Drug Design, Development and Therapy最新文献

{"title":"Integrative Lipid Pseudotargeted Metabolomics and Amino Acids Targeted Metabolomics Unravel the Therapeutic Mechanism of Rhizoma Paridis Saponins on Experimental Colitis of Damp-Heat Type.","authors":"Qi Wu, Kexin Liu, Ruijuan Hou, Xingxing Wu, Xiaoyu Ruan, Mao Wang, Zhiting Sun, Lingchang Meng, Guoliang Dai, Changyin Li, Jing Wu, Genglin Mu","doi":"10.2147/DDDT.S476494","DOIUrl":"10.2147/DDDT.S476494","url":null,"abstract":"<p><strong>Purpose: </strong>Inflammatory bowel disease (IBD) is a serious disease that affects the metabolism and inflammatory responses of human beings. From the perspective of traditional Chinese medicine, damp-heat syndrome is one of the main syndromes of IBD. Rhizoma Paridis, also known as the root of Paris polyphylla, a well-known herbal medicine used in China, is used to treat IBD with damp-heat syndrome (IBD-DH). However, uncertainty still exists regarding the underlying mechanisms and the impact of Rhizoma Paridis on IBD-DH.</p><p><strong>Methods: </strong>The rats in the model (DAT) and medication administration (Rhizoma Paridis total saponins (RPTS) and Pennogenin (PN)) groups were given a high temperature and high humidity environment, high fat and high sugar diet combined with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish the model of experimental colitis of damp-heat type, and the normal control group (RNC) rats were given a normal diet at normal temperature and humidity. Damp-heat control group (DNC) was set with the same condition as DAT without TNBS. Hematoxylin-Eosin (HE) staining was used to observe the histopathological morphology of the rat colorectum. The expression of the metabolism-related genes (Phospholipase A2 (sPLA2, cPLA2), and phosphatidylethanolamine N-methyltransferase (PEMT)) was assessed by using real-time quantitative PCR analysis (RT-qPCR). And the levels of the metabolism-related proteins (sPLA2, cPLA2), S100A8/9, Arg-1, and cytokines were detected by enzyme-linked immunosorbent assay (ELISA) kit. To investigate lipids and amino acids which closely associated with the IBD and IBD-DH, lipid pseudotargeted metabolomics with UHPLC-TQ/MS analysis method, as well as targeted quantitative amino acid analysis were performed.</p><p><strong>Results: </strong>Our data showed that RPTS (50 mg/kg) and PN (20 mg/kg) significantly ameliorated the severity of TNBS-induced colitis and downregulated the levels of circulating proinflammatory cytokines. Compared with RNC group, lipid pseudotargeted metabolomics demonstrated that glycerophospholipids, sphingolipids, carnitine, and glycerolipids were the four most perturbed lipid classes, and amino acids targeted metabolomics demonstrated that serine, N-acetylneuraminic acid, histidine, proline, taurine, and kynurenine changed significantly in DAT group . Correlation analyses showed tight associations between most of differential metabolites and proinflammatory cytokines. RPTS and PN both regulated glycerophospholipid metabolism and sphingolipid metabolism. However, both of them did not have a significant effect on amino acid modulation. RPTS and PN potentially regulated sPLA2, cPLA2, and PEMT.</p><p><strong>Conclusion: </strong>These results showed that RPTS (50 mg/kg) and PN (20 mg/kg) effectively alleviated rats' colitis of damp-heat type, affected cytokines, and altered lipid metabolism without significant modulation on amino acid metabolism.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5087-5108"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic/Pharmacodynamic Study of Linezolid in Hospital-Acquired Pneumonia Patients with Renal Insufficiency.","authors":"Jinhui Xu, Xianglong Chen, Qian Zhang, Zhiwei Zhuang, Yunlong Yuan, Lufen Duan, Lu Shi, Chenqi Zhu, JingJing Li, Jian Lu, Yanxia Yu, Lian Tang","doi":"10.2147/DDDT.S474470","DOIUrl":"10.2147/DDDT.S474470","url":null,"abstract":"<p><strong>Purpose: </strong>The optimal treatment strategy in patients with hospital-acquired pneumonia (HAP) due to Gram-positive bacteria and renal insufficiency remains challenging. The objective of this study was to compare the outcomes of linezolid versus teicoplanin in HAP patients with renal insufficiency and to explore optimal dosage strategy for linezolid.