RESUMO
Aging-related sarcopenia exerts harmful impacts on muscle mass, strength, and physical mobility. Protein supplementation has been demonstrated to augment efficacy of resistance training (RT) in elderly. This study compared the relative effects of different protein supplements on muscle mass, strength, and mobility outcomes in middle-aged and older individuals undergoing RT. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) examining the efficacy of protein supplement plus RT in untrained community-dwelling adults, hospitalized, or institutionalized residents who suffered acute or chronic health conditions. Network meta-analysis (NMA) was performed using a frequentist method for all analyses. Treatment effects for main outcomes were expressed as standard mean difference (SMD) with 95% confidence interval (CI). We used the surface-under-the cumulative-ranking (SUCRA) scores to rank probabilities of effect estimation among all identified treatments. Meta-regression analyses were performed to identify any relevant moderator of the treatment efficacy and results were expressed as ß with 95% credible interval (CrI). We finally included 78 RCTs (5272 participants) for analyses. Among the six protein sources identified in this NMA, namely whey, milk, casein, meat, soy, and peanut, whey supplement yielded the most effective treatments augmenting efficacy of RT on muscle mass (SMD = 1.29, 95% CI: 0.96, 1.62; SUCRA = 0.86), handgrip strength (SMD = 1.46, 95% CI: 0.92, 2.00; SUCRA = 0.85), and walking speed (SMD = 0.73, 95% CI: 0.39, 1.07; SUCRA = 0.84). Participant's health condition, sex, and supplementation dose were significant factors moderating the treatment efficacy on muscle mass (ß = 0.74; 95% CrI: 0.22, 1.25), handgrip strength (ß = -1.72; 95% CrI: -2.68, -0.77), and leg strength (ß = 0.76; 95% CrI: 0.06, 1.47), respectively. Our findings suggest whey protein yields the optimal supplements to counter sarcopenia in older individuals undergoing RT.
Assuntos
Proteínas Alimentares , Suplementos Nutricionais , Força Muscular , Músculo Esquelético , Ensaios Clínicos Controlados Aleatórios como Assunto , Treinamento Resistido , Sarcopenia , Humanos , Idoso , Força Muscular/efeitos dos fármacos , Proteínas Alimentares/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Masculino , Vida Independente , Feminino , Metanálise em Rede , Hospitalização , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
Knee osteoarthritis (KOA) is associated with a high risk of sarcopenia. Both intra-articular injections (IAIs) and physical therapy (PT) exert benefits in KOA. This network meta-analysis (NMA) study aimed to identify comparative efficacy among the combined treatments (IAI+PT) in patients with KOA. Seven electronic databases were systematically searched from inception until January 2023 for randomized controlled trials (RCTs) reporting the effects of IAI+PT vs. IAI or PT alone in patients with KOA. All RCTs which had treatment arms of IAI agents (autologous conditioned serum, botulinum neurotoxin type A, corticosteroids, dextrose prolotherapy (DxTP), hyaluronic acid, mesenchymal stem cells (MSC), ozone, platelet-rich plasma, plasma rich in growth factor, and stromal vascular fraction of adipose tissue) in combination with PT (exercise therapy, physical agent modalities (electrotherapy, shockwave therapy, thermal therapy), and physical activity training) were included in this NMA. A control arm receiving placebo IAI or usual care, without any other IAI or PT, was used as the reference group. The selected RCTs were analyzed through a frequentist method of NMA. The main outcomes included pain, global function (GF), and walking capability (WC). Meta-regression analyses were performed to explore potential moderators of the treatment efficacy. We included 80 RCTs (6934 patients) for analyses. Among the ten identified IAI+PT regimens, DxTP plus PT was the most optimal treatment for pain reduction (standard mean difference (SMD) = -2.54) and global function restoration (SMD = 2.28), whereas MSC plus PT was the most effective for enhancing WC recovery (SMD = 2.54). More severe KOA was associated with greater changes in pain (ß = -2.52) and WC (ß = 2.16) scores. Combined IAI+PT treatments afford more benefits than do their corresponding monotherapies in patients with KOA; however, treatment efficacy is moderated by disease severity.
