RESUMO
To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.
Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Vitamina E , Animais , Camundongos , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Fator Estimulador de Colônias de Granulócitos/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Primatas , Proteínas Recombinantes/farmacologia , Vitamina E/análogos & derivados , Vitamina E/uso terapêuticoRESUMO
Major depressive disorder (MDD) ranks among the top 10 leading causes of death. However, exercise is known to improve depressive symptoms but the mechanism responsible is still unknown. To date, numerous studies have shown that molecular rhythms and exercise are associated with MDD. Thus, we hypothesized that exercise could affect the expression of central nervous system clock genes to improve depressive symptoms. Ninety adult male Sprague-Dawley rats (250 g) were divided into a control Normal Group, an unpredictable chronic mild stress (CMS) treated CMS Group and an Exercise Group, which was intervened by a moderate-intensity exercise training on a treadmill at 2 p.m. every day for 4 weeks after CMS treatment. The open field test, elevated plus maze and forced swim test were employed to test mood-related behaviors. The telemetry recording method recorded voluntary locomotor activity and core body temperature. Expression of core clock genes in the suprachiasmatic nucleus (SCN) was tested by qRT-PCR. Compared with the CMS Group, depressive symptoms were improved in the Exercise Group ( P â <â 0.05). Moreover, the periodic changes of molecular rhythms in the Exercise Group were close to those of rats in Normal Group. Next, exercise increased oscillations of expression of core clock genes in SCN after CMS treatment, and the amplitudes of core clock gene expression oscillations were negatively correlated with depressive-like behavior. Our findings suggested that exercise could change the expressions of central clock genes in MDD animals, and this effect was positively correlated with the improvement of depressive symptoms by exercise.
Assuntos
Depressão , Transtorno Depressivo Maior , Ratos , Masculino , Animais , Depressão/metabolismo , Ratos Sprague-Dawley , Núcleo Supraquiasmático/metabolismo , Exercício Físico , Modelos Animais de DoençasRESUMO
A series of derivatives of salidroside with mirror isomer glucose and different phenyl moieties were synthesized by Schmidt glycosylation in satisfactory yields, and their antioxidant and anti-inflammatory activities were evaluated by using LPS-induced RAW264.7 cells. One of the synthesized derivatives Ê-Sal-4, bearing Ê-glycosyl and -OMe modification at the phenyl ring, exhibited high activity in inhibiting the production of pro-inflammatory cytokines and oxidative stress biomarker MDA as well as in enhancing the activity of SOD enzyme, compared with the natural product and its corresponding á´ -enantiomer. Further proteomic analysis suggested that Ê-Sal-4 exerted its anti-inflammatory activity through metabolic reprogramming. The in vitro activity showed that Ê-Sal-4 is a potent antioxidant and anti-inflammatory agent. Our finding indicated that the Ê-glucose-derived salidroside might be a promising lead compound in the development of salidroside derivatives as therapeutic agents.