</p><p><strong>Methods: </strong>The retrospective study enrolled adult patients treated with intravenous linezolid or teicoplanin at Suzhou Municipal Hospital between July 2018 and August 2023. For the comparative pharmacodynamic study, effectiveness, safety and target attainment of trough concentration (C_min) for teicoplanin versus linezolid treatment in HAP patients with document Gram-positive bacteria and renal insufficiency were compared. For the population pharmacokinetics (PPK) analyses, linezolid concentrations collected exclusively from HAP patients with renal insufficiency were used and the optimal dosage strategy was investigated using Monte Carlo simulations.</p><p><strong>Results: </strong>Linezolid-treated patients had a higher bacterial eradication rate than teicoplanin-treated patients (88.5% vs 63.4%, <i>P</i> < 0.001). A higher proportion of patients in the linezolid group experienced at least one adverse reaction (42.0% vs 25.0%, <i>P</i> = 0.025). Significantly more supratherapeutic C_min, less therapeutic C_min were achieved in the linezolid group (adjusted <i>P</i> < 0.05). A total of 207 linezolid concentrations from 166 patients with renal insufficiency were available for the PPK analysis. Age and creatinine clearance (CrCL) were identified as significant covariates that influenced clearance. Simulations show that 300 mg q12h provide the optimal exposure in patients with a CrCL of 60 or 45 mL/min, and 200 mg q12h was recommended for patients with a CrCL of 30 or 15 mL/min.</p><p><strong>Conclusion: </strong>Linezolid-treated patients with HAP and renal insufficiency had higher bacterial eradication rates, supratherapeutic exposure and adverse reactions than teicoplanin-treated patients. Linezolid dose reduction in patients with renal insufficiency improved the probability of achieving optimal exposure.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5073-5086"},"PeriodicalIF":4.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed Intermittent Epidural Bolus vs Manual Epidural Bolus for Labor Analgesia Initiation: A Randomized Non-Inferiority Trial.","authors":"Yan Lu, Yueqi Zhang, Yuhan Zheng, Yujie Song, Yu Zang, Zhiqiang Liu, Zhendong Xu","doi":"10.2147/DDDT.S488920","DOIUrl":"https://doi.org/10.2147/DDDT.S488920","url":null,"abstract":"<p><strong>Purpose: </strong>Typically, labor analgesia is initiated with a manual loading dose. The programmed intermittent epidural bolus (PIEB) effectively maintains labor analgesia. However, no PIEB method has been studied for the initial loading dose. This study aimed to compare the effectiveness of loading doses administered via a PIEB versus a manual bolus.</p><p><strong>Patients and methods: </strong>In total, 164 full-term singleton parturients were randomly assigned to receive a 12 mL loading dose (0.1% ropivacaine and 0.3 μg·mL^-1 sufentanil) via manual or pump-driven injection. A standardized maintenance protocol was employed. The primary outcome was the percentage of parturients with adequate analgesia 20 min after the initial epidural injection. Adequate analgesia was defined as a numeric rating score (NRS) of ≤3 during two consecutive uterine contractions, without an additional analgesia request. Kaplan-Meier survival curves were constructed for the time interval needed to achieve adequate analgesia. A non-inferiority analysis was conducted by comparing the 90% confidence interval of the pain score difference with the non-inferiority margin.</p><p><strong>Results: </strong>The percentage of parturients achieving adequate analgesia was comparable (75.61% manual injection vs 76.83% pump injection, <i>P</i>=0.05 for non-inferiority). The median NRS was similar, except at 2 min (7 [5-8] manual injection vs 8 [6-9] pump injection, <i>P</i>=0.04). Median time to adequate analgesia, median ropivacaine consumption, median duration of epidural analgesia, incidence of requests for patient-controlled epidural analgesia (PCEA), median number of PCEA boluses, percentage of bilateral S₂ blocks at 20 min, incidence of breakthrough pain, percentage of highest block level ≥T6 at 20 min, adverse effects, and obstetric and neonatal outcomes were similar between the groups.</p><p><strong>Conclusion: </strong>Within 20 min of administering a loading dose through a PIEB pump, non-inferior analgesia comparable to that achieved with manual injection was observed. This hands-free approach could help mitigate the impact of individual operational differences on analgesic efficacy.