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1.
Eur J Pharmacol ; 876: 173065, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32171792

RESUMO

Inhibition of Aß aggregation and neurotoxicity has been developed as an attractive therapeutic strategy to combat Alzheimer's disease (AD). Bis(propyl)-cognitin (B3C) is a multifunctional dimer derived from tacrine. Herein, the anti-aggregation and disassembly effects of B3C on Aß, together with the neuroprotective effects and underlying mechanisms of B3C against Aß-induced neurotoxicity were investigated in silico, in vitro and in vivo. Data from Thioflavin-T fluorescence and atomic force microscopy assays indicated that B3C (1-10 µM), but not its monomer tacrine, greatly inhibited the formation of Aß fibrils and disaggregated pre-formed mature Aß fibrils. Comparative molecular dynamics simulation results revealed a possible binding mode that prevented Aß fibrils formation, showing that B3C favorably bound to Aß via hydrophobic interactions. Additionally, B3C was able to block the neurotoxicity caused by Aß fibrils in cultured PC12 cells. Very encouragingly, B3C (0.3 and 0.45 mg/kg) markedly alleviated the cognitive impairments in rats insulted by intra-hippocampal injection of Aß1-42 fibrils, more potently than tacrine (1 and 2 mg/kg). Furthermore, mechanistic studies demonstrated that B3C reversed the inhibition of phospho-GSK3ß at Ser9 site in vitro and in vivo caused by Aß, suggesting the neuroprotection of B3C was achieved through the inhibition of GSK3ß pathway. These findings indicate that B3C could serve as an effective inhibitor of Aß aggregation and neurotoxicity, and provide novel molecular insights into the potential application of B3C in AD prevention and treatment.

2.
Biomed Pharmacother ; 124: 109883, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32004938

RESUMO

Intestinal mucositis causes great suffering to cancer patients who undergo chemotherapy and radiotherapy. Owing to the uncertain side effects of anticancer drugs to attenuate patients' intestinal mucositis, many studies focused on traditional Chinese medicine (TCM). Patchouli alcohol (PA) is an active compound extracted from Pogostemon cablin, and has potent gastrointestinal protective effect. However, whether PA has an effect on intestinal mucositis is still unknown. Therefore, we established a rat model of intestinal mucositis via intraperitoneal injection of 5-fluorouracil, and intragastrically administrated PA (10, 20, and 40 mg/kg) to evaluate the effect of PA on intestinal mucositis. The routine observation (body weight, food intake, and diarrhea) in rats was used to detect whether PA had an effect on intestinal mucositis. Levels of inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10, and MPO), mucosal barrier proteins (zonula occludens -1 (ZO-1), claudin-1, occludin, myosin light chain (MLC), and mucin-2) and intestinal microbiota were determined to elucidate the underlying mechanism of PA action on intestinal mucositis in rats. The results showed that PA could effectively improve body weight, food intake, and diarrhea in intestinal mucositis rats, preliminary confirming PA efficacy. Further experiments revealed that PA not only decreased the levels of TNF-α, IL-1ß, IL-6, and MPO but also increased the level of IL-10 significantly. In addition, the expression of mucosal barrier proteins and microbiota community were also improved after PA treatment in diseased rats. Hence, PA may prevent the development and progression of intestinal mucositis by improving inflammation, protecting mucosal barrier, and regulating intestinal microbiota.

