Hasil untuk "Therapeutics. Pharmacology"

J. Bilezikian, L. Raisz, G. Rodan

Basic principles - cell biology biochemistry bone re-modelling and mineral homeostasis the hormones of bone other systemic hormones that influence bone metabolism local regulators of bone molecular mechanisms of metabolic bone diseases pharmacological mechanisms of therapeutics methods in bone research.

T. Hwang, D. Carpenter, J. Lauffenburger et al.

Chander K Negi, P. Babica, Lola Bajard et al.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. With no Food and Drug Administration approved drugs, current treatment options include dietary restrictions and lifestyle modification. NAFLD is closely associated with metabolic disorders such as obesity, type 2 diabetes, and dyslipidemia. Hence, clinically various pharmacological approaches using existing drugs such as antidiabetic, anti-obesity, antioxidants, and cytoprotective agents have been considered in the management of NAFLD and nonalcoholic steatohepatitis (NASH). However, several pharmacological therapies aiming to alleviate NAFLD-NASH are currently being examined at various phases of clinical trials. Emerging data from these studies with drugs targeting diverse molecular mechanisms show promising outcomes. This review summarizes the current understanding of the pathogenic mechanisms of NAFLD and provides an insight into the pharmacological targets and emerging therapeutics with specific interventional mechanisms. In addition, we also discuss the importance and utility of new approach methodologies and regulatory perspectives for NAFLD-NASH drug development.

Siming Lin, Siming Lin, Siming Lin et al.

BackgroundEndoplasmic reticulum stress (ERS) plays a critical role in skeletal muscle physiology and pathology, though the precise mechanisms remain unclear. Salubrinal, a selective inhibitor of eIF2α dephosphorylation, has been shown as a potential therapeutic agent for various conditions, but its effects on sarcopenia are not well understood. This study investigated the protective effects of salubrinal against H2O2-induced muscle cell injury and its impact on the eIF2α/ATF4 signaling pathway.MethodsGastrocnemius muscle samples from aged mice were used and cultured C2C12 myotubes were also used to explore the effects of Salubrinal through Western blotting, immunofluorescence, and apoptosis assays.ResultsOur results demonstrated that H2O2 treatment induced significant muscle cell damage, evidenced by reduced MHC1 expression and increased apoptosis. Salubrinal, in a concentration-dependent manner, mitigated these effects, preserving MHC1 expression and reducing apoptosis. Furthermore, salubrinal enhanced the expression of p-eIF2α and ATF4, suggesting that its protective effects are mediated through the eIF2α/ATF4 pathway.ConclusionThese findings highlight salubrinal’s potential as a therapeutic agent for muscle wasting conditions, particularly those related to oxidative stress and ERS.

Kang Cheng, Guangbo He, Xiaxia Li et al.

Background: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder with limited treatment options. Emerging evidence reveals bidirectional crosstalk between gut and brain through inflammatory signaling, leading us to hypothesize that anti-neuroinflammatory agents may concurrently ameliorate intestinal inflammation. The scorpion venom-derived heat-resistant synthetic peptide (SVHRSP), a bioactive peptide initially identified in scorpion venom and subsequently synthesized by our laboratory, possesses neuroprotective, anti-inflammatory, and antioxidative activities. Its properties make SVHRSP a promising candidate for investigating the therapeutic potential of anti-neuroinflammatory strategies in mitigating intestinal inflammation. Methods: Using a chronic dextran sodium sulfate (DSS)-induced colitis model in wild-type and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, along with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, we assessed SVHRSP’s effects on inflammation, histopathology, gut permeability, oxidative stress markers, and α7nAChR-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Results: SVHRSP treatment significantly ameliorated colitis symptoms in wild-type mice by reducing inflammation, repairing histological damage, restoring gut barrier function, and attenuating oxidative stress, with these effects abolished in α7nAChR knockout mice. Mechanistically, SVHRSP activated JAK2/STAT3 signaling through α7nAChR engagement, suppressing proinflammatory cytokine production in macrophages. Conclusion: These results demonstrated that SVHRSP alleviated intestinal inflammation via α7nAChR-dependent JAK2/STAT3 activation. Combined with its known neuroprotective properties, our findings support the repurposing of this neuroactive peptide, SVHRSP, for treating intestinal inflammatory disorders.

