Hasil untuk "Therapeutics. Pharmacology"

Xinhai Wang, Jing Guo, Kaiyan Zhang et al.

Dimethyl sulfoxide (DMSO) is widely utilized in the vitrification of oocytes, but DMSO exhibits concentration-dependent toxicity, which can compromise oocyte developmental potential by disrupting key cellular processes. This study reports the first successful use of cold shock protein B (CspB protein) as a substitute for DMSO in vitrification solutions for oocyte vitrification. Combining dynamics simulations and experimental validation, we demonstrated CspB’s ability to inhibit ice crystallization and recrystallization by stabilizing its position at the ice–water interface and reducing ice formation rates. Recombinant CspB was successfully expressed and shown to bind to the oolemma. In vitrification solutions, CspB (1–2 mg/mL) effectively reduced ice crystal size and enabled a significant reduction or complete replacement of DMSO. This strategy markedly improved the post-thaw survival rates of both mouse and bovine metaphase II (MII) oocytes. Furthermore, oocytes vitrified with an optimized formulation (15% ethylene glycol + 2 mg/mL CspB) exhibited developmental competence (cleavage and blastocyst rates), oxidative stress markers (ROS, GSH), mitochondrial function (membrane potential and content), and apoptosis levels (Caspase-3/9) comparable to those treated with a standard DMSO-containing system. Transcriptomic analysis revealed that CspB’s cryoprotection involves the modulation of the mTOR signaling pathway. This role was functionally confirmed, as activation of mTOR abolished CspB’s beneficial effects, reinstating oxidative damage, mitochondrial dysfunction, and apoptosis. Thus, the CspB protein replaces DMSO with direct ice crystal formation suppression and mTOR-mediated oxidative stress regulation. This study offers a protein-based alternative to conventional permeable cryoprotectants. This approach holds promise for improving reproductive biotechnologies across species.

Dongling Gu, Yi Feng, Hongyan Li et al.

Immunotherapy plays a crucial role in cancer treatment, but its efficacy varies among patients, with some showing suboptimal responses. Recent studies indicate that radiotherapy not only kills tumor cells locally but also induces immunogenic cell death and modulates the tumor immune microenvironment, acting like an “in situ vaccine.” This provides a strong biological basis for combining radiotherapy and immunotherapy. However, challenges remain, including individual variability in responses, complex treatment regimens, and overlapping toxicities. Artificial intelligence (AI), especially through machine learning, presents new solutions by processing high-dimensional multi-omics data. This article explores how AI enhances radiotherapy and immunotherapy combinations by optimizing synergistic effects, developing predictive biomarkers, and elucidating the regulatory mechanisms of radiotherapy on the immune microenvironment, while also discussing future directions for AI in oncology.

J. Beaulieu, R. Gainetdinov, M. Caron

M. Youdim, Y. Bakhle

Daniel A. Riccio, M. Schoenfisch

Shih-Kai Chiang, Mei-Ying Sin, Jun-Wen Lin et al.

Broiler breeder hens allowed ad libitum (Ad) feed intake developed obesity and cardiac pathogenesis and thereby were susceptible to sudden death. A supplement of 69 µg 25-hydroxycholecalciferol (25-OH-D3)/kg feed rescued the livability of feed-restricted (R) and Ad-hens (mortality; 6.7% vs. 8.9% and 31.1% vs. 48.9%). Necropsy with the surviving counterparts along the time course confirmed alleviation of myocardial remodeling and functional failure by 25-OH-D3, as shown by BNP and MHC-β expressions, pathological hypertrophy, and cardiorespiratory responses (<i>p</i> < 0.05). 25-OH-D3 mitigated cardiac deficient bioenergetics in Ad-hens by rescuing PGC-1α activation, mitochondrial biogenesis, dynamics, and electron transport chain complex activities, and metabolic adaptions in glucose oxidation, pyruvate/lactate interconversion, TCA cycle, and β-oxidation, as well as in TG and ceramide accumulation to limit lipotoxic development (<i>p</i> < 0.05). Supplemental 25-OH-D3 also sustained Nrf2 activation and relieved MDA accumulation, protein carbonylation, and GSH depletion to potentiate cell survival in the failing heart (<i>p</i> < 0.05). Parts of the redox amendments were mediated via lessened blood hematocrit and heme metabolism, and improved iron status and related gene regulations (<i>p</i> < 0.05). In conclusion, 25-OH-D3 ameliorates cardiac pathological remodeling and functional compromise to rescue the livability of obese hens through metabolic flexibility and mitochondrial bioenergetics, and by operating at antioxidant defense, and heme and iron metabolism, to maintain redox homeostasis and sustain cell viability.