3.
J Ethnopharmacol ; 249: 112367, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678637

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du Decoction (HLJDD), is a well-known traditional Chinese herbal formula first written in the Tang dynasty. In Chinese medicine practice, HLJDD is commonly prescribed to treat various inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis. AIM OF THE STUDY: The present study aimed at investigating the therapeutic effect of HLJDD extract (HLJDE) and to elucidate the underlying molecular mechanisms of action in the 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like mice. MATERIALS AND METHODS: Female Balb/c mice were sensitized with DNCB for three days. After sensitization, mice were challenged with DNCB every three days and orally administrated with HLJDE (150, 300 and 600 mg/kg) daily from day 14 to day 29 for consecutive 16 days. At the end of experiment, the clinical AD scores of the mice were calculated to evaluate the therapeutic effect of HLJDE, and serum, ears and dorsal skin of the mice were collected for unravelling molecular mechanisms. RESULTS: HLJDE significantly reduced the clinical symptoms in the AD-like mice by inhibiting eosinophil and mast cell infiltration, suppressing the production of Th2-associated cytokine (IL-4) and pro-inflammatory cytokines (TNF-α). In addition, HLJDE significantly suppressed the NF-κB and MAPKs pathways. Moreover, HLJDE was able to accentuate filaggrin expression in the skin lesion when compared to the sensitized mouse without treatment. CONCLUSION: HLJDE significantly improved the AD-like symptoms on the DNCB-sensitized mice through mitigating the production of inflammatory mediators via suppressing MAPKs and NF-κB pathways. Additionally, the elevated expression of filaggrin in the skin lesion by HLJDE contributes to the recovery of dysfunctional skin barrier on the DNCB-sensitized mice.

4.
Mol Neurobiol ; 57(1): 278-289, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31325023

RESUMO

Cerebral amyloid angiopathy (CAA) refers to pathological changes occurring in cerebral blood vessels caused by deposition of beta amyloid (Aß) protein. However, the mechanisms involved in the origin of Aß for the formation of CAA and its link to parenchymal amyloid depositions remained to be unraveled. Here, we found CAA and parenchymal plaques distributed separately instead of mingling with each other in the spinal cord of TgCRND8 mice. Parenchymal plaques predominantly located in the dorsal horn whereas CAA distributed in the ventral horn. We further found that the ratio of Aß40/Aß42 was significantly higher in the ventral than that in the dorsal by ELISA assay, suggesting that origin of Aß forming parenchymal plaques may be different from that of CAA in the spinal cord. This hypothesis was further demonstrated by the surgical methods which indicated eliminating parenchymal plaques did not alter CAA in the affected spinal cord. We also examined the ratio of Aß40/Aß42 in the cerebral spinal fluid (CSF) in order to identify the origin of the CAA formation, and found the Aß40/Aß42 ratio was similar to that of CAA formation in the ventral horn. We further demonstrated that CSF tracer distributed along ventral horn vessels, in exactly the same pattern as Aß deposition in CAA in ventral part of spinal cord. These findings verified the concept that CSF influx may act as a constant source for delivering Aß, and contribute to the growth of paraarterial deposits in CAA. Taken together, the results of the present study highlight the important role of the Aß40/Aß42 ratio in determining vascular versus parenchymal amyloid deposition. Unlike parenchymal plaques, Aß of CAA comes from CSF; thus, manipulation of CSF Aß could represent a novel strategy to treat CAA.

5.
Pharmacol Res ; 152: 104603, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863867

RESUMO

Berberine (BBR), a naturally-occurring isoquinoline alkaloid isolated from several Chinese herbal medicines, has been widely used for the treatment of dysentery and colitis. However, its blood concentration was less than 1 %, and intestinal microflora-mediated metabolites of BBR were considered to be the important material basis for the bioactivities of BBR. Here, we investigated the anti-colitis activity and potential mechanism of oxyberberine (OBB), a novel gut microbiota metabolite of BBR, in DSS-induced colitis mice. Balb/C mice treated with 3 % DSS in drinking water to induce acute colitis were orally administrated with OBB once daily for 8 days. Clinical symptoms were analyzed, and biological samples were collected for microscopic, immune-inflammation, intestinal barrier function, and gut microbiota analysis. Results showed that OBB significantly attenuated DSS-induced clinical manifestations, colon shortening and histological injury in the mice with colitis, which achieved similar therapeutic effect to azathioprine (AZA) and was superior to BBR. Furthermore, OBB remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. OBB appreciably inhibited TLR4-MyD88-NF-κB signaling pathway through down-regulating the protein expressions of TLR4 and MyD88, inhibiting the phosphorylation of IκBα, and the translocation of NF-κB p65 from cytoplasm to nucleus. Moreover, OBB markedly modulated the gut dysbiosis induced by DSS and restored the dysbacteria to normal level. Taken together, the result for the first time revealed that OBB effectively improved DSS-induced experimental colitis, at least partly through maintaining the colonic integrity, inhibiting inflammation response, and modulating gut microflora profile.