</p><p><strong>Registration: </strong>This trial was registered at chictr.org.cn (ChiCTR2300074063).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5063-5072"},"PeriodicalIF":4.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing Pharmacological and Immunological Properties of Therapeutic Proteins Through PEGylation: Investigating Key Parameters and Their Impact.","authors":"João Gonçalves, Paolo Caliceti","doi":"10.2147/DDDT.S481420","DOIUrl":"https://doi.org/10.2147/DDDT.S481420","url":null,"abstract":"<p><p>Protein PEGylation represents a significant technological advancement in the development of protein-based therapeutics and is widely used to reduce immunogenicity, enhance pharmacokinetics, and/or improve stability. The improved pharmacokinetic profile of PEGylated proteins compared with the native protein results in sustained versus fluctuating plasma concentrations and carries the potential of less frequent administration. However, attachment of PEG to therapeutic proteins can alter their structural conformation, which exposes new epitopes to the immune system. The design of PEGylated proteins thus needs to balance the intended benefits with the potential risks associated with the immunogenicity of the PEG moiety itself or resulting from alterations in the conformation of the therapeutic protein. In recent years, advancements in protein PEGylation chemistry have offered the capability to target PEG attachment to specific amino acids to create more stable and bioactive therapies. The biophysical and biopharmaceutical features of PEGylated proteins can vary based on polymer size, shape, density, and conjugation site, and the immunogenicity of the conjugate can be further impacted by the properties of the therapeutic protein itself and the characteristics of the patient. It is important to note that not all patients will develop an immune response toward the PEG moiety, and not all immune responses are clinically meaningful. A comprehensive understanding of the factors that influence immunogenic responses to PEGylated proteins is important to optimize their therapeutic benefits. This article reviews the design and optimization of PEGylation strategies to enhance the clinical performance of protein-based therapeutics while minimizing immunogenic responses to the PEG moiety or PEGylated proteins.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5041-5062"},"PeriodicalIF":4.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Status and Future Prospects of TROP-2 ADCs in Lung Cancer Treatment.","authors":"Mingyi Li, Meng Jin, Hao Peng, Haitao Wang, Qian Shen, Lei Zhang","doi":"10.2147/DDDT.S489234","DOIUrl":"https://doi.org/10.2147/DDDT.S489234","url":null,"abstract":"<p><p>Lung cancer is the leading cause of mortality worldwide, and non-small cell lung cancer accounts for the majority of lung cancer cases. Chemotherapy and radiotherapy constitute the mainstays of lung cancer treatment; however, their associated side effects involving the kidneys, nervous system, gastrointestinal tract, and liver further add to dismal outcomes. The advent of antibody‒drug conjugates (ADCs) could change this situation. Trophoblast surface antigen 2 (TROP-2), a human trophoblast surface antigen, is a tumor-associated antigen that is expressed at low levels in normal tissues and is overexpressed in a variety of malignant tumors. The differential expression of the TROP-2 protein in a variety of tumors makes tumor immunotherapy with ADCs targeting TROP-2 a promising approach. Previous studies have shown that the expression of TROP-2 is related to the prognosis of patients with lung cancer and that TROP-2 expression is different across different histological types; however, research on TROP-2 and TROP-2 ADCs in patients with lung cancer is not comprehensive. The aims of this study were to review the mechanism of action and clinical efficacy of TROP-2 and related drugs in the treatment of lung cancer, to elucidate the prognostic value of TROP-2 in lung cancer, and to discuss the future prospects of TROP-2 ADCs to provide a reference for the precise treatment of lung cancer.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5005-5021"},"PeriodicalIF":4.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy.","authors":"Laura Camillo, Marco Pozzi, Pia Bernardo, Simone Pisano, Maria Nobile","doi":"10.2147/DDDT.S383133","DOIUrl":"https://doi.org/10.2147/DDDT.S383133","url":null,"abstract":"<p><p>Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone -related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"5023-5040"},"PeriodicalIF":4.