Ramesh R. Boinpally, Pushpa Chandrasekar, Joshua M. Rowe

ABSTRACT Atogepant, a calcitonin gene‐related peptide (CGRP) receptor antagonist, is approved for the preventive treatment of migraine in adults. This open‐label, phase 1 study examined radiolabeled atogepant (14C‐atogepant) metabolism, elimination, and mass balance after a single dose (50 mg, ~200 μCi) in healthy adult males. Blood, urine, and feces were collected ≤ 28 days for atogepant, metabolite, and radioactivity level measurement. Six participants were enrolled (mean age: 33.3 years; body mass index: 28.8 kg/m2); five completed the study (one withdrew on Day 7 for family emergency). For atogepant, median time to maximum concentration (Tmax) was 1 h and mean terminal elimination half‐life (T1/2) was 18.5 h; for total radioactivity, Tmax was 1.5 h and mean T1/2 was 11.6 h. Unchanged atogepant was the major circulating species in plasma (mean atogepant/total radioactivity area under the curve ratio: ~0.75). In the 14 days after dosing, ~81% and ~8% of the radioactive dose were recovered in feces and urine, respectively. In feces, parent drug (unabsorbed drug, biliary excretion, and/or intestinal secretion) accounted for 42% of administered radioactivity. At least 11 metabolites were identified in feces, and each represented < 10% of administered radioactivity. In plasma, atogepant and metabolite M23 were the only radiometric peaks detected. Metabolite M23, tentatively characterized as dioxygenated methylated glucuronide of atogepant, represented ~15% of plasma radioactivity and was short‐lived. There were no treatment‐emergent adverse events or clinically meaningful changes in laboratory values, vital signs, or the electrocardiogram.

Teng P, Peng J, Zhang X et al.

Peikun Teng,1 Jinglan Peng,1 Xingyu Zhang,2 Yujie Wang,3 Chen Jiang,4 Shengyao Wang,1 Mingyu Wang,1,5 Xiudi Han,1 Xuedong Liu1 1Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 2Human Resources Department, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 3Microbiology Laboratory, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 4Pathology Department, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China; 5State Key Laboratory of Microbial Technology, Microbial Technology Institute, Shandong University, Qingdao, 266237, People’s Republic of ChinaCorrespondence: Xuedong Liu, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China, Tel +86 18661678256, Email xuedongliu@263.net Xiudi Han, Department of Respiratory and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266000, People’s Republic of China, Tel +86 15315002781, Email hanxiudi@163.comPurpose: Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative pathogen with strong colonization ability and multidrug resistance. Disseminated infection complicated by secondary organizing pneumonia is extremely uncommon.Patients and Methods: We describe a rare case of severe community-acquired pneumonia due to highly virulent P. aeruginosa, complicated by endophthalmitis, ecthyma gangrenosum, and secondary organizing pneumonia. Clinical features, microbiological results, histopathology, and treatment were analyzed.Results: A 61-year-old woman developed a disseminated infection caused by highly virulent P. aeruginosa, presenting with persistent high fever, impaired consciousness, ocular involvement, mucocutaneous erosions, and widespread erythematous papules. The diagnosis was confirmed by consistent isolation of P. aeruginosa from sputum, blood, and ocular pus, and detection in bronchoalveolar lavage fluid by metagenomic sequencing. Whole-genome sequencing of the ocular isolate identified multiple virulence factors, including Type III secretion system effectors ExoS, ExoT, and ExoY, reflecting the pathogen’s capacity for systemic dissemination. Lung biopsy revealed extensive necrosis with fibrinoid exudation and granulation tissue, consistent with secondary organizing pneumonia. The patient received combined antimicrobial and anti-inflammatory therapy targeting both the disseminated infection and the organizing pneumonia, resulting in rapid defervescence, restoration of consciousness and oral intake, and clinical improvement. She was subsequently discharged in stable condition.Conclusion: This case highlights the disseminated potential of highly virulent P. aeruginosa and underscores the need for vigilance regarding secondary organizing pneumonia in such infections. Timely recognition, together with a treatment strategy combining appropriate antimicrobial and anti-inflammatory therapy, is crucial to improving patient outcomes.Keywords: systemic disseminated infection, highly virulent Pseudomonas aeruginosa, secondary organizing pneumonia

Emmanouil Zacharioudakis, E. Gavathiotis

The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.

Chi-Tung Lu, Kai-Yen Chang, Chin-Yuan Yii et al.

Di Wu, Anliang Xia, Tianlong Fan et al.

Jia-Yu Zou, Qi-Lei Chen, Xiao-Ci Luo et al.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

Kirsten E. Smith, Jeffrey D. Feldman, Kelly E. Dunn et al.

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly.Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10).Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called “the wobbles” (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs.Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Laurence Lafanechère

Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on the structure of tubulin, the regulation of microtubule dynamics and their deregulation in pathological processes, new therapeutic strategies are emerging, both for the treatment of cancer and for other diseases, such as neuronal or even heart diseases and parasite infections. In addition, a better understanding of the mechanism of action of well-known drugs such as colchicine or certain kinase inhibitors contributes to the development of these new therapeutic approaches. Nowadays, chemists and biologists are working jointly to select drugs which target the microtubule cytoskeleton and have improved properties. On the basis of a few examples this review attempts to depict the panorama of these recent advances.