6.
Int J Mol Med ; 44(6): 2015-2026, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638181

RESUMO

Bruceine D is one of the active components of Brucea javanica (L.) Merr., which is widely used to treat cancer in China. The aim of the present study was to evaluate the potential effect of bruceine D against non­small­cell lung cancer (NSCLC) cells and delineate its underlying mechanisms. The results indicated that treatment with bruceine D markedly inhibited the proliferation of wild­type NSCLC cells and epidermal growth factor receptor­mutant cells in a dose­ and time­dependent manner, and significantly decreased the colony­forming ability and migration of A549 cells. Hoechst 33342 staining and flow cytometric analysis demonstrated that treatment with bruceine D effectively induced apoptosis of A549 cells. In addition, the proapoptotic effect of bruceine D was found to be associated with G0­G1 cell cycle arrest, accumulation of intracellular reactive oxygen species (ROS) and malondialdehyde, depletion of glutathione levels and disruption of mitochondrial membrane potential. Additionally, pretreatment with N­acetylcysteine, a ROS scavenger, significantly attenuated the bruceine D­induced inhibition in A549 cells. Western blotting demonstrated that treatment with bruceine D significantly suppressed the expression of the anti­apoptotic proteins Bcl­2, Bcl­xL and X­linked inhibitor of apoptosis, enhanced the expression levels of apoptotic proteins Bax and Bak, and inhibited the expression of pro­caspase­3 and pro­caspase­8. Based on these results, it may be suggested that inhibition of A549 NSCLC cell proliferation by bruceine D is associated with the modulation of ROS­mitochondrial­mediated death signaling. This novel insight may provide further evidence to verify the anticancer efficacy of B. javanica, and support a role for bruceine D in the anti­NSCLC treatment.

7.
Biomolecules ; 9(10)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575007

RESUMO

STAT3 is a latent transcription factor that plays a vital role in the transmission of extracellular signal from receptors to the nucleus. It has been regarded as a master transcription factor due to its role in the regulation of a broad spectrum of genes, which can contribute to oncogenesis. Persistent activation of STAT3 and deregulation of its signaling has been observed in various human cancers including head and neck squamous cell carcinoma (HNSCC). In the present work, we identified brusatol (BT) as a potential blocker of STAT3 signaling pathway in diverse HNSCC cells. The data from the cell-based experiments suggested that BT-induced cytotoxicity and abrogated the activation of STAT3 and that of upstream kinases such as JAK1, JAK2, and Src. It reduced the levels of nuclear STAT3 and its DNA binding ability. BT treatment increased annexin-V-positive cells, promoted procaspase-3 and PARP cleavage, and downregulated the mRNA and protein expression of diverse proteins (Bcl-2, Bcl-xl, survivin) in HNSCC cells. Taken together, brusatol can function as a promising inhibitor targeting STAT3 signaling pathway in HNSCC.

8.
Nat Prod Res ; : 1-8, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31512485

RESUMO

One new xanthone, (±) garciesculenxanthone C (1), two new biphenyls, garciesculenbiphenyls A (2) and B (3), together with two known compounds, doitungbiphenyl B (4) and morusignin D (5), were isolated from Garcinia esculenta. The structures of new compounds were elucidated by spectroscopic analysis, and the absolute configuration of (±) garciesculenxanthone C (1) was assigned by a modified Mosher's method. All isolates were evaluated for their antistaphylococcal activities against Staphylococcus aureus Newman, USA300 LAC, USA400 MW2, and Mu50 strains. Among these, (±) garciesculenxanthone C (1) showed the best antistaphylococcal activity, and its effect was determined to be bactericidal by time-kill experiment.