S. Goodman, M. Picard

Jin Niu, R. Straubinger, D. Mager

Pharmacodynamic drug–drug interactions (DDIs) occur when the pharmacological effect of one drug is altered by that of another drug in a combination regimen. DDIs often are classified as synergistic, additive, or antagonistic in nature, albeit these terms are frequently misused. Within a complex pathophysiological system, the mechanism of interaction may occur at the same target or through alternate pathways. Quantitative evaluation of pharmacodynamic DDIs by employing modeling and simulation approaches is needed to identify and optimize safe and effective combination therapy regimens. This review investigates the opportunities and challenges in pharmacodynamic DDI studies and highlights examples of quantitative methods for evaluating pharmacodynamic DDIs, with a particular emphasis on the use of mechanism‐based modeling and simulation in DDI studies. Advancements in both experimental and computational techniques will enable the application of better, model‐informed assessments of pharmacodynamic DDIs in drug discovery, development, and therapeutics.

S. Zhang, Zhon-Yin Zhang

M. F. Nagoor Meeran, S. Goyal, Kapil Suchal et al.

Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.

Simone Ortiz Moura Fideles, Adriana de Cássia Ortiz, Daniela Vieira Buchaim et al.

Quercetin is a dietary flavonoid present in vegetables, fruits, and beverages, such as onions, apples, broccoli, berries, citrus fruits, tea, and red wine. Flavonoids have antioxidant and anti-inflammatory effects, acting in the prevention of several diseases. Quercetin also has neuroprotective properties and may exert a beneficial effect on nervous tissue. In this literature review, we compiled in vivo studies that investigated the effect of quercetin on regeneration and functional recovery of the central and peripheral nervous system. In spinal cord injuries (SCI), quercetin administration favored axonal regeneration and recovery of locomotor capacity, significantly improving electrophysiological parameters. Quercetin reduced edema, neutrophil infiltration, cystic cavity formation, reactive oxygen species production, and pro-inflammatory cytokine synthesis, while favoring an increase in levels of anti-inflammatory cytokines, minimizing tissue damage in SCI models. In addition, the association of quercetin with mesenchymal stromal cells transplantation had a synergistic neuroprotective effect on spinal cord injury. Similarly, in sciatic nerve injuries, quercetin favored and accelerated sensory and motor recovery, reducing muscle atrophy. In these models, quercetin significantly inhibited oxidative stress and cell apoptosis, favoring Schwann cell proliferation and nerve fiber remyelination, thus promoting a significant increase in the number and diameter of myelinated fibers. Although there is still a lack of clinical research, in vivo studies have shown that quercetin contributed to the recovery of neurological functions, exerting a beneficial effect on the regeneration of the central and peripheral nervous system.

Vincent Onoriode Igben, Wilson Josiah Iju, Omogbiya Adrian Itivere et al.

