The effects of alpha-pinene on the Nrf2-HO1 signaling pathway in gastric damage in rats.

BACKGROUND: Alpha-pinene (α-pinene) is a monoterpene with gastroprotective activity. We evaluated the gastroprotective effect of α-pinene in the gastric damage model with ethanol. METHODS: We evaluated the macroscopic evaluation of the stomach cavity, alteration in pH, mRNA expression of nuclear factor erythroid 2- related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), total antioxidant capacity (TAC) levels, and histopathological changes. RESULTS: Pretreatment with α-pinene (10, 50 and 100 mg/kg i.p.) before oral administration of ethanol reduced gastric mucosal damage by increasing the percentage of ulcer inhibition. Alpha-pinene also increased gastric pH similar to omeprazole. In addition, the histopathological examination showed that in the groups pretreated with α-pinene 50 and 100 mg/kg, and omeprazole20 mg/kg, the lesions were less than the control group. Moreover, α- pinene 10, 50, 100, and omeprazole 20 mg/kg upregulated the NRF2 and HO1. CONCLUSIONS: Our results show that pretreatment with α-pinene is effective in reducing ethanol-induced gastric damage through regulation of Nrf2/HO-1.

VEGFR3 suppression through miR-1236 inhibits proliferation and induces apoptosis in ovarian cancer via ERK1/2 and AKT signaling pathways.

Vascular endothelial growth factor receptor 3 (VEGFR3) is expressed in cancer cell lines and exerts a critical role in cancer progression. However, the signaling pathways of VEGFR3 in ovarian cancer cell proliferation remain unclear. This study aimed to demonstrate the signaling pathways of VEGFR3 through the upregulated expression of miR-1236 in ovarian cancer cells. We found that the messenger RNA and protein of VEGFR3 were expressed in the ovarian cancer cell lines, but downregulated after microRNA-1236 (miR-1236) transfection. The inhibition of VEGFR3, using miR-1236, significantly reduced cell proliferation, clonogenic survival, migration, and invasion ability in SKOV3 and OVCAR3 cells (p < 0.01). The flow cytometry results indicated that the rate of apoptotic cells in SKOV3 (38.65%) and OVCAR3 (41.95%) cells increased following VEGFR3 inhibition. Moreover, VEGFR3 stimulation (using a specific ligand, VEGF-CS) significantly increased extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation (p < 0.01), whereas VEGFR3 suppression reduced p-ERK1/2 (67.94% in SKOV3 and 93.52% in OVCAR3) and p-AKT (59.56% in SKOV3 and 78.73% in OVCAR3) compared to the VEGF-CS treated group. This finding demonstrated that miR-1236 may act as an endogenous regulator of ERK1/2 and AKT signaling by blocking the upstream regulator of VEGFR3. Overall, we demonstrated the important role of the miR-1236/VEGFR3 axis in ovarian cancer cell proliferation by regulating the ERK1/2 and AKT signaling that might be an effective strategy against ovarian cancer.

Molecular mechanisms of miR-1236 in the assessment of tumor lymphangiogenesis in human ovarian cancer patients.

