented with ANE @ 0.5, 1.0 and 2.0 g/L of drinking water, respectively; group AX were only given ANE @ 2.0 g/L in the drinking water. ANE treatment was started from day 4 and was continuously given in the drinking water up to day 21. E. coli infection was given to the birds on day 7 of their age. The effect of the plant extract was evaluated on the basis of gross, microscopic and ultrastructural alterations in E. coli challenged broiler chickens. The extract of A. nilagirica was found to show antibacterial, cardioprotective and hepatoprotective properties in a dose-dependent manner on the basis of gross and microscopic examination. The methanol extract of A. nilagirica leaves revealed no toxic effect on the hepatocytes on ultrastructural evaluation. This study demonstrates the antimicrobial, hepatoprotective and cardioprotective activities of ANE in broiler chickens infected with E. coli organism.

Genus Amorphophallus: A Comprehensive Overview on Phytochemistry, Ethnomedicinal Uses, and Pharmacological Activities.

The genus Amorphophallus belongs to the family Araceae. Plants belonging to this genus are available worldwide and have been used in traditional medicines since ancient times, mainly in Ayurveda and Unani medical practices. Amorphophallus species are an abundant source of polyphenolic compounds; these are accountable for their pharmacological properties, such as their analgesic, neuroprotective, hepatoprotective, anti-inflammatory, anticonvulsant, antibacterial, antioxidant, anticancer, antiobesity, and immunomodulatory effects, as well as their ability to prevent gastrointestinal disturbance and reduce blood glucose. Moreover, Amorphophallus species contain numerous other classes of chemical compounds, such as alkaloids, steroids, fats and fixed oils, tannins, proteins, and carbohydrates, each of which contributes to the pharmacological effects for the treatment of acute rheumatism, tumors, lung swelling, asthma, vomiting, abdominal pain, and so on. Additionally, Amorphophallus species have been employed in numerous herbal formulations and pharmaceutical applications. There has been no extensive review conducted on the Amorphophallus genus as of yet, despite the fact that several experimental studies are being published regularly discussing these plants' pharmacological properties. So, this review discusses in detail the pharmacological properties of Amorphophallus species. We also discuss phytochemical constituents in the Amorphophallus species and their ethnomedicinal uses and toxicological profiles.

Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study.

Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

A computational simulation appraisal of banana lectin as a potential anti-SARS-CoV-2 candidate by targeting the receptor-binding domain.

BACKGROUND: The ongoing concern surrounding coronavirus disease 2019 (COVID-19) primarily stems from continuous mutations in the genome of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to the emergence of numerous variants. The receptor-binding domain (RBD) in the S1 subunit of the S protein of the virus plays a crucial role in recognizing the host's angiotensin-converting enzyme 2 (hACE2) receptor and facilitating cell membrane fusion processes, making it a potential target for preventing viral entrance into cells. This research aimed to determine the potential of banana lectin (BanLec) proteins to inhibit SARS-CoV-2 attachment to host cells by interacting with RBD through computational modeling. MATERIALS AND METHODS: The BanLecs were selected through a sequence analysis process. Subsequently, the genes encoding BanLec proteins were retrieved from the Banana Genome Hub database. The FGENESH online tool was then employed to predict protein sequences, while web-based tools were utilized to assess the physicochemical properties, allergenicity, and toxicity of BanLecs. The RBDs of SARS-CoV-2 were modeled using the SWISS-MODEL in the following step. Molecular docking procedures were conducted with the aid of ClusPro 2.0 and HDOCK web servers. The three-dimensional structures of the docked complexes were visualized using PyMOL. Finally, molecular dynamics simulations were performed to investigate and validate the interactions of the complexes exhibiting the highest interactions, facilitating the simulation of their dynamic properties. RESULTS: The BanLec proteins were successfully modeled based on the RNA sequences from two species of banana (Musa sp.). Moreover, an amino acid modification in the BanLec protein was made to reduce its mitogenicity. Theoretical allergenicity and toxicity predictions were conducted on the BanLecs, which suggested they were likely non-allergenic and contained no discernible toxic domains. Molecular docking analysis demonstrated that both altered and wild-type BanLecs exhibited strong affinity with the RBD of different SARS-CoV-2 variants. Further analysis of the molecular docking results showed that the BanLec proteins interacted with the active site of RBD, particularly the key amino acids residues responsible for RBD's binding to hACE2. Molecular dynamics simulation indicated a stable interaction between the Omicron RBD and BanLec, maintaining a root-mean-square deviation (RMSD) of approximately 0.2 nm for a duration of up to 100 ns. The individual proteins also had stable structural conformations, and the complex demonstrated a favorable binding-free energy (BFE) value. CONCLUSIONS: These results confirm that the BanLec protein is a promising candidate for developing a potential therapeutic agent for combating COVID-19. Furthermore, the results suggest the possibility of BanLec as a broad-spectrum antiviral agent and highlight the need for further studies to examine the protein's safety and effectiveness as a potent antiviral agent.

Effect of Smartphone Use on Sleep in Undergraduate Medical Students: A Cross-Sectional Study.

