RESUMO
Protein and peptide-based drugs have greater therapeutic efficacy and potential application and lower toxicity compared to chemical entities in long-term use within optimum concentration as they are easily biodegradable due to biological origin. While oral administration is preferable, most of these substances are currently administered intravenously or subcutaneously. This is primarily due to the breakdown and poor absorption in the GI tract. Hence, ongoing research is focused on investigating absorption enhancers, enzyme inhibitors, carrier systems, and stability enhancers as potential strategies to facilitate the oral administration of proteins and peptides. Investigations have been directed towards advancing novel technologies to address gastrointestinal (GI) barriers associated with protein and peptide medications. The current review intensifies formulation and stability approaches for oral protein & peptide drug delivery systems with all significant parameters intended for patient safety. Notably, certain innovative technologies have been patented and are currently undergoing clinical trials or have already been introduced into the market. All the approaches stated for the administration of protein and peptide drugs are critically discussed, having their current status, future directions, and recent patents published in the last decades.
Assuntos
Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Patentes como Assunto , Peptídeos , Proteínas , Humanos , Peptídeos/administração & dosagem , Administração Oral , Sistemas de Liberação de Medicamentos/métodos , Proteínas/administração & dosagem , Proteínas/farmacocinética , AnimaisRESUMO
Background and Purpose: Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. Methods: We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. Results: PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. Conclusion: ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.
Assuntos
Infarto do Miocárdio , Miócitos Cardíacos , Polietilenoglicóis , Espécies Reativas de Oxigênio , Animais , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Modelos Animais de Doenças , Hormônio Liberador de Hormônio do Crescimento/agonistas , Hormônio Liberador de Hormônio do Crescimento/farmacocinética , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Apoptose/efeitos dos fármacos , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologia , Sulfetos/administração & dosagem , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BLRESUMO
Current pharmacotherapy remains futile in acute alveolar inflammation induced by Gram-negative bacteria (GNB), eliciting consequent respiratory failure. The release of lipid polysaccharides after antibiotic treatment and subsequent progress of proinflammatory cascade highlights the necessity to apply effective inflammation management simultaneously. This work describes modular self-assembling peptides for rapid anti-inflammatory programming (SPRAY) to form nanoparticles targeting macrophage specifically, having anti-inflammation and bactericidal functions synchronously. SPRAY nanoparticles accelerate the self-delivery process in macrophages via lysosomal membrane permeabilization, maintaining anti-inflammatory programming in macrophages with efficacy close to T helper 2 cytokines. By pulmonary deposition, SPRAY nanoparticles effectively suppress inflammatory infiltration and promote alveoli regeneration in murine aseptic acute lung injury. Moreover, SPRAY nanoparticles efficiently eradicate multidrug-resistant GNB in alveoli by disrupting bacterial membrane. The universal molecular design of SPRAY nanoparticles provides a robust and clinically unseen local strategy in reverse acute inflammation featured by a high accumulation of proinflammatory cellularity and drug-resistant bacteria.
Assuntos
Infecções por Bactérias Gram-Negativas , Nanopartículas , Animais , Camundongos , Nanopartículas/química , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Administração por Inalação , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologiaRESUMO
OBJECTIVE: Osteoarthritis (OA) is the most common joint disorder in humans and dogs. Due to its chronic progressive nature, the predominant clinical signs after a certain point are pain and immobility. The similar pathogenesis allows conclusions to be drawn from canine to human OA. Current treatments are limited and often attempt to treat OA symptoms rather than improve joint structure and function. Collagen hydrolysates as oral supplements are a promising therapeutic option to achieve this advanced therapeutic aim in both species. The effects of oral supplementation were therefore investigated in canine OA patients. METHOD: In a systematic, placebo-controlled, double-blind interventional study in 31 dogs with naturally occurring OA, the efficacy of oral supplementation of specific bioactive collagen peptides (BCP) was tested in comparison to the approved combination of the active substances omega-3 fatty acids and vitamin E. The dogs were examined on a horizontal treadmill with 4 integrated piezoelectric force plates at the beginning and end of a twelve-week test period. At both points, the owners completed a specific questionnaire containing the validated Canine Brief Pain Inventory (CBPI) and the dogs were fitted with accelerometers to record total daily activity data. RESULTS: Only the oral supplementation of BCP resulted in a significant improvement of several kinetic parameters measured using a force-plate fitted treadmill, and the quality of life assessed by CBPI, while accelerometry was unaffected by the intervention. CONCLUSION: The results of this three-month BCP supplementation study using objective measurement parameters in dogs with naturally occurring OA demonstrate an efficacy, suggesting the therapeutic use of BCP in canine OA patients and demonstrating the relevance of this collagen hydrolysate formulation for the treatment of OA in human patients as well.