Assuntos
Osteoartrite do Joelho , Sarcopenia , Humanos , Terapia por Exercício , Ácido Hialurônico , Injeções Intra-Articulares , Metanálise em Rede , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcopenia/tratamento farmacológico , Resultado do TratamentoRESUMO
Surgical resection and ablation therapy have been shown to achieve the purpose of a radical cure for liver cancer with a size of less than 3 cm; however, tiny liver cancer lesions of diameters smaller than 2 cm remain challenging to diagnose and cure due to the failure of the generation of new blood vessels within tumors. Emerging evidence has revealed that optical molecular imaging combined with nanoprobes can detect tiny cancer from the perspective of molecular and cellular levels and kill cancer cells by the photothermal effect of nanoparticles in real time, thereby achieving radical goals. In the present study, we designed and synthesized multicomponent and multifunctional ICG-CuS-Gd@BSA-EpCAM nanoparticles (NPs) with a potent antineoplastic effect on tiny liver cancer. Using subcutaneous and orthotopic liver cancer xenograft mouse models, we found that the components of the NPs, including ICG and CuS-Gd@BSA, showed synergistic photothermal effects on the eradication of tiny liver cancer. We also found that the ICG-CuS-Gd@BSA-EpCAM NPs exhibited triple-modal functions of fluorescence imaging, magnetic resonance imaging, and photoacoustic imaging, with targeted detection and photothermal treatment of tiny liver cancer under near-infrared light irradiation. Together, our study demonstrates that the ICG-CuS-Gd@BSA-EpCAM NPs in combination with optical imaging technique might be a potential approach for detecting and noninvasively and radically curing tiny liver cancer by the photothermal effect.
Assuntos
Antineoplásicos , Neoplasias Hepáticas , Nanopartículas , Humanos , Animais , Camundongos , Terapia Fototérmica , Molécula de Adesão da Célula Epitelial , Fototerapia/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapiaRESUMO
Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Bevacizumab/uso terapêutico , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Sorafenibe/uso terapêuticoRESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH), characterized by pulmonary artery constriction and vascular remodeling, has a high mortality rate. New drugs for the treatment of PAH urgently need to be developed. PURPOSE: This study was designed to investigate the vasorelaxant activity of OTNA in isolated pulmonary arteries, and explore its molecular mechanism. METHODS: Pulmonary arteries and thoracic aortas were isolated from mice, and vascular tone was tested with a Wire Myograph System. Nitric oxide levels were determined with DAF-FM DA and DAX-J2™ Red. Cellular thermal shift assays, microscale thermophoresis, and molecular docking were used to identify the interaction between OTNA and aryl hydrocarbon receptor (AhR). The levels of PI3K, p-PI3K, Akt, p-Akt, eNOS, p-eNOS, and AhR were analyzed by Western blotting. RESULTS: OTNA selectively relaxed the isolated pulmonary artery rings in an endothelium-dependent manner. Mechanistic study showed that OTNA induced NO production through activation of the PI3K/Akt/eNOS pathway in endothelial cells. Furthermore, we also found that OTNA directly bound to AhR and activated the PI3K/Akt/eNOS pathway to dilate pulmonary arteries by inhibiting AhR. CONCLUSIONS: OTNA relaxes pulmonary arteries by antagonizing AhR. This study provides a new natural antagonist of AhR as a promising lead compound for PAH treatment.
