Diapocynin neuroprotective effects in 3-nitropropionic acid Huntington's disease model in rats: emphasis on Sirt1/Nrf2 signaling pathway.

BACKGROUND AND AIM: Huntington's disease (HD) is a rare inherited disease portrayed with marked cognitive and motor decline owing to extensive neurodegeneration. NADPH oxidase is considered as an important contributor to the oxidative injury in several neurodegenerative disorders including HD. Thus, the present study explored the possible neuroprotective effects of diapocynin, a specific NADPH oxidase inhibitor, against 3-nitropropionic acid (3-NP) model of HD in rats. METHODS: Animals received diapocynin (10 mg/kg/day, p.o), 30 min before 3-NP (10 mg/kg/day, i.p) over a period of 14 days. RESULTS: Diapocynin administration attenuated 3-NP-induced oxidative stress with significant increase in reduced glutathione, glutathione-S-transferase, nuclear factor erythroid 2-related factor 2, and brain-derived neurotrophic factor striatal contents contrary to NADPH oxidase (NOX2; gp91phox subunit) diminished expression. Moreover, diapocynin mitigated 3-NP-associated neuroinflammation and glial activation with prominent downregulation of nuclear factor-Ðšß p65 and marked decrement of inducible nitric oxide synthase content in addition to decreased immunoreactivity of ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein; markers of microglial and astroglial activation, respectively. Treatment with diapocynin hindered 3-NP-induced apoptosis with prominent decrease in tumor suppressor protein and Bcl-2-associated X protein contents whereas the anti-apoptotic marker; B-cell lymphoma-2 content was noticeably increased. Diapocynin neuroprotective effects could be attributed to silent information regulator 1 upregulation which curbed 3-NP-associated hazards resulting in improved motor functions witnessed during open field, rotarod, and grip strength tests as well as attenuated 3-NP-associated histopathological derangements. CONCLUSION: The present findings indicated that diapocynin could serve as an auspicious nominee for HD management.

Quercetin attenuates lipopolysaccharide-mediated inflammatory injury in human nasal epithelial cells via regulating miR-21/DMBT1/NF-κB axis.

BACKGROUND: Quercetin (Qu) belongs to a flavonoid polyphenolic compound present in fruits and vegetables which has been confirmed to exert anti-inflammatory properties. Our study aimed to explore the impacts of quercetin on lipopolysaccharide (LPS)-induced inflammatory injury and signal transduction of miR-21/DMBT1/NF-κB axis in human nasal epithelial cells (HNEpC). METHODS: HNEpCs were cultured and treated with 1 µg/mL of LPS and a gradient concentration (10, 100, and 200 µM) of quercetin for 24 h. Cell viability, apoptosis, and cytokines were detected to assess the inflammatory injury in LPS-exposed HNEpCs. The expressions of miR-21, DMBT1, and NF-κB mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of DMBT1 and NF-κB protein were measured by western blotting. RESULTS: LPS treatment reduced cell viability, promoted cell apoptosis and inflammatory response, down-regulated miR-21 expression and up-regulated DMBT1, and NF-κB in HNEpC cells. Quercetin exerted the opposite effects to attenuate LPS-induced inflammatory injury in HNEpC cells at a concentration-dependent way. Additionally, miR-21 directly targeted DMBT1 to reduce its expression and further inducing cell viability via inhibiting cell apoptosis and inflammatory response. MiR-21 inhibition or DMBT1 over-expression weakened the protective effects of quercetin against LPS-induced inflammatory injury in HNEpC cells. CONCLUSIONS: Quercetin could protect HNEpC cells against LPS-induced inflammatory injury via inducing miR-21/DMBT1/NF-κB axis. Therefore, quercetin could be utilized as a potential compound to treat for allergic rhinitis.

Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer.

Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of LGR5+ CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse LGR5+ cells exists in a slow-cycling state and identify a unique 22-gene signature that characterizes these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling LGR5+ cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes, and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy. SIGNIFICANCE: These findings illustrate the importance of a slow-cycling CSC subpopulation in colon cancer development and chemoresistance, with potential implications for the identified slow-cycling CSC signatures and the TCF1-PROX1-CDKN1C pathway as therapeutic targets.

Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer.

Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

The neuroimmune guidance cue netrin-1: a new therapeutic target in cardiovascular disease.

Netrins are a family of proteins involved in cell migration and axon guidance during embryogenesis. The different functions and mechanisms of action of this family of proteins have been better characterized with the study of netrin-1. They are chemotropic and act as a bifunctional regulator of neuron migration. Apart from its role in the central nervous system, researchers have proven that netrin-1 plays a role in the development and formation of non-neural tissue; netrin-1 is thereby involved in regulation of cancers, cardiovascular diseases, kidney diseases, and other diseases. Concerning the cardiovascular realm, netrin-1 promotes angiogenesis and accelerates atherosclerosis, protects the heart against ischemia-reperfusion injury, and reduces the infarct size. These findings make the neuroimmune guidance cue netrin-1 an important therapeutic target. This work seeks to review the subject based on studies that have been conducted over the past decade to identify the perspectives and extent of the research on this protein in the field of cardiology.

Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis.

BACKGROUND: Kisspeptin is a critical regulator of normal reproductive function. A single injection of kisspeptin in healthy human volunteers potently stimulates gonadotropin release. However, the effects of kisspeptin on gonadotropin release in women with hypothalamic amenorrhea (HA) and the effects of repeated administration of kisspeptin to humans are unknown. AIM: The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA. METHODS: We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed. RESULTS: On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 +/- 3.5 IU/liter; FSH, 9.1 +/- 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 +/- 2.2 IU/liter, P < 0.05; FSH, 0.5 +/- 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed. CONCLUSION: Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.