Assuntos
Colágeno , Suplementos Nutricionais , Marcha , Osteoartrite , Qualidade de Vida , Animais , Cães , Osteoartrite/veterinária , Osteoartrite/tratamento farmacológico , Osteoartrite/dietoterapia , Administração Oral , Masculino , Marcha/efeitos dos fármacos , Feminino , Modelos Animais de Doenças , Método Duplo-Cego , Peptídeos/uso terapêutico , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Doenças do Cão/tratamento farmacológico , Doenças do Cão/dietoterapiaRESUMO
Lack of effective tumorspecific delivery systems remains an unmet clinical challenge for the employment of chemotherapy using cytotoxic drugs. Extracellular vesicles (EVs) have recently been investigated for their potential as an efficient drugdelivery platform, due to their good biodistribution, biocompatibility and low immunogenicity. In the present study, the formulation of GE11 peptidemodified EVs (GE11EVs) loaded with doxorubicin (DoxGE11EVs), was developed to target epidermal growth factor receptor (EGFR)positive tumor cells. The results obtained demonstrated that GE11EVs exhibited highly efficient targeting and drug delivery to EGFRpositive tumor cells compared with nonmodified EVs. Furthermore, treatment with DoxGE11EVs led to a significantly inhibition of cell proliferation and increased apoptosis of EGFRpositive tumor cells compared with DoxEVs and free Dox treatments. In addition, it was observed that treatment with either free Dox or DoxEVs exhibited a high level of cytotoxicity to normal cells, whereas treatment with DoxGE11EVs had only a limited effect on cell viability of normal cells. Taken together, the findings of the present study demonstrated that the engineered DoxGE11EVs can treat EGFRpositive tumors more accurately and have higher safety than traditional tumor therapies.
Assuntos
Proliferação de Células , Doxorrubicina , Sistemas de Liberação de Medicamentos , Receptores ErbB , Vesículas Extracelulares , Peptídeos , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Receptores ErbB/metabolismo , Humanos , Vesículas Extracelulares/metabolismo , Proliferação de Células/efeitos dos fármacos , Peptídeos/administração & dosagem , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).
Assuntos
Eptifibatida , Hemorragias Intracranianas , AVC Isquêmico , Peptídeos , Ácidos Pipecólicos , Sulfonamidas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Arginina/administração & dosagem , Arginina/efeitos adversos , Arginina/análogos & derivados , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Eptifibatida/administração & dosagem , Eptifibatida/efeitos adversos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Infusões Intravenosas , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/epidemiologia , AVC Isquêmico/mortalidade , AVC Isquêmico/terapia , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Ácidos Pipecólicos/administração & dosagem , Ácidos Pipecólicos/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Método Simples-Cego , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Terapia Trombolítica/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Trombectomia/efeitos adversos , Trombectomia/métodos , Resultado do Tratamento , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Incidência , AdultoRESUMO
The oral administration of antioxidants may suppress UV-B-induced skin damage. HITHION YH-15, the extract of Torula yeast (Cyberlindnera jadinii), is rich in cysteine-containing peptides such as reduced and oxidized glutathione (GSH and GSSG), γ-glutamylcysteine (γ-Glu-Cys), and cysteinylglycine (Cys-Gly). These four constituents are termed cysteine peptides. In this study, we investigated the protective effects of cysteine peptides against UV-B in a randomized, placebo-controlled, double-blind, parallel-group study. A total of 90 healthy males and females aged 30-59 years were enrolled and randomized into two groups of 45 individuals each (cysteine peptides (48 mg/day) and placebo). Changes in UV-B-induced erythema and pigmentation were compared between groups after 5 weeks of test food intake. The minimal erythema dose (MED) significantly increased (*p = 0.019) in the cysteine peptides group compared to that in the placebo group, indicating suppression of UV-B-induced erythema. ΔL* value significantly increased (***p < 0.0001) in the cysteine peptides group compared to that in the placebo, indicating pigmentation suppression. We demonstrated that oral administration of cysteine peptides suppresses UV-B-induced erythema and pigmentation through multiple mechanisms. Thus, cysteine peptides may find use as nutricosmetics for maintaining skin health and well-being.UMIN Clinical Trials Registry ID: UMIN 000050157.