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispectral Index-Monitored Anesthesia Induction in Older Adults Undergoing Elective Surgery: Comparing Ciprofol and Propofol in a Prospective, Single-Center, Double-Blind, Randomized Controlled Study.","authors":"Haibin Zou, Fangfang Xi, Yuanyuan Fu, Jinhui Xu, Ping Zhang, Dongge Li, Heguo Luo","doi":"10.2147/DDDT.S484532","DOIUrl":"https://doi.org/10.2147/DDDT.S484532","url":null,"abstract":"<p><strong>Purpose: </strong>Ciprofol, a new sedative anesthetic developed in China, offers rapid onset and recovery, reduced injection pain, and stable circulation. However, its effect on blood pressure during anesthesia induction in older adults remains unclear. To compare the effects of propofol and ciprofol on hypotension induced by general anesthesia in older adults.</p><p><strong>Patients and methods: </strong>This prospective, single-center, double-blind, randomized, controlled clinical study enrolled 117 older adults undergoing surgery. Patients in the ciprofol group (group C) received an intravenous injection of ciprofol (0.3 mg/kg, n=57), while the propofol group (group P) received an intravenous injection of propofol (1.5 mg/kg, n=58). The primary outcome was the incidence of hypotension (mean arterial pressure (MAP) decreased by > 30% from baseline or MAP< 65 mmHg). Secondary outcomes included induction success rate (bispectral index (BIS) value ≤60 and Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) score ≤1), injection pain, number of drug additions, time to BIS 60, time to eyelash reflex disappearance, blood pressure changes, incidence of hypertension, tachycardia and BIS values before and after administration.</p><p><strong>Results: </strong>The incidence of induced hypotension was 26.3% (15/57) in group C and 48.3% (28/58) in group P (OR=0.383, 95% CI:175-0.837, P =0.015). Group C had significantly lower injection pain incidence (5.3% vs 20.7%, OR=0.213, 95% CI: 0.057-0.801, p=0.014). Both groups had a 100% induction success rate, with no significant difference in the number of additional doses. Post-intubation hypertension and tachycardia incidence were not significantly different. Group C showed less blood pressure decrease during induction and a deeper anesthesia level.</p><p><strong>Conclusion: </strong>Compared to propofol, ciprofol reduces the incidence of induced hypotension in older adults and maintains more stable blood pressure during induction. Additionally, ciprofol reduces injection pain and provides a good depth of anesthesia, making it a safe and effective option for anesthesia induction in older adults.</p><p><strong>Trial registration clinicaltrialsgov identifier: </strong>ChiCTR2200066053.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4993-5003"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protopine Exerts Neuroprotective Effects on Neonatal Hypoxic-Ischemic Brain Damage in Rats via Activation of the AMPK/PGC1α Pathway.","authors":"Liying Lu, Mengdan Pang, Tingting Chen, Yingying Hu, Likai Chen, Xiaoyue Tao, Shangqin Chen, Jianghu Zhu, Mingchu Fang, XiaoLing Guo, Zhenlang Lin","doi":"10.2147/DDDT.S484969","DOIUrl":"https://doi.org/10.2147/DDDT.S484969","url":null,"abstract":"<p><strong>Introduction: </strong>Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.</p><p><strong>Methods: </strong>In this study, we established a CoCl₂-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.</p><p><strong>Results: </strong>Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.</p><p><strong>Discussion: </strong>Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4975-4992"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Macrophage Phenotype for Treating Heart Failure: A New Approach.","authors":"Min Shi, Hui Yuan, Ya Li, Zhihua Guo, Jiaming Wei","doi":"10.2147/DDDT.S486816","DOIUrl":"https://doi.org/10.2147/DDDT.S486816","url":null,"abstract":"<p><p>Heart failure (HF) is a disease with high morbidity and mortality rates worldwide and significantly affects human health. Currently, the treatment options for HF are limited, and there is an urgent need to discover new therapeutic targets and strategies. Macrophages are innate immune cells involved in the development of HF. They