Assuntos
Anti-Inflamatórios , Antioxidantes , Glucosídeos , Fenóis , Fenóis/farmacologia , Fenóis/química , Fenóis/síntese química , Camundongos , Animais , Glucosídeos/farmacologia , Glucosídeos/síntese química , Glucosídeos/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Relação Estrutura-Atividade , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Acute kidney injury (AKI), characterized by necroptosis and activation of MAPK pathway, causes sudden declines in renal function. To date, efficacious treatments are lacking. JianPiYiShen Formula (JPYSF) has a protective effect on the kidneys. The aim of this study is to explore the mechanism of JPYSF in cisplatin-induced AKI. METHODS: Male C57/BL6J mice were divided into control group, cisplatin group and cisplatin + JPYSF group. Before establishing the model, the cisplatin + JPYSF group was administered JPYSF (18.35 g/kg/day) by gavage for 5 consecutive days. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to establish AKI model. Measurement of renal function and H&E staining were performed to assess renal damage. WB, PCR, TUNEL staining and immunohistochemistry were used to detect related indicators of mitochondrial function, oxidative stress, necroptosis, inflammation and MAPK pathway. And one-way analysis of variance was used to compare group differences. RESULTS: Compared with the cisplatin group, JPYSF can attenuate AKI, reflected by the decrease in Scr and BUN levels, the improvement of renal tubular injury, and the downregulation of NGAL and KIM1. Cisplatin can induce mitochondrial dysfunction and oxidative stress, triggering necroptosis. In this study, JPYSF improved mitochondrial dysfunction to enhance oxidative stress, as manifested by upregulation of OPA1, PGC-1α, SOD and CAT, and downregulation of DRP1 and MFF. Then JPYSF showed a significant protective effect in necroptosis, as embodied by reduced number of TUNEL-positive cells, decreased the gene expression of RIPK3 and MLKL, as well as downregulation the proteins expression of P-RIPK1, P-RIPK3, and P-MLKL. Moreover, necroptosis can aggravate inflammation. JPYSF ameliorated inflammation by improving inflammatory and anti-inflammatory indexes, including downregulation of TNF-α, IL-6, MCP-1 and LY6G, and upregulation of IL-10. In addition, JPYSF also inhibited MAPK pathway to improve necroptosis by decreasing the expression of P-JNK and P-ERK. CONCLUSION: Our data showed that JPYSF prevents cisplatin-induced AKI by improving necroptosis through MAPK pathway, which is related to the improvement of mitochondrial dysfunction, oxidative stress, and inflammation.
Assuntos
Injúria Renal Aguda , Doenças Mitocondriais , Masculino , Camundongos , Animais , Cisplatino/efeitos adversos , Necroptose , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , InflamaçãoRESUMO
A novel method for the glycosylation of selenoglycosides activated by iodosylbenzene was developed. The glycosylation reaction conditions were mild, fast, and efficient, with a high tolerance to diverse protecting groups and a wide substrate scope, which is advantageous for synthesizing complex glycosides. In addition, selenoglycosides were shown to be orthogonal to thioglycosides under the promotion of iodosylbenzene. Notably, a high yield of the poorly reactive glucuronidation reaction product was obtained by acetyl-protected selenoglycoside. Finally, the orthogonal one-pot synthesis of ß-(1â6) oligoglucans demonstrated the usefulness of this method in oligosaccharide synthesis.
Assuntos
Iodobenzenos , Tioglicosídeos , Glicosilação , Glicosídeos , OligossacarídeosRESUMO
Considering the increasing risk of nuclear attacks worldwide, the development of develop potent and safe radioprotective agents for nuclear emergencies is urgently needed. γ-tocotrienol (GT3) and δ-tocotrienol (DT3) have demonstrated a potent radioprotective effect by inducing the production of granulocyte-colony stimulating factor (G-CSF) in vivo. However, their application is limited because of their low bioavailability. The utilization of ester prodrugs can be an effective strategy for modifying the pharmacokinetic properties of drug molecules. In this study, we initially confirmed that DT3 exhibited the most significant potential for inducing G-CSF effects among eight natural vitamin E homologs. Consequently, we designed and synthesized a series of DT3 ester and ether derivatives, leading to improved radioprotective effects. The metabolic study conducted in vitro and in vivo has identified DT3 succinate 5b as a prodrug of DT3 with an approximately seven-fold higher bioavailability compared to DT3 alone. And DT3 ether derivative 8a were relatively stable and approximately 4 times more bioavailable than DT3 prototype. Furthermore, 5b exhibited superior ability to mitigate radiation-induced pancytopenia, enhance the recovery of bone marrow hematopoietic stem and progenitor cells, and promote splenic extramedullary hematopoiesis in sublethal irradiated mice. Similarly, 8a shown potential radiation protection, but its radiation protection is less than DT3. Based on these findings, we identified 5b as a DT3 prodrug, and providing an attractive candidate for further drug development.
Assuntos
Sistema Hematopoético , Pró-Fármacos , Proteção Radiológica , Vitamina E/análogos & derivados , Animais , Camundongos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Ésteres/farmacologia , Éteres , Pró-Fármacos/farmacologia , GranulócitosRESUMO
Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.