Hong Kim, Seung Yeon Baik, Yong Wook Kim et al.

Abstract Introduction Vortioxetine has a positive effect on cognitive function in patients with major depressive disorder (MDD). This study aimed to examine the changes in cognitive function and EEG (spectral power and mismatch negativity (MMN)) in patients with MDD pre‐ and postvortioxetine treatment. Methods Thirty patients with MDD were included in the study. They were given vortioxetine (10‐20mg po per day) for eight weeks. Depression and anxiety severities, social function (Korean version of the social adjustment scale (K‐SAS)), and cognitive function (digit‐symbol substitution Test (DSST), Korean version of the attentional control questionnaire (K‐ACQ), and Korean version of the perceived deficits questionnaire for depression (K‐PDQD)) were evaluated. Spectral power of EEG and MMN was also measured pre‐ and postvortioxetine treatment. Results Depression and anxiety severity, social function, and cognitive functioning significantly improved after vortioxetine treatment. Also, there was a significant decrease in the right central delta band and an increase in the right central beta 2 band following vortioxetine treatment. The changes in EEG spectral power were not related to changes in cognitive functions. Baseline MMN significantly predicted changes in DSST score after controlling for the baseline clinical variables. Conclusion Vortioxetine treatment improved cognitive function and induced changes in EEG (decreased theta power and increased beta power) in patients with MDD. Our results suggest that greater negative MMN amplitude is associated with greater potential for cognitive improvement following vortioxetine treatment.

Jing Sun, Wugui Chen, Songtao Li et al.

Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Via conducting a series of biochemical experiments with in vitro cell lines, this study investigated the role and mechanism of NADPH oxidase 4 (Nox4) in RANKL-induced autophagy and osteoclastogenesis. In the current study, we found that RANKL dramatically induced autophagy and osteoclastogenesis, inhibition of autophagy with chloroquine (CQ) markedly attenuates RANKL-induced osteoclastogenesis. Interestingly, we found that the protein level of Nox4 was remarkably upregulated by RANKL treatment. Inhibition of Nox4 by 5-O-methyl quercetin or knockdown of Nox4 with specific shRNA markedly attenuated RANKL-induced autophagy and osteoclastogenesis. Furthermore, we found that Nox4 stimulated the production of nonmitochondrial reactive oxygen species (ROS), activating the critical unfolded protein response (UPR)-related signaling pathway PERK/eIF-2α/ATF4, leading to RANKL-induced autophagy and osteoclastogenesis. Blocking the activation of PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS scavenger (NAC) or PERK inhibitor (GSK2606414) significantly inhibited autophagy during RANKL-induced osteoclastogenesis. Collectively, this study reveals that Nox4 promotes RANKL-induced autophagy and osteoclastogenesis via activating ROS/PERK/eIF-2α/ATF4 pathway, suggesting that the pathway may be a novel potential therapeutic target for osteoclastogenesis-related disease.

Jeremiah Oshiomame Unuofin, Nelisiwe Prenate Masuku, Oluwatomiwa Kehinde Paimo et al.

Ginger (Zingiber officinale) is one of the most widely used natural products consumed as a spice and medicine for treating diabetes, flatulent intestinal colic, indigestion, infertility, inflammation, insomnia, a memory booster, nausea, rheumatism, stomach ache, and urinary tract infections. To date, over 400 bioactive components, such as diarylheptanoids, gingerol analogues, phenylalkanoids, sulfonates, monoterpenoid glycosides, steroids, and terpene compounds have been derived from ginger. Increasing evidence has revealed that ginger possesses a broad range of biological activities, especially protective effects against male infertility, nausea and vomiting, analgesic, anti-diabetic, anti-inflammatory, anti-obesity, and other effects. The pharmacological activities of ginger were mainly attributed to its active phytoconstituents such as 6-gingerol, gingerdiol, gingerol, gingerdione, paradols, shogaols, sesquiterpenes, zingerone, besides other phenolics and flavonoids. In recent years, in silico molecular docking studies revealed that gingerol (6-gingerol, 8-gingerol, and 10-gingerol) and Shogaol (6-shogaol, 8-shogaol, 10-shogaol) had the best binding affinities to the receptor protein in disease conditions such as diabetes, inflammation, obesity, and SARS-CoV-2. Furthermore, some clinical trials have indicated that ginger can be consumed for alleviation of nausea and vomiting induced by surgery, pain, diabetes, obesity, inflammation, male infertility. This review provides an updated understanding of the scientific evidence on the development of ginger and its active compounds as health beneficial agents in future clinical trials.

Leon G. Martens, Jiao Luo, Fleur L. Meulmeester et al.

