Hasil untuk "Therapeutics. Pharmacology"

Bing Bai, Wenming Bao, Ling Wang et al.

Marcos Roberto de Oliveira, Marcos Roberto de Oliveira, Marcos Roberto de Oliveira et al.

Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich’s ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type–specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.

W. Pardridge

Xu H, Xu Y, Wang X et al.

Haowen Xu,1,* Yifan Xu,2,* Xueyi Wang,3 Zhisheng Yan,4 Ting Geng,5 Jinpeng Wu,2 Yongxin Li,1 Mingjin Guo1 1Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 3Department of Vascular Surgery, Rongcheng City People’s Hospital, Rongcheng, 264300, People’s Republic of China; 4Department of Interventional Medicine, The Eighth People’s Hospital of Qingdao, Qingdao, 266000, People’s Republic of China; 5Interventional Operating Room, The Eighth People’s Hospital of Qingdao, Qingdao, 266000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingjin Guo, Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, 16 Jiang Su Road, Qingdao, 266000, People’s Republic of China, Email qduahvasc@163.com Yongxin Li, Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, 16 Jiang Su Road, Qingdao, 266000, People’s Republic of China, Email Li.yongxin@outlook.comPurpose: Atherosclerosis (AS) and calcific aortic valve disease (CAVD) are common in aging populations and share metabolic dysregulation, chronic inflammation, and cellular aging. Shared immunometabolic biomarkers and therapeutic targets remain insufficiently defined. This study aimed to identify Cross-disease biomarkers linking AS and CAVD and to explore their translational potential.Methods: Four Gene Expression Omnibus (GEO) microarray datasets related to AS and CAVD were integrated. Differentially expressed genes (DEGs) were identified within each disease, and Cross-disease genes (CGs) were obtained by intersecting DEGs across the two diseases. Functional enrichment and protein–protein interaction analyses were performed. Machine learning (LASSO and Random Forest) refined candidate biomarkers. Immune infiltration was estimated with CIBERSORT, and a microRNA–transcription factor regulatory network was constructed. Molecular docking screened small molecules targeting the hub gene. Diagnostic performance was evaluated in independent datasets, and expression was validated in human tissues by qPCR and Western blot.Results: We identified 147 CGs enriched in immune and metabolic pathways. Fructose-1,6-bisphosphatase 1 (FBP1) emerged as a hub gene with strong diagnostic value across datasets. FBP1 expression correlated with alterations in multiple immune cell populations and was embedded within a regulatory network of predicted microRNAs and transcription factors. Docking analysis highlighted apigenin and kaempferol as candidate FBP1-targeting compounds. Experimental validation confirmed FBP1 upregulation in AS and CAVD tissues.Discussion: FBP1 represents a shared immunometabolic biomarker and potential therapeutic target that links metabolic reprogramming to immune dysregulation in AS and CAVD. These findings provide a rationale for further translational studies evaluating FBP1-centered interventions.Keywords: atherosclerosis, calcific aortic valve disease, machine learning, immunology, molecular docking

Clarissa A. Seidler, Vera A. Spanke, Jakob Gamper et al.

The Observed Antibody Space provides the most abundant collection of annotated paired antibody variable domain sequences, thus offering a unique platform for the systematic investigation of the factors governing the pairing of antibody heavy and light chains. By examining a range of characteristics, including amino acid conservation, structural features, charge distribution, and interface residue identity, we challenge the prevailing assumption that pairing is random. Our findings indicate that specific physicochemical properties of single amino acid residues may influence the compatibility and affinity of heavy and light chain combinations. Further structural analyses based on antibody Fv fragments deposited in the Protein Data Bank (PDB) provide insights into the underlying structural features driving these pairing preferences, including a novel definition for the residues constituting the VH-VL interface, based on a collection of over 3500 structures. These results have significant implications for understanding antibody assembly and may guide the rational design of therapeutic antibodies with desired properties. Moreover, we provide a complete description and reference characterizing the various human germlines.