Abstract Background Datura metel (DM) stramonium is a medicinal plant often abused by Nigerians due to its psychostimulatory properties. Hallucinations, confusion, agitation, aggressiveness, anxiety, and restlessness are reported amongst DM users. Earlier studies suggest that DM induces neurotoxicity and affect brain physiology. However, the exact neurological effects of DM extract in the medial prefrontal cortex (mPFC) and hippocampal morphology have not been elucidated. In this study, we evaluated the hypothesis that oral exposure to DM extract exerts a neurotoxic effect by increasing oxidative stress in the mPFC and the hippocampus and induces behavioral deficits in mice. Results DM methanolic extract exposure significantly increased MDA and NO levels and reduced SOD, GSH, GPx and CAT activities in mice brains. In addition, our results showed that DM exposure produced cognitive deficits, anxiety, and depressive-like behaviour in mice following oral exposure for 28 days. Moreover, the mPFC and hippocampus showed neurodegenerative features, loss of dendritic and axonal arborization, a dose-dependent decrease in neuronal cell bodies’ length, width, area, and perimeter, and a dose-dependent increase in the distance between neuronal cell bodies. Conclusions Oral exposure to DM in mice induces behavioural deficits, mPFC and hippocampal neuronal degenerations via redox imbalance in the brain of mice. These observations confirm the neurotoxicity of DM extracts and raises concerns on the safety and potential adverse effects of DM in humans. Graphical abstract

G. Verdine, Gerard J. Hilinski

J. Imig

Jessica B Casaletto, A. McClatchey

Manisha B. Sinha, Gopal Gupta, N.N. Kolhe et al.

Introduction: Common carotid artery is a gateway to the blood supply to the head and neck region, including the brain. Previous cadaveric and few radiological studies have shown variation in the level of division and varying patterns of branches of the common carotid artery. Aim: The aim of the study is to investigate the prevalence of the commonest level of division of CCA in vivo through the use of CT angiography and the distance of STA (superior thyroid artery) from the level of bifurcation. Material and method: A total of 88 angiograms evaluated for study purpose, both right & left-sided views of the neck of all the 44 patients, have been taken into consideration during three years. Patients with intraparenchymal bleed and stroke, who had undergone CT angiography of the head and neck region, were selected and evaluated for study. Result: In the present study, the most frequent site of bifurcation of CCA was found to be type-II, which was at the level above the greater cornua of the hyoid bone (43.18%), and the least common site was type-V, which was at the level below the superior border of thyroid cartilage (1.13%). Conclusion: Variation in the bifurcation level of CCA results in variation in the origin and other parameters of other vessels (especially STA in this case) originating from the carotid arterial trunk. It leads to the possibility of misleading information to the clinicians during surgical and radiological procedures.

Mauro Finicelli, Filomena Anna Digilio, Umberto Galderisi et al.

Chronic obstructive pulmonary disease (COPD) is one of the most common airway diseases, and it is considered a major global health problem. Macrophages are the most representative immune cells in the respiratory tract, given their role in surveying airways, removing cellular debris, immune surveillance, and resolving inflammation. Macrophages exert their functions by adopting phenotypical changes based on the stimuli they receive from the surrounding tissue. This plasticity is described as M1/M2 macrophage polarization, which consists of a strictly coordinated process leading to a difference in the expression of surface markers, the production of specific factors, and the execution of biological activities. This review focuses on the role played by macrophages in COPD and their implication in inflammatory and oxidative stress processes. Particular attention is on macrophage polarization, given macrophage plasticity is a key feature in COPD. We also discuss the regulatory influence of extracellular vesicles (EVs) in cell-to-cell communications. EV composition and cargo may influence many COPD-related aspects, including inflammation, tissue remodeling, and macrophage dysfunctions. These findings could be useful for better addressing the role of macrophages in the complex pathogenesis and outcomes of COPD.

Chijioke E. Ezeobiora, Nwamaka H. Igbokwe, Dina H. Amin et al.