9.
Brain Behav Immun ; 82: 264-278, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476414

RESUMO

Isorhynchophylline (IRN) has been demonstrated to have distinct anti-Alzheimer's disease (AD) activity in several animal models of AD. In this study, we aimed at evaluating the preventive effect of IRN on the cognitive deficits and amyloid pathology in TgCRND8 mice. Male TgCRND8 mice were administered with IRN (20 or 40 mg/kg) by oral gavage daily for 4 months, followed by assessing the spatial learning and memory functions with the Radial Arm Maze (RAM) test. Brain tissues were determined immunohistochemically or biochemically for changes in amyloid pathology, tau hyperphosphorylation and neuroinflammation. Our results revealed that IRN (40 mg/kg) significantly ameliorated cognitive deficits in TgCRND8 mice. In addition, IRN (40 mg/kg) markedly reduced the levels of Aß40, Aß42 and tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1ß, and modulated the amyloid precursor protein (APP) processing and phosphorylation by altering the protein expressions of ß-site APP cleaving enzyme-1 (BACE-1), phosphorylated APP (Thr668), presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as insulin degrading enzyme (IDE), a major Aß-degrading enzyme. IRN was also found to inhibit the phosphorylation of tau at the sites of Thr205 and Ser396. Immunofluorescence showed that IRN reduced the Aß deposition, and suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the cerebral cortex and hippocampus of TgCRND8 mice. Furthermore, IRN was able to attenuate the ratios of p-c-Jun/c-Jun and p-JNK/JNK in the brains of TgCRND8 mice. IRN also showed marked inhibitory effect on JNK signaling pathway in the Aß-treated rat primary hippocampus neurons. We conclude that IRN improves cognitive impairment in TgCRND8 transgenic mice via reducing Aß generation and deposition, tau hyperphosphorylation and neuroinflammation through inhibiting the activation of JNK signaling pathway, and has good potential for further development into pharmacological treatment for AD.

10.
Free Radic Biol Med ; 143: 454-470, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472247

RESUMO

Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA.

11.
Trials ; 20(1): 480, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391104

RESUMO

BACKGROUND: Heel pain is a common foot disorder that causes pain and functional limitations. The prevalence of disabling foot pain will increase as the population ages. Previous studies have reported the positive therapeutic effects of electroacupuncture, warm needling, or the combination of both for heel pain but with limitations in the study methodologies. The current study is a rigorously designed randomized controlled trial that aims to evaluate the clinical efficacy and safety of electroacupuncture plus warm needling therapy in patients with heel pain. METHODS/DESIGN: The study protocol describes a prospective, open-label, parallel-group, randomized controlled trial to be conducted in Hong Kong. Eighty patients aged 50-80 years who have reported heel pain and first-step pain equal to or exceeding 50 mm on the 100-mm visual analog scale (VAS) will be recruited. They will be randomly assigned (1:1 ratio) to the electroacupuncture plus warm needling therapy (i.e., treatment) group or the waitlist (i.e., control) group. The treatment group will undergo six treatment sessions in 4 weeks. The control group will receive no treatment during the study period. The primary outcome measure is a mean change in the first-step pain VAS score from the baseline to week 4. Secondary outcome measures include a mean change in first-step pain VAS score from the baseline to week 2, a mean change in Foot Function Index (FFI) subscale scores and the total score from the baseline to week 2 and week 4, and patients' self-reported level of improvement at week 4. Additional week 8 follow-up assessments with first-step pain VAS and FFI measurements will be arranged for the treatment group. Any adverse events will be recorded throughout the study to evaluate safety. An intention-to-treat approach will be used to analyze the study results. DISCUSSION: This study will provide evidence on the efficacy and safety of electroacupuncture plus warm needling therapy as an alternative treatment method for heel pain. The findings will determine whether the treatment protocol is efficacious in relieving pain and improving foot function among older adults with heel pain. The study will also provide information for subsequent large-scale randomized controlled trials in the future. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800014906 . Registered on 12 February 2018.