Saurav Suresh, Shreeshail Anjutagi, S. Shyam

Eosinophilic lung diseases are defined by a prominent infiltration of the lung parenchyma by eosinophils, which respond dramatically to corticosteroid treatment and generally heal without significant sequelae when treated, out of this, idiopathic chronic eosinophilic pneumonia is characterized by a progressive onset of symptoms over a few weeks or months with cough and increasing dyspnea, malaise, and weight loss. A 42-year-old male, nonsmoker with no known comorbidities, presented with symptoms of breathlessness and cough with expectoration, along with a lack of appetite. The patient had a history of allergic rhinitis and pulmonary tuberculosis, high-resolution computed tomography showed peripheral nodules in upper lobes and a bilateral mosaic pattern of attenuation, complete blood count (CBC) showed 80% eosinophils and an AEC of 26870 BAL analysis showed elevated eosinophils Sputum and BAL analysis did not show the presence of Mycobacterium tuberculosis and hence the patient was diagnosed with idiopathic chronic eosinophilic. Eosinophilic pneumonia and was treated with methylprednisolone 20 mg IV, symptoms resolved completely within 72 h after initiation of steroids, and repeat CBC showed 0.2% eosinophils.

Fang Ren, Jing Wei, Qingxin Chen et al.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.

Ranjith Kumar R, Suresh Janadri, Manjunatha PM et al.

Background: Urolithiasis refers to the formation of stones in the urinary system. β-Caryophyllene, a bicyclic sesquiterpene found in herbs like cloves (Dīng Zǐ Xiāng), cinnamon (Ròu Guì), Black Pepper (Hú Jiāo) and Ginseng (Rén Shēn). Despite its potential, the antiurolithiatic activity of β-Caryophyllene, particularly in liposomal formulations, remains unexplored. This study aimed to evaluate the antiurolithiatic effects of liposomal β-Caryophyllene in ethylene glycol-induced urolithiasis in Wistar albino rats and elucidate its underlying mechanisms. Materials & methods: IN-VITRO: Using various in-vitro methods like aggregation, nucleation and titrimetric assay the percentage inhibition of calcium oxalate using the calcium chloride (Caox) and sodium oxalate solutions against the liposomal β-carryophyllene was performed for assessing anti-urolithiatic effect.IN-VIVO: Ethylene glycol was used as the inducing agent. Albino rats were separated into 6 groups. Group-I named as normal diet. Group II-VI was given 0.75 % v/v EG was mixed in drinking water for causing renal stones, along with group III- V was treated with liposomal β-carryophyllene 100 mg/kg, 200 mg/kg and 400 mg/kg respectively. Group-VI was treated with standard drug, cystone (750 mg/kg). Results: The study proved that liposomal β-caryophyllene (BCP) significantly inhibits calcium oxalate crystal formation, aggregation, and dissolution in both in-vitro and in-vivo models. BCP significantly reduced serum and urine markers of renal dysfunction and oxidative stress, with the highest dose (400 mg/kg) demonstrating effects similar to the standard drug (cystone). Conclusion: Liposomal β-caryophyllene (BCP) shows promising therapeutic agent for urolithiasis, effectively preventing crystal formation and improving renal function. It demonstrated comparable efficacy to the standard treatment, suggesting its potential as a viable alternative or complementary therapy for managing urolithiasis.

Sudhir Kshirsagar, Neha Sawant, Hallie Morton et al.

S. Azam, Md. Ezazul Haque, M. Jakaria et al.

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

Jiarui Wang, Jingyi Chen, Joey Studts et al.

The implementation of process analytical technologies is positioned to play a critical role in advancing biopharmaceutical manufacturing by simultaneously resolving clinical, regulatory, and cost challenges. Raman spectroscopy is emerging as a key technology enabling in-line product quality monitoring, but laborious calibration and computational modeling efforts limit the widespread application of this promising technology. In this study, we demonstrate new capabilities for measuring product aggregation and fragmentation in real-time during a bioprocess intended for clinical manufacturing by applying hardware automation and machine learning data analysis methods. We reduced the effort needed to calibrate and validate multiple critical quality attribute models by integrating existing workflows into one robotic system. The increased data throughput resulting from this system allowed us to train calibration models that demonstrate accurate product quality measurements every 38 s. In-process analytics enable advanced process understanding in the short-term and will lead ultimately to controlled bioprocesses that can both safeguard and take necessary actions that guarantee consistent product quality.

Yi-Wei Du, Xiao-Kang Li, Ting-Ting Wang et al.