Assuntos
Cisteína , Eritema , Pigmentação da Pele , Raios Ultravioleta , Humanos , Masculino , Raios Ultravioleta/efeitos adversos , Adulto , Feminino , Eritema/etiologia , Eritema/tratamento farmacológico , Eritema/prevenção & controle , Pessoa de Meia-Idade , Administração Oral , Cisteína/farmacologia , Cisteína/administração & dosagem , Método Duplo-Cego , Pigmentação da Pele/efeitos dos fármacos , Pigmentação da Pele/efeitos da radiação , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/patologia , Antioxidantes/farmacologia , Antioxidantes/administração & dosagemRESUMO
SOURCE CITATION: Meissner WG, Remy P, Giordana C, et al; LIXIPARK Study Group. Trial of lixisenatide in early Parkinson's disease. N Engl J Med. 2024;390:1176-1185. 38598572.
Assuntos
Progressão da Doença , Doença de Parkinson , Peptídeos , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Peptídeos/uso terapêutico , Peptídeos/administração & dosagem , Injeções Subcutâneas , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Receptor do Peptídeo Semelhante ao Glucagon 2RESUMO
BACKGROUND AND AIM: The ideal bowel cleansing program still needs to be explored. The aim was to compare the bowel cleansing effect and patient tolerance of low-dose polyethylene glycol (PEG) combined with different doses of linaclotide in fractionated bowel preparation. METHODS: The subjects were randomly assigned to the 3LPEG group, 2LPEG + 2L group, or 2LPEG + L group. The primary outcome was to use the Ottawa Bowel Preparation Scale (OBPS) to evaluate the efficacy of bowel cleansing, and the secondary outcomes were the detection rate of adenomas and polyps, adverse reactions, tolerance, and defecation dynamics; subsets of patients with chronic constipation and irritable bowel syndrome were also analyzed. RESULTS: A total of 753 patients were randomly assigned. In ITT analysis, the success of preparation of the 2LPEG + 2L group was better than that of the 2LPEG + L group or the 3LPEG group (92.0% vs. 82.3% vs. 82.1%; P = 0.002). Compared with the 3LPEG group, the 2LPEG + L group showed similar but non-inferior results (82.3% vs. 82.1%, P > 0.05). The 2LPEG + 2L group was similar to the 2LPEG + L group in terms of adverse reaction, tolerance, willingness to reuse, and sleep quality, but both were superior to the 3LPEG group. In a subgroup analysis of chronic constipation, the 2LPEG + 2L group had the best cleansing effect on the right colon and mid colon, while in the subgroup analysis of irritable bowel syndrome, the tolerance was better in the 2LPEG + 2L group and the 2LPEG + L group than the 3LPEG group. CONCLUSIONS: 2LPEG + 2L is a feasible bowel preparation regimen.
Assuntos
Colonoscopia , Polietilenoglicóis , Humanos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Catárticos/administração & dosagem , Catárticos/efeitos adversos , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Constipação Intestinal , Adulto , Relação Dose-Resposta a Droga , Idoso , Defecação/efeitos dos fármacos , Resultado do Tratamento , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/diagnósticoRESUMO
BACKGROUND AND AIMS: Information on effective bowel preparation (BP) methods for patients with constipation is limited. We recently reported the efficacy of 1 L polyethylene glycol plus ascorbic acid (PEG-Asc) combined with senna for BP; however, this regimen was insufficient in patients with constipation. We hypothesized that the addition of linaclotide, which is approved for the treatment of chronic constipation, to 1 L PEG-Asc would yield results superior to those of senna in patients with constipation. METHODS: This was a retrospective, single-center study that included outpatients with constipation who underwent BP prior to colonoscopy between March and December 2019 (receiving 1 L PEG-Asc with 24 mg senna) and between January and October 2020 (receiving 1 L PEG-Asc with 500 mg linaclotide). RESULTS: A total of 543 patients with constipation were included, of whom 269 received linaclotide and 274 received senna. The rate of inadequate BP was significantly lower (11% vs 20%, p < 0.01) and the adenoma detection rate was significantly higher (54% vs 45%, p = 0.04) in the linaclotide group than in the senna group. Multivariate analysis revealed that the linaclotide regimen significantly reduced the risk of inadequate BP (odds ratio = 0.36, 95% confidence interval = 0.21-0.60, p < 0.01). CONCLUSIONS: The linaclotide regimen significantly increased BP efficacy and the adenoma detection rate compared with the senna regimen without reducing tolerability and is therefore a promising new option for BP in patients with constipation.