Abstract Background Antibiotic resistance is on the rise, and new antibiotic research has slowed in recent years, necessitating the discovery of possibly novel microbial resources capable of producing bioactive compounds. Microbial infections are gaining resistance to existing antibiotics, emphasizing the need for novel medicinal molecules to be discovered as soon as possible. Because the possibilities of isolating undiscovered actinomycetes strains have decreased, the quest for novel products has shifted to rare actinomycetes genera from regular environments or the identification of new species identified in unusual habitats. Main body of the abstract The non-streptomyces actinobacteria are known as rare actinomycetes that are extremely difficult to cultivate. Rare actinomycetes are known to produce a variety of secondary metabolites with varying medicinal value. In this review, we reported the diversity of rare actinomycetes in several habitat including soil, plants, aquatic environment, caves, insects and extreme environments. We also reported some isolation methods to easily recover rare Actinobacteria from various sources guided with some procedures to identify the rare Actinobacteria isolates. Finally, we reported the biosynthetic potential of rare actinomycetes and its role in the production of unique secondary metabolites that could be used in medicine, agriculture, and industry. These microbial resources will be of interest to humanity, as antibiotics, insecticides, anticancer, antioxidants, to mention but a few. Short conclusion Rare actinomycetes are increasingly being investigated for new medicinal compounds that could help to address existing human health challenges such as newly emerging infectious illnesses, antibiotic resistance, and metabolic disorders. The bioactive secondary metabolites from uncommon actinomycetes are the subject of this review, which focuses on their diversity in different habitats, isolation, identification and biosynthetic potentials.

Glauco Chisci, Luca Fredianelli

Most of research in regenerative oral surgery describes materials or techniques for increasing volumetric results for implant-supported prosthesis. The use of bio-materials in alveolar ridge preservation after tooth extraction commonly leads to a delayed recovery. Bromelain is an enzyme that belongs to a family of proteolytic enzymes derived from the stem of the pineapple plant (<i>Ananas comosus</i>) with effectiveness in decreasing the inflammation development and swelling. The present paper reports a prospective comparative study performed in order to test the possible use of oral bromelain 40 mg in alveolar ridge preservation. Evaluations were performed at three time points after the surgery: after 2 days (t1), after 7 days (t2) and after 14 days (t3). A statistically significant difference among patients that used bromelain and patients that used placebo resulted among the use of bromelain and lower Visual Analogue Scale (VAS) at t1 (r = −0.75, <i>p</i> = 0.0067), t2 (r = −0.90, <i>p</i> = 0.0001) and t3 (r = −0.8566, <i>p</i> = 0.0008). Bromelain therapy reported a statistically significant difference among patients that used bromelain and patients that used placebo even with regards to the use of bromelain and postoperative swelling at t1 (r = −0.79, <i>p</i> = 0.0034), t2 (r = −0.81, <i>p</i> = 0.0020) but not at t3 (r = −0.34, <i>p</i> = 0.2967). With the result of the present paper, and the poorness of contraindication of the investigated drug, bromelain may be suggested to be used for patients that undergo to alveolar ridge preservation after tooth extraction.

Betina M. R. Carvalho, Laranda C. Nascimento, Jessica C. Nascimento et al.

This study aims to obtain scientific evidence on the use of Citrus to control dyslipidemia. The surveys were carried out in 2020 and updated in March 2021, in the PubMed, Scopus, LILACS, and SciELO databases, using the following descriptors: Citrus, dyslipidemias, hypercholesterolemia, hyperlipidemias, lipoproteins, and cholesterol. The risk of bias was assessed according to the Cochrane methodology for clinical trials and ARRIVE for preclinical trials. A meta-analysis was performed using the application of R software. A total of 958 articles were identified and 26 studies demonstrating the effectiveness of the Citrus genus in controlling dyslipidemia were selected, of which 25 were included in the meta-analysis. The effects of Citrus products on dyslipidemia appear consistently robust, acting to reduce total cholesterol, LDL, and triglycerides, in addition to increasing HDL. These effects are associated with the composition of the extracts, extremely rich in antioxidant, as flavonoids, and that act on biochemical targets involved in lipogenesis and beta-oxidation. The risk of bias over all of the included studies was considered critically low to moderate. The meta-analysis demonstrated results favorable to control dyslipidemia by Citrus products. On the other hand, high heterogeneity values were identified, weakening the evidence presented. From this study, one can suggest that Citrus species extracts are potential candidates for dyslipidemia control, but more studies are needed to increase the strength of this occurrence.