Smartphone use, particularly at night, has been shown to provoke various circadian sleep-wake rhythm disorders such as insomnia and excessive daytime tiredness. This relationship has been mainly scrutinized among patient groups with higher rates of smartphone usage, particularly adolescents and children. However, it remains obscure how smartphone usage impacts sleep parameters in adults, especially undergraduate college students. This study sought to (1) investigate the association between smartphone use (actual screen time) and four sleep parameters: Pittsburgh sleep quality score (PSQI), self-reported screen time, bedtime, and rise time; (2) compare the seven PSQI components between good and poor sleep quality subjects. In total, 264 undergraduate medical students (aged 17 to 25 years) were recruited from the Government Doon Medical College, Dehradun, India. All participants completed a sleep questionnaire, which was electronically shared via a WhatsApp invitation link. Hierarchical and multinomial regression analyses were performed in relation to (1) and (2). The average PSQI score was 5.03 ± 0.86, with approximately one in two respondents (48.3%) having a poor sleep index. Smartphone use significantly predicted respondents' PSQI score (ß = 0.142, p = 0.040, R2 = 0.027), perceived screen time (ß = 0.113, p = 0.043, R2 = 343), bedtime (ß = 0.106, p = 0.042, R2 = 045), and rise time (ß = 0.174, p = 0.015, R2 = 0.028). When comparing poor-quality sleep (PSQI ≥ 5) to good-quality sleep (PSQI < 5), with good-quality sleep as the reference, except sleep efficiency and sleep medications (p > 0.05), five PSQI components declined significantly: subjective sleep quality (ß = -0.096, p < 0.001); sleep latency (ß = -0.034, p < 0.001); sleep duration (ß = -0.038, p < 0.001); sleep disturbances (ß = 1.234, p < 0.001); and sleep dysfunction (ß = -0.077, p < 0.001). Consequently, public health policymakers should take this evidence into account when developing guidelines around smartphone use-i.e., the when, where, and how much smartphone use-to promote improved sleep behaviour and reduce the rate of sleep-wake rhythm disorders.

Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.

Neuropharmacological potential of honokiol and its derivatives from Chinese herb Magnolia species: understandings from therapeutic viewpoint.

Honokiol is a neolignan biphenol found in aerial parts of the Magnolia plant species. The Magnolia plant species traditionally belong to China and have been used for centuries to treat many pathological conditions. Honokiol mitigates the severity of several pathological conditions and has the potential to work as an anti-inflammatory, anti-angiogenic, anticancer, antioxidant, and neurotherapeutic agent. It has a long history of being employed in the healthcare practices of Southeast Asia, but in recent years, a greater scope of research has been conducted on it. Plenty of experimental evidence suggests it could be beneficial as a neuroprotective bioactive molecule. Honokiol has several pharmacological effects, leading to its exploration as a potential therapy for neurological diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety, depression, spinal cord injury, and so on. So, based on the previous experimentation reports, our goal is to discuss the neuroprotective properties of honokiol. Besides, honokiol derivatives have been highlighted recently as possible therapeutic options for NDs. So, this review focuses on honokiol's neurotherapeutic actions and toxicological profile to determine their safety and potential use in neurotherapeutics.

Research Progress of Indole Alkaloids: Targeting MAP Kinase Signaling Pathways in Cancer Treatment.

Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted.

Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment.

Cognitive impairment is anotable complication of type 2 diabetes (T2DM), accompanied by reduced brain-derived neurotrophic factor (BDNF) in the brain and blood. Anti-diabetic drugs reduce hyperglycemia, yet their effect on cognitive improvement is unknown. We aimed to investigate the effect of anti-diabetic drugs regulating BDNF in T2DM through computational and case-control study design. We obtained T2DMproteins viatext-mining to construct a T2DMprotein network. From the T2DMnetwork, the metformin and glimepiride interactomes and their crucial shortest-path-stimulating BDNF were identified. Using qRTPCR, the genes encoding the shortest-path proteins were assessed in four groups (untreated-T2DM, metformin-treated, glimepiride-treated, and healthy controls). Finally, ELISA was used to assess serum BDNF levels to validate drug efficacy. As a result of this investigation, aT2DMnetwork was constructed with 3683 text-mined proteins. Then, the T2DMnetwork was explored to generate a metformin and glimepiride interactome that establishes the critical shortest-path for BDNF stimulation. Metformin stimulates BDNF via APP binding to the PRKAB1 receptor. Whereas, glimepiride increases BDNF by binding to KCNJ11 via AP2M1 and ESR1 proteins. Both drug shortest-path encoding genes differed significantly between the groups. Unlike metformin, BDNF gene and protein expression rise significantly with glimepiride. Overall, glimepiride can effectively increase BDNF, which could benefit T2DM patients with cognitive deterioration.

Elucidating the Histone Deacetylase Gene Expression Signatures in Peripheral Blood Mononuclear Cells That Correlate Essential Cardiac Function and Aid in Classifying Coronary Artery Disease through a Logistic Regression Model.

A proinflammatory role of HDACs has been implicated in the pathogenesis of atherosclerosis as an emerging novel epigenetic diagnostic biomarker. However, its association with the clinical and cardiovascular function in coronary artery disease is largely unknown. The study aimed to profile the gene expression of HDAC1-11 in human peripheral blood mononuclear cells and to evaluate their influence on hematological, biochemical, and two-dimensional echocardiographic indices in CAD. The HDAC gene expression profiles were assessed in 62 angioproven CAD patients and compared with 62 healthy controls. Among the HDACs, upregulated HDACs 1,2, 4, 6, 8, 9, and 11 were upregulated, and HDAC3 was downregulated, which was significantly (p ≤ 0.05) linked with the hematological (basophils, lymphocytes, monocytes, and neutrophils), biochemical (LDL, HDL, and TGL), and echocardiographic parameters (cardiac function: biplane LVEF, GLS, MV E/A, IVRT, and PV S/D) in CAD. Furthermore, our constructed diagnostic model with the crucial HDACs establishes the most crucial HDACs in the classification of CAD from control with an excellent accuracy of 88.6%. Conclusively, our study has provided a novel perspective on the HDAC gene expression underlying cardiac function that is useful in developing molecular methods for CAD diagnosis.

Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.

Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.