Assuntos
Ácido Ascórbico , Catárticos , Colonoscopia , Constipação Intestinal , Peptídeos , Polietilenoglicóis , Humanos , Constipação Intestinal/tratamento farmacológico , Masculino , Polietilenoglicóis/administração & dosagem , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/uso terapêutico , Catárticos/administração & dosagem , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Idoso , Adulto , Doença Crônica , Extrato de Senna/administração & dosagem , Adenoma/tratamento farmacológicoRESUMO
Introduction: Asthma, a chronic respiratory disease closely associated with inflammation, presents ongoing treatment challenges. IALLIPF (le-Ala-Leu-Leu-Ile-Pro-Phe) is one of millet prolamins peptides (MPP) which shows anti-oxidant bioactivity by reducing the production of reactive oxygen species (ROS). Tryptophan (Trp, W) is an amino acid that has been demonstrated to possess anti-inflammatory effects. We introduce a novel cathepsin B-activatable bioactive peptides nanocarrier, PEG-IALLIPF-GFLG-W (MPP-Trp), designed for immunotherapy of asthma. Methods: MPP-Trp is synthesized, purified, and its characteristics are investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß) are examined to evaluate anti-inflammatory effects of IALLIPF, Trp and MPP-Trp. The immunomodulatory effects of IALLIPF, Trp and MPP-Trp on Th1/Th2 cell populations and cytokines are investigated by flow cytometry, qRT-PCR and ELISA assays. We explore the therapeutic effect of MPP-Trp in the mouse model of asthma by the analysis of lung histology and ELISA. It is necessary to study the biocompatibility of MPP-Trp by CCK8 assay and histopathologic analysis using hematoxylin and eosin (HE) staining. Results: In asthmatic peripheral blood mononuclear cells (PBMCs), IALLIPF, Trp and MPP-Trp are able to significantly alleviate inflammation by inhibiting the yield of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), especially MPP-Trp. MPP-Trp significantly upregulates Th1 cell levels while notably reducing Th2 cell levels. Furthermore, MPP-Trp effectively elevates the expression and production of interferon-gamma (IFN-γ), an essential cytokine from Th1 cells. Additionally, MPP-Trp markedly diminishes the mRNA expression and levels of key asthma pathogenesis cytokines, such as interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-5 (IL-5), in asthma PBMCs. MPP-Trp ameliorates pulmonary pathological alterations and significantly inhibits OVA-induced inflammation in mice with asthma. It has little influence on the cell viability in Asthma-PBMCs treated with various concentrations or durations of MPP-Trp. No pathological changes, including in the heart, liver, spleen, lung, and kidney tissues, are observed in non-sensitized and non-challenged mice treated with MPP-Trp (20 mg/kg). Discussion: Our research demonstrates that MPP-Trp has immunomodulatory effects on Th1/Th2 cell populations, essential in managing asthma. It considerably alleviates OVA-induced asthma by shifting the immune response towards a Th1-dominant profile, thereby reducing Th2-driven inflammation. Therefore, this novel bioactive peptide nanocarrier, MPP-Trp, holds promise as a candidate for asthma immunotherapy.