The antioxidant vitamin E (α-tocopherol, α-TOH) protects lipids from oxidation by reactive oxygen species. We hypothesized that lifestyle factors associate with vitamin E metabolism marked by urinary α-tocopheronolactone hydroquinone (α-TLHQ) and α-carboxymethyl-hydroxychroman (α-CEHC levels), as potential reflection of lipid oxidation. We conducted a cross-sectional study in the Netherlands Epidemiology of Obesity Study. Serum α-TOH, and urinary α-TLHQ and α-CEHC were quantified by liquid chromatography coupled with tandem mass spectrometry. Information on the lifestyle factors (sleep, physical activity (PA), smoking and alcohol) were collected through questionnaires. Multivariable linear regression analyses were performed to assess the associations between the lifestyle factors and α-TOH measures. A total of 530 participants (46% men) were included with mean (SD) age of 56 (6) years. Of the examined lifestyle factors, only poor sleep was associated with a higher serum α-TOH (mean difference: 4% (95% CI: 1, 7%)). Current smoking was associated with higher urinary α-CEHC (32%: (14%, 53%)), with evidence of a dose–response relationship with smoking intensity (low pack years, 24% (2, 52%); high pack years, 55% (25, 93%)). Moderate physical activity was associated with a lower α-TLHQ relative to α-CEHC (−17%: (−26, −6%), compared with low PA). Only specific lifestyle factors associate with vitamin E metabolism. Examining serum α-TOH does not provide complete insight in vitamin E antioxidant capacity.

Rong Chen, Rong Chen, Ling-hua Tang et al.

Fentanyl-induced cough (FIC) often occurs after intravenous bolus administration of fentanyl analogs during induction of general anesthesia and analgesia procedure. The cough is generally benign, but sometimes it causes undesirable side effects, including elevated intra-abdominal, intracranial or intraocular pressure. Therefore, understanding the related mechanisms and influencing factors are of great significance to prevent and treat the cough. This paper reviews the molecular mechanism, influencing factors and preventive administration of FIC, focusing on the efficacy and side effects of various drugs in inhibiting FIC to provide some medical reference for anesthesiologists.

Luna E. Ferreira, Elaine A. Azevedo, Marceli C. Falcão et al.

Introduction: The record of the activities performed by the health professional should compose the patient’s medical record, whose fundamental role is communication. One way to make registration easier is to create semi-structured models. Objective: To evaluate the applicability and reproducibility of a semi-structured model for the medication therapy management record in hospitals. Methods: A convenience sampling of fifteen clinical pharmacists working in public hospitals in Minas Gerais was used. The participants received the semi-structured model for medical record and detailed report of two simulated clinical cases. The records made by each participant were compared to a standard record - template and the verification items were evaluated and categorized into: 1- compliant, 2- partially compliant, and 3- non-compliant. Participants also answered an electronic questionnaire with questions related to clinical experience and training. The main variable evaluated was the compliance percentage, considering the total of items evaluated. And for all variables under study, absolute and relative frequency were determined. The influence of the participants’ individual characteristics was univariate analyzed. Results: Most of the group (58%) had been graduated in Pharmacy for over ten years and most (83%) reported having been trained in the clinical area. The characteristics of the participants did not affect the results obtained. The overall compliance percentage showed a good performance of pharmacists using this model (76%) and most participants considered the model to be highly applicable / useful (75%). Conclusion: The high percentage of compliance achieved demonstrates that the semi-structured medical record model developed in this study was considered applicable by most participants, who also had a good performance in its use, and may be a starting point for other pharmacists and services to develop their own models, adapted to the reality of each service.

Yumeng Liu, Shengyu Chen, Xiaolong Wang et al.

Accurate identification of intrinsically disordered proteins/regions (IDPs/IDRs) is critical for predicting protein structure and function. Previous studies have shown that IDRs of different lengths have different characteristics, and several classification-based predictors have been proposed for predicting different types of IDRs. Compared with these classification-based predictors, the previously proposed predictor IDP-CRF exhibits state-of-the-art performance for predicting IDPs/IDRs, which is a sequence labeling model based on conditional random fields (CRFs). Motivated by these methods, we propose a predictor called IDP-FSP, which is an ensemble of three CRF-based predictors called IDP-FSP-L, IDP-FSP-S, and IDP-FSP-G. These three predictors are specially designed to predict long, short, and generic disordered regions, respectively, and they are constructed based on different features. To the best of our knowledge, IDP-FSP is the first predictor that combines a sequence labeling algorithm with IDRs of different lengths. Experimental results using two independent test datasets show that IDP-FSP achieves better or at least comparable predictive performance with 26 existing state-of-the-art methods in this field, proving the effectiveness of IDP-FSP. Keywords: intrinsically disordered proteins/regions, ensemble predictor, length-dependent predictors, conditional random fields, CRFs