Abstract Background Ferroptosis, which is characterized by lipid peroxidation and iron accumulation, is closely associated with the pathogenesis of acute renal injury (AKI). Cyanidin-3-glucoside (C3G), a typical flavonoid that has anti-inflammatory and antioxidant effects on ischemia‒reperfusion (I/R) injury, can induce AMP-activated protein kinase (AMPK) activation. This study aimed to show that C3G exerts nephroprotective effects against I/R-AKI related ferroptosis by regulating the AMPK pathway. Methods Hypoxia/reoxygenation (H/R)-induced HK-2 cells and I/R-AKI mice were treated with C3G with or without inhibiting AMPK. The level of intracellular free iron, the expression of the ferroptosis-related proteins acyl-CoA synthetase long chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4), and the levels of the lipid peroxidation markers 4-hydroxynonenal (4-HNE), lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were examined. Results We observed the inhibitory effect of C3G on ferroptosis in vitro and in vivo, which was characterized by the reversion of excessive intracellular free iron accumulation, a decrease in 4-HNE, lipid ROS, MDA levels and ACSL4 expression, and an increase in GPX4 expression and glutathione (GSH) levels. Notably, the inhibition of AMPK by CC significantly abrogated the nephroprotective effect of C3G on I/R-AKI models in vivo and in vitro. Conclusion Our results provide new insight into the nephroprotective effect of C3G on acute I/R-AKI by inhibiting ferroptosis by activating the AMPK pathway.

Antonella Minutolo, Angelo Gismondi, Rossella Chirico et al.

Hydrodynamic cavitation (HC), as an effective, efficient, and scalable extraction technique for natural products, could enable the affordable production of valuable antioxidant extracts from plant resources. For the first time, whole pomegranate (<i>Punica granatum</i> L.) fruits, rich in bioactive phytochemicals endowed with anti-cancer properties, were extracted in water using HC. Aqueous fractions sequentially collected during the process (M1–M5) were lyophilized (L), filtered (A), or used as such, i.e., crude (C), and analyzed for their biochemical profile and in vitro antioxidant power. The fractions M3 and M4 from the L and C series showed the highest antiradical activity and phytochemical content. While the lyophilized form is preferable for application purposes, sample L-M3, which was produced faster and with lower energy consumption than M4, was used to assess the potential antiproliferative effect on human breast cancer line (AU565-PAR) and peripheral blood mononuclear (PBMC) cells from healthy donors. In a pilot study, cell growth, death, and redox state were assessed, showing that L-M3 significantly reduced tumor cell proliferation and intracellular oxygen reactive species. No effect on PBMCs was detected. Thus, the antioxidant phytocomplex extracted from pomegranate quickly (15 min), at room temperature (30 °C), and efficiently showed potential anticancer activity without harming healthy cells.

Muhammad Adnan, A. Rasul, G. Hussain et al.

Natural products, being richly endowed with curative powers, have become spotlight for biomedical and pharmaceutical research to develop novel therapeutics during recent years. Ginkgetin, a natural non-toxic biflavone, has been shown to exhibit anti-cancer, anti-inflammatory, anti-microbial, anti-adipogenic, and neuroprotective activities. Ginkgetin combats cancer progression by arresting cell cycle, inducing apoptosis, stimulating autophagy, and targeting many deregulated signaling pathways such as JAK/STAT and MAPKs. Ginkgetin halts inflammation mediators like interleukins, iNOS, COX-2, PGE2, NF-κB, and acts as an inhibitor of PLA2. GK shows strong neuroprotection against oxidative stress-promoted cell death, inhibits cerebral micro-hemorrhage, decreases neurologic deficits, and halts apoptosis of neurons. Ginkgetin also acts as anti-fungal, anti-viral, anti-bacterial, leishmanicidal and anti-plasmodial agent. Ginkgetin shows substantial preventive or therapeutic effects in in vivo models of many diseases including atherosclerosis, cancer, neurodegenerative, hepatic, influenza, and inflammatory diseases. Based on various computational, in vitro and in vivo evidences, this article demonstrates the potential of ginkgetin for development of therapeutics against various diseases. Although GK has been systematically studied from pharmacological point of view, a vast field of pharmacokinetics, pre-clinical and clinical studies is still open for the researchers to fully validate its potential for the treatment of various diseases.

V. Rapalli, Tejashree Waghule, Srividya Gorantla et al.

Psoriasis is a chronic autoimmune skin disorder triggered by either genetic factors, environmental factors, life style, or a combination thereof. Clinical investigations have identified pathogenesis, such as T cell and cytokine-mediated, genetic disposition, antimicrobial peptides, lipocalin-2, galectin-3, vaspin, fractalkine, and human neutrophil peptides in the progression of psoriasis. In addition to traditional therapies, newer therapeutics, including phosphodiesterase type 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, monoclonal antibodies (mAbs), gene therapy, anti-T cell therapy, and phytoconstituents have been explored. In this review, we highlight nanotechnology-related developments for psoriasis treatment, including patented delivery systems and therapeutics currently in clinical trials.