Assuntos
Asma , Catepsina B , Citocinas , Imunoterapia , Animais , Asma/tratamento farmacológico , Asma/imunologia , Camundongos , Citocinas/metabolismo , Imunoterapia/métodos , Catepsina B/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas/química , Óxido Nítrico , Portadores de Fármacos/química , Feminino , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/administração & dosagem , Células Th2/imunologia , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Humanos , Triptofano/química , Triptofano/farmacologia , Triptofano/administração & dosagem , Células Th1/imunologia , Células Th1/efeitos dos fármacosRESUMO
Age-related macular degeneration (AMD) is an eye disorder that can lead to visual impairment in elder patients, and current treatments include repeated injections of monoclonal antibody-based antivascular endothelial growth factor (anti-VEGF) agents. This study investigates the potential of a nanoformulation of a peptide anti-VEGF molecule for neovascular AMD. Anti-VEGF peptide HRHTKQRHTALH (HRH), which has high affinity to VEGF-Fc receptor, was used as the bioactive agent to control neovascularization of the retina. The nanoformulation consisting of hyaluronic acid nanogel was generated by incorporating divinyl sulfone and cholesterol to increase the stability and control the size of the nanodrug. The encapsulation efficacy of nanogel was 65%, and drug release was 34.72% at the end of 192 h. Obtained nanogels were efficiently internalized in 15 min by human umbilical vascular endothelial cells (HUVECs) and ARPE-19 cells, and results indicate that nanoformulation is not toxic to ARPE-19 cells, whereas it inhibits HUVEC proliferation owing to anti-VEGF peptide in the nanogel structure. In the coculture experiment in which retinal penetration was modeled, it was observed that the nanogel reached HUVECs and negatively affected their proliferation without disturbing the monolayer of ARPE-19 cells. In vivo experiments with chick chorioallantoic membrane revealed that nanogel formulation has higher antiangiogenesis activity compared to free HRH. Additionally, in an oxygen-induced retinopathy model, the excessive growth of blood vessels was notably suppressed in mice treated with HRH-loaded nanogel. This research indicates that nanogels formulated in this study are promising candidates as a topical treatment for AMD.
Assuntos
Nanogéis , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/química , Animais , Nanogéis/química , Tamanho da Partícula , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Teste de Materiais , Proliferação de Células/efeitos dos fármacos , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/administração & dosagem , Degeneração Macular/tratamento farmacológico , Degeneração Macular/patologia , Degeneração Macular/metabolismo , Polietilenoimina/química , Camundongos , Linhagem CelularRESUMO
BACKGROUND: Obesity and localized fat accumulation continue to drive the demand for minimally invasive body contouring technologies including injectable compounds for local fat reduction. siRNA offers a potential for an injectable to specifically target and silence genes involved in adipogenesis with minimal inflammatory side effects. AIMS: This study evaluates the efficacy of STP705, an injectable containing siRNA encapsulated within histidine-lysine polypeptide (HKP) nanoparticles targeting transforming growth factor ß1 (TGF-ß1) and cyclooxygenase-2 (COX-2), crucial mediators in adipocyte differentiation and fat retention, using in vitro, porcine, and murine models. METHODS: In vitro experiments on mouse preadipocytes and in vivo trials using Diet Induced Obese (DIO) mice and Yucatan minipigs were conducted to assess the gene silencing efficiency, tissue localization, pharmacodynamics, and safety profile of STP705. RESULTS: STP705 effectively reduced the expression of TGF-ß1 and COX-2, with a notable decrease in adipocyte volume and lipid content without adverse systemic effects. In DIO mice, the HKP-siRNA complex demonstrated precise localization to injected adipose tissue, maintaining significant gene silencing, and detectable levels of siRNA for up to 14 days post-administration. Similar results in minipigs showed a significant reduction in subcutaneous adipose tissue thickness. CONCLUSION: The results of these studies support the use of targeted siRNA therapy specifically targeting TGF-ß1 and COX-2, for localized fat reduction, offering a potential minimally invasive alternative to current fat reduction methods.
Assuntos
Adipócitos , Ciclo-Oxigenase 2 , Nanopartículas , Peptídeos , RNA Interferente Pequeno , Porco Miniatura , Fator de Crescimento Transformador beta1 , Animais , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Nanopartículas/administração & dosagem , Suínos , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Camundongos , Peptídeos/administração & dosagem , Adipócitos/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/terapia , Adipogenia/efeitos dos fármacos , Modelos Animais de Doenças , Inativação Gênica/efeitos dos fármacos , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismoRESUMO
Diabetes mellitus is a typical metabolic disease that has become a major threat to human health worldwide. Ginseng polypeptide (GP), a small molecule active substance isolated from ginseng, has shown positive hypoglycemic effects in preliminary studies. However, its mechanism in ameliorating multiorgan damage in db/db mice is unclear. In this study, we utilized network pharmacology, molecular docking, and animal experiments to explore the targets and biological mechanisms of GP to ameliorate multiorgan damage in T2DM. The results showed that GP improves T2DM by inhibiting inflammation and oxidative damage, thereby alleviating hyperglycemia, insulin resistance, and multiorgan damage in db/db mice. These effects are potentially mediated through the PI3K-Akt signaling pathway and the MAPK signaling pathway. This study establishes GP's efficacy in alleviating T2DM and provides a robust theoretical basis for the development of new drugs or functional foods for treating this disease.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Simulação de Acoplamento Molecular , Farmacologia em Rede , Panax , Peptídeos , Animais , Panax/química , Camundongos , Hipoglicemiantes/química , Hipoglicemiantes/administração & dosagem , Masculino , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Extratos Vegetais/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Resistência à Insulina , Transdução de Sinais/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/efeitos dos fármacosRESUMO
Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.
Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Convulsões , Animais , Masculino , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Pilocarpina , Ácido Caínico/análogos & derivados , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/administração & dosagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
PT1 peptide isolated from the venom of spider Geolycosa sp. is a modulator of P2X3 receptors that play a role in the development of inflammation and the transmission of pain impulses. The anti-inflammatory and analgesic efficacy of the PT1 peptide was studied in a model of complete Freund's adjuvant-induced paw inflammation in CD-1 mice. The analgesic activity of PT1 peptide was maximum after intramuscular injection at a dose of 0.01 mg/kg, which surpassed the analgesic effect of diclofenac at a dose of 1 mg/kg. The anti-inflammatory activity was maximum after intramuscular injection at a dose of 0.0001 mg/kg; a decrease in paw thickness was observed as soon as 2 h after the administration of the PT1 peptide against the background of inflammation development. All tested doses of PT1 peptide showed high anti-inflammatory activity 4 and 24 h after administration. PT1 peptide at a dose of 0.01 mg/kg when injected intramuscularly simultaneously produced high anti-inflammatory and analgesic effects compared to other doses of the peptide. Increasing the dose of PT1 peptide led to a gradual decrease in its analgesic and anti-inflammatory activity; increasing the dose of intramuscular injection to 0.1 and 1 mg/kg is inappropriate.
Assuntos
Analgésicos , Anti-Inflamatórios , Inflamação , Peptídeos , Animais , Camundongos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Masculino , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Injeções Intramusculares , Adjuvante de Freund , Venenos de Aranha/farmacologia , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Diclofenaco/administração & dosagem , Modelos Animais de Doenças , Dor/tratamento farmacológicoRESUMO
Subcutaneous (SC) injection is a common route of administration for drug compounds with poor oral bioavailability. However, bioavailability is often variable and incomplete, and there is as yet no standard accepted medium for simulation of the human SC environment. In this work we evaluate a FRAP based method for quantitative determination of local self-diffusion coefficients within extracellular matrix (ECM) mimetic hydrogels, potentially useful as in vitro models for drug transport in the ECM after SC injection. Gels were made consisting of either agarose, cross-linked collagen (COL) and hyaluronic acid (HA) or cross-linked HA. The diffusivities of uncharged FITC-dextran (FD4), the highly charged poly-lysine (PLK20) and poly-glutamic acid (PLE20) as well as the GLP-1 analogue exenatide were determined within the gels using FRAP. The diffusion coefficients in uncharged agarose gels were in the range of free diffusion in PBS. The diffusivity of cationic PLK20 in gels containing anionic HA was substantially decreased due to strong electrostatic interactions. Peptide aggregation could be observed as immobile fractions in experiments with exenatide. We conclude that the FRAP method provides useful information of peptides' interactions and transport properties in hydrogel networks, giving insight into the mechanisms affecting absorption of drug compounds after subcutaneous injection.
Assuntos
Dextranos , Exenatida , Matriz Extracelular , Ácido Hialurônico , Hidrogéis , Peptídeos , Hidrogéis/química , Difusão , Matriz Extracelular/metabolismo , Injeções Subcutâneas , Exenatida/farmacocinética , Exenatida/química , Exenatida/administração & dosagem , Ácido Hialurônico/química , Dextranos/química , Dextranos/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Ácido Poliglutâmico/química , Ácido Poliglutâmico/análogos & derivados , Polilisina/química , Colágeno/química , Sefarose/química , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/administração & dosagem , Fluoresceína-5-Isotiocianato/farmacocinética , HumanosRESUMO
Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient's life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1ß) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.