Assuntos
Terapia por Acupuntura , Eletroacupuntura , Doenças do Pé/terapia , Manejo da Dor/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia por Acupuntura/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Eletroacupuntura/efeitos adversos , Calcanhar , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Projetos de Pesquisa
12.
Front Pharmacol ; 10: 706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293425

RESUMO

Angelica sinensis (AS, Danggui) has long been regarded to stimulate breast cancer growth; hence, the use of AS in breast cancer patients remains a major concern for both patients and practitioners. Since safety studies of herbs would be unethical to carry out in patients, the present study aimed to investigate the potential unsafe effects of AS in a systematic pre-clinical approach. Human breast cancer cells, breast orthotopic tumor-bearing mouse models, as well as primary breast cancer cells from patients' tumors were used to evaluate the effect of AS hot water extract on the progression of breast tumors and/or growth of breast cancer cells. We showed that AS is not that stimulatory in breast cancer both in vitro and in vivo, though AS should still be used with caution in estrogen receptor-positive breast cancer patients. This novel approach of applying breast cancer cell lines, xenograft, and syngeneic tumors models, as well as primary breast cancer cells from patients' tumors in Chinese medicines safety evaluation was proven feasible. Our finding is important information for patients, Chinese medicine practitioners, and clinicians on the safety use of AS in breast cancer, which will affect future clinical practice.

13.
Curr Vasc Pharmacol ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31272356

RESUMO

BACKGROUND: Uncaria rhynchophylla (Miq.) Jacks (Rubinaceae), a common herbal medicine known as Gou-teng in Chinese, is commonly used in Chinese medicine practice for the treatment of convulsions, hypertension, epilepsy, eclampsia and other cerebral diseases. The major active components of U. rhynchophylla are alkaloids, terpenoids and flavonoids. The protective effects of U. rhynchophylla and its major components on central nervous system (CNS) have become a focus of research in recent decades. OBJECTIVE: To systematically summarize the pharmacological activities of U. rhynchophylla and its major components on the CNS. METHOD: This review summarized the experimental findings from our laboratories, together with other literature data obtained through a comprehensive search on databases including the Pubmed and the Web of Science. RESULTS: U. rhynchophylla and its major components such as rhynchophylline and isorhynchophylline have been shown to have neuroprotective effects on Alzheimer's disease, Parkinson's disease, depression, cerebral ischaemia through a number of mechanisms including anti-oxidant, anti-inflammatory actions and regulation on neurotransmitters. CONCLUSION: U. rhynchophylla and its major components possess multiple beneficial pharmacological actions on CNS. Futher studies on U. rhynchophylla and its major components are warranted to fully illustrate the underlying molecular mechanisms, pharmacokinetics, and toxicological profiles of these naturally occurring compounds and their potential for clinical application.

14.
FASEB J ; 33(9): 10393-10408, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31233346

RESUMO

Isorhynchophylline (IRN), an oxindole alkaloid isolated from Uncaria rhynchophylla, elicited distinct antidepressant-like activity in mice. The present study aimed to investigate the antidepressant-like effects of IRN in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and to illustrate its possible mechanisms of action. The mice were subjected to CUMS for 6 wk and administered with IRN (20 or 40 mg/kg) daily by oral gavage for 3 wk. The PI3K/protein kinase B (Akt) inhibitor and glycogen synthase kinase-3ß (GSK-3ß) inhibitors were used to determine the involvement of the PI3K/Akt/GSK-3ß pathway in the antidepressant-like effects of IRN in the mice. The results showed that CUMS caused depression-like behaviors in the mice, such as behavioral despair by the forced swim test (FST) and anhedonia by the sucrose preference test. In addition, CUMS could significantly reduce the levels of nerve growth factor and brain-derived neurotrophic factor but markedly increase the release of TNF-α and IL-6 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS markedly suppressed the levels of phosphorylated GSK-3ß (Ser9) and phosphorylated Akt (Ser473) but significantly enhanced the translocation of NF-κB p65 from cytosol to nuclei in the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF-κB binding activity in the hippocampus and cerebral cortex of the mice, whereas IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in the mice. Moreover, the antidepressant-like effect of IRN was completely abolished by the PI3K/Akt inhibitor. Combination treatment with IRN and GSK-3ß inhibitors in the mice exerted a synergistic anti-immobility action in the FST. The results of mechanistic investigations indicated that the antidepressant-like action of IRN was mediated, at least in part, by enhancing neurotrophins and attenuating neuroinflammation via modulating the PI3K/Akt/GSK-3ß pathway.-Xian, Y.-F., Ip, S.-P., Li, H.-Q., Qu, C., Su, Z.-R., Chen, J.-N., Lin, Z.-X. Isorhynchophylline exerts antidepressant-like effects in mice via modulating neuroinflammation and neurotrophins: involvement of the PI3K/Akt/GSK-3ß signaling pathway.