BACKGROUND: Tumor lymphangiogenesis is a critical component in the progression of cancers and specific microRNAs have been reported to be implicated in this process. Recent studies revealed the involvement of miR-1236 in lymphangiogenic signaling by targeting vascular endothelial growth factor receptor 3 (VEGFR3). However, the prognostic importance of miR-1236 and its clinical relevance for lymphangiogenesis in ovarian cancer (OC) remains unclear. METHODS: The study included 52 ovarian tumors and 28 normal ovarian tissues. Quantitative real-time PCR was utilized to analyze the VEGFR3, VEGF-C, LYVE-1 and PROX1 mRNA expression as well as miR-1236. VEGFR3 protein expression was measured by immunohistochemistry staining. Immunohistochemistry for the podoplanin marker (D2-40) was performed to measure lymphatic vessel density (LVD). In addition, diagnostic evaluation based on the receiver-operating characteristic (ROC) curve was performed. The influence of miR-1236 on overall survival was evaluated by Kaplan-Meier method. RESULTS: Here, we show that miR-1236 expression was significantly decreased in ovarian tumors compared with control tissues (p < 0.001) and correlated with advanced clinical stage, lymph node metastasis, distant metastasis and patient survival (All P < 0.05). Moreover, in ovarian tumors, LVD as well as the gene expression of VEGFR3, VEGF-C and LYVE-1, but not PROX1, were found to be remarkably higher compared with control tissues. We also detected a more robust positive staining for VEGFR3 in OC tissues than in control tissues. Furthermore, our results demonstrated an inverse association of miR-1236 expression with LVD, VEGFR3, LYVE-1 and PROX1 expression in OC tissues. The ROC curve analysis indicated that miR-1236 expression has the potential to be used as a diagnostic and prognostic biomarker in OC. Survival analysis further verified a lowered overall survival rate in patients with low miR-1236 expression than in those with high expression. CONCLUSIONS: Our results provide evidence for the translational involvement of miR-1236 in the lymphangiogenesis of OC by regulating lymphangiogenesis-related factors and support the clinical importance of miR-1236 as a new diagnostic and prognostic biomarker for OC.

Photobiomodulation Therapy and the Glymphatic System: Promising Applications for Augmenting the Brain Lymphatic Drainage System.

The glymphatic system is a glial-dependent waste clearance pathway in the central nervous system, devoted to drain away waste metabolic products and soluble proteins such as amyloid-beta. An impaired brain glymphatic system can increase the incidence of neurovascular, neuroinflammatory, and neurodegenerative diseases. Photobiomodulation (PBM) therapy can serve as a non-invasive neuroprotective strategy for maintaining and optimizing effective brain waste clearance. In this review, we discuss the crucial role of the glymphatic drainage system in removing toxins and waste metabolites from the brain. We review recent animal research on the neurotherapeutic benefits of PBM therapy on glymphatic drainage and clearance. We also highlight cellular mechanisms of PBM on the cerebral glymphatic system. Animal research has shed light on the beneficial effects of PBM on the cerebral drainage system through the clearance of amyloid-beta via meningeal lymphatic vessels. Finally, PBM-mediated increase in the blood-brain barrier permeability with a subsequent rise in Aß clearance from PBM-induced relaxation of lymphatic vessels via a vasodilation process will be discussed. We conclude that PBM promotion of cranial and extracranial lymphatic system function might be a promising strategy for the treatment of brain diseases associated with cerebrospinal fluid outflow abnormality.

Photobiomodulation Therapy for Dementia: A Systematic Review of Pre-Clinical and Clinical Studies.

BACKGROUND: Photobiomodulation (PBM) involves the use of red and/or near-infrared light from lasers or LEDs to improve a wide range of medical disorders. Transcranial PBM, sometimes accompanied by intranasal PBM, has been tested to improve many brain disorders, including dementia. OBJECTIVE: To conduct a systematic review according to PRISMA guidelines of pre-clinical and clinical studies reporting the use of PBM, which were considered relevant to dementia. METHODS: Literature was searched between 1967 and 2020 using a range of keywords relevant to PBM and dementia. The light source and wavelength(s), output power, irradiance, irradiation time, fluence or total energy (dose), operation mode (continuous or pulsed) irradiation, approach and site, number of treatment sessions, as well as study outcome(s) were extracted. RESULTS: Out of 10,473 initial articles, 36 studies met the inclusion criteria. Nine articles reported in vitro studies, 17 articles reported studies in animal models of dementia, and 10 studies were conducted in dementia patients. All of the included studies reported positive results. The clinical studies were limited by the small number of patients, lack of placebo controls in some instances, and only a few used objective neuroimaging methods. CONCLUSION: The preliminary evidence of clinical benefit, the lack of any adverse effects, and the remarkable ease of use, suggest larger clinical trials should be conducted as soon as possible.