Assuntos
Analgésicos , Anti-Inflamatórios , Ciclo-Oxigenase 2 , Edema , Inflamação , Dor , Animais , Analgésicos/uso terapêutico , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Camundongos , Dor/tratamento farmacológico , Masculino , Inflamação/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Edema/tratamento farmacológico , Edema/induzido quimicamente , Venenos de Anfíbios/uso terapêutico , Venenos de Anfíbios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Citocinas/metabolismo , Peptídeos/uso terapêutico , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Humanos , Modelos Animais de Doenças , Carragenina , Mediadores da Inflamação/metabolismo , Dinoprostona/metabolismoRESUMO
BACKGROUND & AIMS: Skeletal muscle is an important contributor to joint health. Previous studies have shown that age-related muscle mass and strength loss are closely associated with the development of knee osteoarthritis. The objective of this study is to investigate whether a high plant protein/peptide nutrition supplementation can alleviate knee osteoarthritis by improving muscle mass and strength. METHODS: This randomized, double-blind, placebo-controlled trial that included participants aged 50-70 years diagnosed with knee osteoarthritis and sarcopenia was conducted in China from February 2022 to September 2022 (ChiCTR2200056415). Participants were randomly assigned to receive either a 12-week high plant protein/peptide nutrition supplementation or a placebo twice daily, with one serving each after breakfast and dinner, respectively. The primary outcome analyzed using intention-to-treat analysis was difference in Short Physical Performance Battery (SPPB) from baseline to week 12 between the two groups. The secondary outcomes included changes in muscle mass, strength, symptom and imaging of knee osteoarthritis, body composition, biochemical parameters, and health quality scores. RESULTS: After 12 weeks, a total of 124 participants (38.7% male) completed the trial and were included in the final analysis. Over the 12-week follow-up, the experimental group showed a significant improvement in the SPPB total score (1.03, 95% CI, 0.69 to 1.38, P < 0.0001) compared with the placebo group. Grip strength (2.83 kg, 95% CI, 2.13 to 3.53, P < 0.0001) and skeletal muscle mass index (0.66 kg/m2, 95% CI, 0.45 to 0.86, P < 0.0001) were also significantly increased in the experimental group relative to the placebo group. The mean change in Western Ontario and McMaster Universities Osteoarthritis Index total score was -3.95 points (95% CI, -5.02 to -2.89, P < 0.0001) in the experimental group and 0.23 points (95% CI, -0.17 to 0.63, P = 0.253) in the placebo group. Additionally, within the experimental group, nine participants experienced an improvement in osteophyte magnetic resonance imaging results, while no improvement was observed in the placebo group. The experimental group also exhibited significant improvements in health quality compared with the placebo group as assessed by Short Form 36, the World Health Organization Quality of Life Brief Scale, and the Chalder Fatigue Scale. No serious adverse events were reported during the trial. CONCLUSION: Oral supplementation with high levels of plant protein/peptides can alleviate symptoms of osteoarthritis in elderly individuals with minor or mild knee osteoarthritis and sarcopenia. This improvement may be attributed to the enhancements of muscle mass, strength, and physical performance.
Assuntos
Suplementos Nutricionais , Osteoartrite do Joelho , Sarcopenia , Humanos , Método Duplo-Cego , Osteoartrite do Joelho/dietoterapia , Osteoartrite do Joelho/terapia , Masculino , Feminino , Idoso , Sarcopenia/dietoterapia , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Peptídeos/administração & dosagem , Proteínas de Plantas/administração & dosagem , Resultado do Tratamento , Composição Corporal , ChinaRESUMO
This study aimed to investigate the effects of corn gluten-derived soluble epoxide hydrolase (sEH) inhibitory peptides on nonalcoholic fatty liver fibrosis induced by a high-fat diet and carbon tetrachloride in mice. Mice treated with corn peptides at doses of 500 or 1000 mg/kg/d for 4 weeks exhibited reduced sEH activity in serum and liver, enhanced lipid metabolism, and decreased lipid accumulation and oxidative stress. Corn peptides effectively downregulated the mRNA levels of Pro-IL-1ß, Pro-IL-18, NOD-like receptor protein 3 (NLRP3), ASC, Pro-caspase-1, Caspase-1, and GSDMD in the liver. This hepatoprotective effect of corn peptides by inhibiting NLRP3 inflammasome activation was further validated in H2O2-induced HepG2 cells. Moreover, corn peptides restored the composition of the gut microbiota and promoted short-chain fatty acid production. This study provides evidence that corn-derived sEH inhibitory peptides have hepatoprotective activity against nonalcoholic fatty liver fibrosis by suppressing NLRP3 inflammasome activation and modulating gut microbiota.