15.
Neuroscience ; 409: 152-161, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31034974

RESUMO

Axonopathy manifested by axon swellings might constitute one of the earliest pathological features of Alzheimer's disease. It has been proposed that axonopathy might be associated with the origin of Aß plaques. However, how axonopathy leads to Aß plaque pathogenesis remains elusive. Our previous studies have shown that Aß neuropathology (mainly diffuse plaques) selectively occurred in the regions of corticospinal tract (CST) pathway and its innervated region in the spinal cord of TgCRND8 mice. In this study, we investigated the occurrence and progression of axonopathy and the possible implication in Aß plaque pathogenesis in the spinal cord of TgCRND8 mice. By anterograde labeling of CST system with a neuroanatomical tracer, we found that dilated corticospinal axons started to appear at 7 months, then exhibited an age-dependent increase. These abnormal structures appear before any plaque deposits are visible in the spinal cord of the mice. Importantly, they colocalized with Aß plaques in either the white matter or gray matter of the spinal cord at later stages, suggesting that these axonal swellings might represent the initial stages of Aß plaque formation, and could play a role in Aß plaque pathogenesis. Furthermore, using ultrastructural analysis we demonstrated that intracellular contents in the axonal dystrophies such as various dense vesicles leaked out into the extracellular matrix under a condition of axon swelling rupture in CST pathways of spinal cord. This provided precise structural evidence that how the Aß leaks out from the axonal dystrophies into extracellular matrix and how an axonal swelling might serve as a nidus of amyloid plaque formation.


Assuntos
Doença de Alzheimer/patologia , Axônios/patologia , Placa Amiloide/patologia , Medula Espinal/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Substância Cinzenta/patologia , Camundongos , Camundongos Transgênicos , Tratos Piramidais/patologia , Substância Branca/patologia
16.
J Pharm Biomed Anal ; 170: 264-272, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30947127

RESUMO

Bruceoside A, an abundant quassinoid glycoside in Fructus Bruceae, was chosen for the pharmacokinetic study. It is the first case report on the pharmacokinetic study of quassinoid glycosides so far. A sensitive, accurate, and repeatable UHPLC-MS/MS method was developed for the determination of bruceoside A and its major metabolite. The results showed bruceoside A could be transformed into the potent anticancer component brusatol in vivo, rather than its direct deglycosylated metabolite bruceosin. And the intestinal bacteria were proposed to take a potential role during such transformation. Based on the present study, it could be concluded that the quassinoid glycosides possessing weak activities in vitro could do contribution to the anticancer properties of Fructus Bruceae in vivo via transforming into more active metabolites.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/farmacocinética , Glicosídeos/farmacocinética , Quassinas/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Glicosídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quassinas/farmacologia , Espectrometria de Massas em Tandem/métodos
17.
Biomed Pharmacother ; 114: 108766, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901719

RESUMO

Brucea javanica is an important Chinese folk medicine traditionally used for the treatment of dysentery (also known as inflammatory bowel diseases). Brucea javanica oil emulsion (BJOE), the most common preparation of Brucea javanica, has a variety of pharmacological activities. In this follow-up investigation, we endeavored to illuminate the potential benefit of BJOE on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced Crohn's disease (CD) in rats and decipher the mechanism of action. The result illustrated that BJOE treatment significantly reduced the body weight loss, disease activity index and macroscopic scores, ameliorated shortening of colon length, arrested colonic histopathological deteriorations, lowered the histological scores in parallel to the model group. Furthermore, BJOE also decreased the levels of MPO and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, IL-23 and IFN-γ), and increased the levels of anti-inflammatory cytokines (IL-4, IL-10 and TGF-ß) as compared with the model group. In addition, the elevated mRNA expression of MMP-1, MMP-3 and RAGE induced by TNBS was remarkably inhibited by BJOE, SASP or AZA treatments, while the mRNA expression of PPAR-γ was significantly enhanced. Furthermore, the activation of TLR4/NF-κB signaling pathway was significantly inhibited by AZA and BJOE treatment when compared with that of TNBS-treated rats. Our study suggested that BJOE exerted superior therapeutic effect to SASP and AZA in treating TNBS-induced colitis in rats. The protective effect of BJOE may involve the inhibition of the TLR4/NF-κB-mediated inflammatory responses. These results indicated that BJOE held promising potential to be further developed into a novel candidate for the treatment of CD.