W. Yin, M. Rogge

The therapeutic pathways that modulate transcription mechanisms currently include gene knockdown and splicing modulation. However, additional mechanisms may come into play as more understanding of molecular biology and disease etiology emerge. Building on advances in chemistry and delivery technology, oligonucleotide therapeutics is emerging as an established, validated class of drugs that can modulate a multitude of genetic targets. These targets include over 10,000 proteins in the human genome that have hitherto been considered undruggable by small molecules and protein therapeutics. The approval of five oligonucleotides within the last 2 years elicited unprecedented excitement in the field. However, there are remaining challenges to overcome and significant room for future innovation to fully realize the potential of oligonucleotide therapeutics. In this review, we focus on the translational strategies encompassing preclinical evaluation and clinical development in the context of approved oligonucleotide therapeutics. Translational approaches with respect to pharmacology, pharmacokinetics, cardiac safety evaluation, and dose selection that are specific to this class of drugs are reviewed with examples. The mechanism of action, chemical evolution, and intracellular delivery of oligonucleotide therapies are only briefly reviewed to provide a general background for this class of drugs.

U. Landmesser, W. Poller, S. Tsimikas et al.

Nucleic acid-based therapeutics are currently developed at large scale for prevention and management of cardiovascular diseases (CVDs), since: (i) genetic studies have highlighted novel therapeutic targets suggested to be causal for CVD; (ii) there is a substantial recent progress in delivery, efficacy, and safety of nucleic acid-based therapies; (iii) they enable effective modulation of therapeutic targets that cannot be sufficiently or optimally addressed using traditional small molecule drugs or antibodies. Nucleic acid-based therapeutics include (i) RNA-targeted therapeutics for gene silencing; (ii) microRNA-modulating and epigenetic therapies; (iii) gene therapies; and (iv) genome-editing approaches (e.g. CRISPR-Cas-based): (i) RNA-targeted therapeutics: several large-scale clinical development programmes, using antisense oligonucleotides (ASO) or short interfering RNA (siRNA) therapeutics for prevention and management of CVD have been initiated. These include ASO and/or siRNA molecules to lower apolipoprotein (a) [apo(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoCIII, ANGPTL3, or transthyretin (TTR) for prevention and treatment of patients with atherosclerotic CVD or TTR amyloidosis. (ii) MicroRNA-modulating and epigenetic therapies: novel potential therapeutic targets are continually arising from human non-coding genome and epigenetic research. First microRNA-based therapeutics or therapies targeting epigenetic regulatory pathways are in clinical studies. (iii) Gene therapies: EMA/FDA have approved gene therapies for non-cardiac monogenic diseases and LDL receptor gene therapy is currently being examined in patients with homozygous hypercholesterolaemia. In experimental studies, gene therapy has significantly improved cardiac function in heart failure animal models. (iv) Genome editing approaches: these technologies, such as using CRISPR-Cas, have proven powerful in stem cells, however, important challenges are remaining, e.g. low rates of homology-directed repair in somatic cells such as cardiomyocytes. In summary, RNA-targeted therapies (e.g. apo(a)-ASO and PCSK9-siRNA) are now in large-scale clinical outcome trials and will most likely become a novel effective and safe therapeutic option for CVD in the near future. MicroRNA-modulating, epigenetic, and gene therapies are tested in early clinical studies for CVD. CRISPR-Cas-mediated genome editing is highly effective in stem cells, but major challenges are remaining in somatic cells, however, this field is rapidly advancing.

Q. Lu, R. Wu, Ming Zhao et al.

In the past decade, we have witnessed considerable developments in understanding the roles and functions of miRNAs. In parallel, the identification of alterations in miRNA expression in inflammatory disease indicates their potential as therapeutic targets. Pharmacological treatments targeting abnormally expressed miRNAs for inflammatory diseases are not yet in clinical practice; however, some small compounds and nucleic acids targeting miRNAs have shown promise in preclinical development. Here, we focus on recent advances in understanding miRNA deregulation in inflammatory diseases and provide an overview of the current development of miRNA-based therapeutics in these diseases with an emphasis on newly discovered miRNA therapeutic targets.

Rujittika Mungmunpuntipantip, Viroj Wiwanitkit

Sin Wi Ng, Yinghan Chan, D. Chellappan et al.

In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.