Assuntos
Fosfatidilinositol 3-Quinases , Artéria Pulmonar , Animais , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Alcaloides Indólicos , Camundongos , Simulação de Acoplamento Molecular , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Therapeutic angiogenesis is a novel strategy for the treatment of ischemic diseases that involves promotion of angiogenesis in ischemic tissues via the use of proangiogenic agents. However, effective proangiogenic drugs that activate the Ang2/Tie2 signaling pathway remain scarce. PURPOSE: We aimed to investigate the proangiogenic activity of notoginsenoside R1 (NR1) isolated from total saponins of Panax notoginseng with regard to activation of the Ang2/Tie2 signaling pathway. METHODS: We examined the proangiogenic effects of NR1 by assessing the effects of NR1 on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). The aortic ring assay and vascular endothelial growth factor receptor inhibitor (VRI)-induced vascular regression in the zebrafish model were used to confirm the proangiogenic effects of NR1 ex vivo and in vivo. Furthermore, the molecular mechanism was investigated by Western blot analysis. RESULTS: We found that NR1 promoted the proliferation, mobility and tube formation of HUVECs in vitro. NR1 also increased the number of sprouting vessels in rat aortic rings and rescued VRI-induced vascular regression in zebrafish. NR1-induced angiogenesis was dependent on Tie2 receptor activation mediated by increased autocrine Ang2 in HUVECs, and inhibition of the Ang2/Tie2 pathway abrogated the proangiogenic effects of NR1. CONCLUSIONS: Our results suggest that NR1 promotes angiogenesis by activating the Ang2/Tie2 signaling pathway. Thus, NR1-induced activation of the Ang2/Tie2 pathway is an effective proangiogenic approach. NR1 may be useful agent for the treatment of ischemic diseases.
Assuntos
Angiopoietina-2/metabolismo , Ginsenosídeos/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Receptor TIE-2/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Axitinibe/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Fisiológica/fisiologia , Panax notoginseng/química , Ratos Sprague-Dawley , Peixe-Zebra/embriologiaRESUMO
Ischemic stroke is one of the most lethal and highly disabling diseases that seriously affects the human health and quality of life. A therapeutic angiogenic strategy has been proposed to alleviate ischemia-induced injury by promoting angiogenesis and improving cerebrovascular function in the ischemic regions. The insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF1R) axis is crucial for cerebral angiogenesis and neurogenesis. However, effective drugs that prevent cerebral ischemic injury by inducing cerebral angiogenesis via activation of the IGF1R pathway are lacking. Here, we screened a pro-angiogenic agent ginsenoside F1 (GF1), a ginseng saponin isolated from a traditional Chinese medicine that was widely used in ischemic stroke treatment. It promoted the proliferation, mobility and tube formation of human umbilical vein endothelial cells and human brain microvascular endothelial cells, as well as pericytes recruitment to the endothelial tubes. GF1 stimulated vessel sprouting in the rat arterial ring and facilitated neovascularization in chicken embryo chorioallantoic membrane (CAM). In the in vivo experiments, GF1 rescued the axitinib-induced vascular defect in zebrafish. It also increased the microvessel density (MVD) and improved focal cerebral blood perfusion in the rat middle cerebral artery occlusion (MCAO) model. Mechanism studies revealed that GF1-induced angiogenesis depended on IGF1R activation mediated by the autocrine IGF-1 loop in endothelial cells. Based on our findings, GF1-induced activation of the IGF-1/IGF1R pathway to promote angiogenesis is an effective approach to alleviate cerebral ischemia, and GF1 is a potential agent that improves cerebrovascular function and promotes recovery from ischemic stroke.
Assuntos
Indutores da Angiogênese/farmacologia , Ginsenosídeos/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Ratos Sprague-Dawley , Ratos Wistar , Peixe-ZebraRESUMO
Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence demonstrates the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition by natural compounds may be a promising strategy for overcoming drug resistance in liver cancer cells. Here, we found that ADCX, a natural cycloartane triterpenoid extracted from the traditional Chinese medicine (TCM) source Cimicifugae rhizoma (Shengma), impaired autophagic degradation by suppressing lysosomal cathepsin B (CTSB) expression in multidrug-resistant liver cancer HepG2/ADM cells, thereby leading to autophagic flux inhibition. Moreover, impairing autophagic flux promoted ADCX-induced apoptotic cell death in HepG2/ADM cells. Interestingly, Akt was overactivated by ADCX treatment, which downregulated CTSB and inhibited autophagic flux. Together, our results provide the first demonstration that an active TCM constituent can overcome multidrug resistance in liver cancer cells via Akt-mediated inhibition of autophagic degradation.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/genética , Saponinas/química , Triterpenos/químicaRESUMO
Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.