Assuntos
Brucea/química , Doença de Crohn/tratamento farmacológico , Emulsões/farmacologia , NF-kappa B/metabolismo , Óleos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Colo/efeitos dos fármacos , Colo/metabolismo , Doença de Crohn/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
18.
Artigo em Inglês | MEDLINE | ID: mdl-30854007

RESUMO

Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer's disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.

19.
Oncol Lett ; 17(3): 3001-3008, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30854078

RESUMO

The aim of the present study was to examine whether erastin influences radioresistance in non-small cell lung cancer (NSCLC) cells and produce a preliminary investigation into its mechanism of action. The radioresistant subtype of NSCLC cells, A549-R and H460-R, were induced by high-dose hypofractionated irradiation. Erastin was used to treat the radioresistant cells and radiosensitivity was examined by colony formation assays. Cell death was determined after the cells were treated with erastin, irradiation (IR) or erastin together with IR. The expression of glutathione peroxidase 4 (GPX4) expression in the parental cells and radioresistance cells was detected by western blotting. GPX4 expression in the radioresistance cells was subsequently inhibited, radiosensitivity and cell death was measured, and erastin enhanced radiosensitivity in A549-R and H460-R cells. Erastin and IR exhibited a combined effect on killing cells, as co-treatment with erastin and IR demonstrated a higher effect on killing cells compared with erastin or IR alone. GPX4 expression was inhibited by erastin in the radioresistant cells. Inhibiting GPX4 expression also radiosensitized NSCLC cells to radiation in the radioresistant cell lines. Erastin-induced and GPX4-inhibition-induced cell death could partially be rescued by deferoxamine, but not Z-VAD-FMK and olaparib, which indicated that erastin and GPX4-inhibition induced ferroptosis in the radioresistant cells. Erastin decreased radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis.

20.
Integr Cancer Ther ; 18: 1534735419828836, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30791742

RESUMO

BACKGROUND AND AIMS: Pancreatic cancer has the lowest survival rate of all cancers (4%), and it accounts for 1.9% of new cancer cases in Hong Kong. Combined treatment with Chinese herbal medicine (CHM) and Western medicine has yielded promising results, leading to improved prognosis and overall survival. This retrospective case series aimed to illustrate the improved survival and quality of life outcomes of pancreatic cancer patients administered CHM based on traditional Chinese medicine theory. METHODS: To investigate the effectiveness of CHM in prolonging overall survival, 182 patients diagnosed with pancreatic cancer who received CHM treatment were observed from 2005 to 2015. RESULTS: One hundred eighty-two pancreatic cancer patients were treated with CHM; 21 patients died. The mean and median survival of these patients were 29.6 and 15.2 months, respectively; the 1-year survival rate was 76% (range = 4 months to 9 years). These results are better than those reported in patients treated with Western medicine, suggesting the need for further study of CHM. CONCLUSION: A superior clinical outcome may be obtained with CHM treatment. The case series illustrates the potential benefits and safety issues of CHM in pancreatic cancer patients that could be relevant for developing strategies to increase individualization of pancreatic cancer treatment and improve survival. This study may facilitate interprofessional communication and improved clinical management of pancreatic cancer patients.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Feminino , Humanos , Masculino , Medicina Tradicional Chinesa/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neoplasias Pancreáticas/patologia , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Taxa de Sobrevida
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