Transcranial Photobiomodulation Improves Cognitive Performance in Young Healthy Adults: A Systematic Review and Meta-Analysis.

Background: Transcranial photobiomodulation (t-PBM) is a noninvasive modality that may improve cognitive function in both healthy and diseased subjects. Objective: This systematic review and meta-analysis addresses the question of whether t-PBM improves cognitive function in healthy adults. Methods: We searched MEDLINE using PubMed, EMBASE, SCOPUS, Web of Science, and Cochrane Library up to March 2019. We also searched ProQuest and Google Scholar databases for unpublished material. The search was limited to articles on the procognitive effects of t-PBM in healthy adults. The initial search resulted in 871 studies, of which nine publications met our criteria for inclusion and exclusion. Seven studies were performed on young, healthy subjects (17-35 years), and two studies were conducted on older (≥49 years), normal subjects. A meta-analysis was performed on six full-text publications whose subjects were young adults. Results: t-PBM administration improved cognition-related outcomes by an 0.833 standardized mean difference (SMD; 95% confidence interval (CI): 0.458-1.209, 14 comparisons) in young, healthy participants. Funnel plotting revealed asymmetry, which was validated using Egger's (p = 0.030) and Begg's regression (p = 0.006) tests. However after reanalysis, this asymmetry disappeared in the attention subgroup, but not in the memory subgroup. The trim-and-fill analysis indicated two studies were lacking required data. Thus, the effect size was adjusted from an SMD of 0.761 (95% CI: 0.573-0.949) to 0.949 (0.779-1.120). The overall quality score of the studies was modest. Conclusions: We demonstrated a significant, beneficial effect of t-PBM on cognitive performance of young, healthy individuals; however, the heterogeneity of the data was high. This could be due to the modest quality or to the low number of included studies, or to the differences between the various subdomains assessed. These shortcomings should be meticulously addressed before concluding that t-PBM is a cognitive-enhancing intervention in healthy individuals.

Intra-articular botulinum toxin type A for treatment of knee osteoarthritis: Clinical trial.

In recent years, there is a growing interest in new medical applications of botulinum toxin, including pain control, osteoarthritis treatment, and wound healing. While clinical applications of botulinum toxin seem promising, existing evidence regarding the therapeutic effects is still inadequate. The aim was to assess the efficacy of a single injection of abobotulinumtoxin A into the knee joint cavity to reduce pain in elderly people. We carried out a single group clinical trial in a University Hospital. Thirty participants (24 women) more than 50 years of age with knee osteoarthritis were included. Diagnosis of osteoarthritis was based on clinical and radiologic findings. We gave a single injection containing 250 units of Dysport (= 100 units of botulinum neurotoxin type A) diluted with 5 ml of normal saline. The primary outcome measure was knee pain. The secondary outcome was the patients' opinion about their knee and associated problems measured with the Knee injury and Osteoarthritis Outcome Score. The outcomes were measured at the baseline and at 4 weeks after the intervention. Within-group comparisons based on the Knee injury and Osteoarthritis Outcome Scores showed favorable results for joint pain and stiffness, sports, severity of symptoms, quality of life, and daily activities (all p-values < 0.001). Also, pain intensity, joint effusion, knee clicking and locking, and flexion-extension scores showed significant beneficial results (all p-values ≤ 0.005). We concluded that botulinum neurotoxin type A is an effective and safe initial treatment of knee osteoarthritis with clear clinical advantages. Patients' satisfaction, minimum adverse effects in addition to single-dose prescription make the toxin as a choice for the first-line therapy of osteoarthritis at least at the short-term in elderly people. The symptom relief increases the patient's compliance and willing to participate in other therapeutic programs. REGISTRATION: Iranian Registry of Clinical Trials (IRCT) website http://www.irct.ir/, a WHO Primary Register setup, with registration code: Irct ID: IRCT20180416039323N1.