play a crucial role in maintaining cardiac homeostasis and regulating cardiac stress. Recently, macrophages have received increasing attention as potential targets for treating HF. With the improvement of technological means, the study of macrophages in HF has made great progress. This article discusses the biological functions of macrophage phagocytosis, immune response, and tissue repair. The polarization, pyroptosis, autophagy, and apoptosis are of macrophages, deeply involved in the pathogenesis of HF. Modulation of the phenotypic changes of macrophages can improve immune-inflammation, myocardial fibrosis, energy metabolism, apoptosis, and angiogenesis in HF.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4927-4942"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalpol Enhances Osteogenic Differentiation of Human Periodontal Stem Cells and Modulates Periodontal Tissue Remodeling in an Orthodontic Tooth Movement Rat Model.","authors":"Jing Hu, Yang Song, Yuxing Zhang, Peng Yang, Siyu Chen, Zhaoyan Wu, Jun Zhang","doi":"10.2147/DDDT.S482969","DOIUrl":"https://doi.org/10.2147/DDDT.S482969","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;This study examines the effects and mechanisms of catalpol (CAT) on the proliferation and osteogenic differentiation of cultured human periodontal ligament stem cells (hPDLSCs) in vitro and assesses the impact of CAT on periodontal remodeling in vivo using an orthodontic tooth movement (OTM) model in rats.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;hPDLSCs were cultured in a laboratory setting, and their proliferation and osteogenic differentiation were assessed using the Cell-counting Kit-8 (CCK-8), Alizarin Red Staining (ARS), quantitative calcium assay, alkaline phosphatase (ALP) staining and activity assay, and immunofluorescence assay. Additionally, the expression of collagen type 1 (COL-1), ALP, and runt-related transcription factor-2 (RUNX-2) was evaluated through qRT-PCR and Western blot analysis. To verify the function of the estrogen receptor-α (ER-α)-mediated phosphatidylinositol-3-kinase-protein kinase B (PI3K/AKT) pathway in this mechanism, LY294002 (a PI3K signaling pathway inhibitor) and the ER-α specific inhibitor methyl-piperidine-pyrazole (MPP) were used. The osteogenic markers ER-α, AKT, and p-AKT (phosphoprotein kinase B) were identified through Western blot analysis. Eighteen male Sprague-Dawley rats were assigned to two groups randomly: a CAT group receiving CAT and a control group receiving an equivalent volume of saline. Micro-computed tomography (micro-CT) analysis was employed to evaluate tooth movement and changes in alveolar bone structure. Morphological changes in the periodontal tissues between the roots were investigated using hematoxylin and eosin (HE) staining and tartaric-resistant acid phosphatase (TRAP) staining. The expression of COL-1, RUNX-2, and nuclear factor-κB (NF-κB) ligand (RANKL) was assessed through immunohistochemical staining (IHC) to evaluate periodontal tissue remodeling. Tests were analyzed using GraphPad Prism 8 software. Differences among more than two groups were analyzed by one-way or two-way analysis of variance (ANOVA) followed by the Tukey's test. Values of &lt;i&gt;p&lt;/i&gt; &lt; 0.05 were regarded as statistically significant.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In vitro experiments demonstrated that 10 μM CAT significantly promoted the proliferation, ALP activity, and calcium nodule formation of hPDLSCs, with a notable increase in the expression of COL-1, ALP, RUNX-2, ER-α, and p-AKT. The PI3K/AKT pathway was inhibited by LY294002, and further analysis using MPP suggested that ER-α mediated this effect. In vivo, experiments indicated that CAT enhanced the expression of COL-1 and RUNX-2 on the tension side of rat tooth roots, reduced the number of osteoclasts on the compression side, inhibited RANKL expression, and suppressed OTM.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;CAT can promote hPDLSCs proliferation and osteogenic differentiation in vitro through the ER-α/PI3K/AKT pathway and enhance periodontal tissue remodeling in vivo using OTM models. These findings suggest the potential for the","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4943-4960"},"PeriodicalIF":4.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11546164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}