PMID: 

Oxid Med Cell Longev. 2019 ;2019:8781690. Epub 2019 Aug 19. PMID: 31531187

Abstract Title: 

Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway.

Abstract: 

Targeting aberrant metabolism is a promising strategy for inhibiting cancer growth and metastasis. Research is now geared towards investigating the inhibition of glycolysis for anticancer drug development. Betulinic acid (BA) has demonstrated potent anticancer activities in multiple malignancies. However, its regulatory effects on glycolysis and the underlying molecular mechanisms are still unclear. BA inhibited invasion and migration of highly aggressive breast cancer cells. Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins. In this study, glucose-regulated protein 78 (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis. Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK. Subsequent phosphorylation of eIF2led to the inhibition of-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis. Coimmunoprecipitation assay revealed that BA interrupted the binding between GRP78 and PERK, thereby initiating the glycolysis inhibition cascade. Finally, the lung colonization model validated that BA inhibited breast cancer metastasis, as well as suppressed the expression of aerobic glycolysis-related proteins. In conclusion, our study not only provided a promising drug for aerobic glycolysis inhibition but also revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during tumor metastasis.

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PMID: 

Biomed Pharmacother. 2019 Oct ;118:109347. Epub 2019 Aug 16. PMID: 31545273

Abstract Title: 

Anti-inflammatory effect and potential mechanism of betulinic acid onλ-carrageenan-induced paw edema in mice.

Abstract: 

λ-Carrageenan (Carr), a seaweed polysaccharide, is used as a proinflammatory agent in research. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, exerts immunomodulatory, antioxidant, anti-inflammatory, antitumor, anti-malarial and anti-HIV effects. The aim of this study was to investigate whether BA exerts anti-inflammatory effect against Carr-induced paw edema in mice, and how BA could mediate the expression of inflammation-associated MAPK-COX-2-PGEsignal pathway. BA pretreatment significantly reduced the inflammatory response to Carr-induced paw edema, especially at 4 h after injection. BA reduced the serum levels of pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-5, IL-6, GM-CSF, KC, MCP-1 and PGEin Carr-treated mice, and increased those of anti-inflammatory cytokines, such as IL-12. It also increased SOD, CAT and GSH-Px activities, and GSH content, and reduced MDA content in the liver of Carr-treated mice. Besides, BA reduced neutrophil infiltration in the basal and subcutaneous layers of the paw of Carr-treated mice, decreased the expression of COX-2 protein, and reduced the phosphorylation of JNK, p38 and ERK1/2. These results indicated that the protective effect of BA on Carr-induced paw edema might be due to its alleviation of inflammatory response and inhibition of oxidative stress, possibly by inhibiting MAPK-COX-2-PGEsignaling pathway activation.

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PMID: 

Biomolecules. 2019 Nov 26 ;9(12). Epub 2019 Nov 26. PMID: 31779213

Abstract Title: 

Betulinic Acid Attenuates T-2-Toxin-Induced Testis Oxidative Damage Through Regulation of the JAK2/STAT3 Signaling Pathway in Mice.

Abstract: 

T-2 toxin is one of the most toxic type A trichothecene mycotoxins in nature, and it exhibits reproductive toxicity. Betulinic acid (BA) is a natural pentacyclic triterpene compound found in species of Betula, and it has been reported to have antioxidant activity. The aim of the present study was to investigate the protective effect of BA on T-2-toxin-induced testicular injury in mice and explore its molecular mechanism. Sixty adult male mice were randomly divided into groups. The mice were pretreated orally with BA (0.25, 0.5, and 1.0 mg/kg) daily for 14 days, and the T-2 toxin (4 mg/kg body weight) was administered via intraperitoneal injection to induce oxidative stress after the last administration of BA. BA pretreatment significantly increased the secreted levels of testosterone and sperm motility. Moreover, BA pretreatment significantly increased the total antioxidant capacity (T-AOC), the activity of SOD and CAT, and the content of GSH, and it reduced the content of MDA. Furthermore, BA relieved testicular injury and reduced the number of apoptotic cells, and it significantly decreased the protein expression of Janus kinase 2 (JAK2), signal transducers and activators of transcription 3 (STAT3), caspsae-3, and Bcl-2-associated X protein (Bax). BA also increased the expression of B-cell lymphoma-2 (Bcl-2). We suggest that BA reduced the oxidative damage induced by T-2 toxin, and that these protective effects may be partially mediated by the JAK2/STAT3 signaling pathway.

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PMID: 

Biomolecules. 2019 Nov 23 ;9(12). Epub 2019 Nov 23. PMID: 31771225

Abstract Title: 

Wasabi Compound 6-(Methylsulfinyl) Hexyl Isothiocyanate Induces Cell Death with Coexisting Mitotic Arrest and Autophagy in Human Chronic Myelogenous Leukemia K562 Cells.

Abstract: 

A natural compound from, 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) was investigated for its anti-leukemia activity and mechanism of action. It was found that 6-MITC inhibited the viability of human chronic myelogenous leukemia K562 cells along with extensive mitotic arrest, spindle multipolarity, and cytoplasmic vacuole accumulation. The evidence of autophagy included the validation of autophagosomes with double-layered membranes under transmission electron microscopy, LC3I/II conversion, and the induction of G2/M phase arrest observed with acridine orange staining of treated cells, as well as the elevation of phosphorylated-histone H3 expression at the M phase. With regard to the expression of proteins related to mitosis, the downregulation of p-CHK1, p-CHK2, p-cdc25c, and p-cdc2, as well as the upregulation of cyclin B1, p-cdc20, cdc23, BubR1, Mad2, and p-plk-1 was observed. The knockdown of cdc20 was unable to block the effect of 6-MITC. The differentiation of k562 cells into monocytes, granulocytes, and megakaryocytes was not affected by 6-MITC. The 6-MITC-induced unique mode of cell death through the concurrent induction of mitosis and autophagy may have therapeutic potential. Further studies are required to elucidate the pathways associated with the counteracting occurrence of mitosis and autophagy.

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PMID: 

Biomolecules. 2019 Aug 19 ;9(8). Epub 2019 Aug 19. PMID: 31430990

Abstract Title: 

Effect of Photobiomodulation in Rescuing Lipopolysaccharide-Induced Dopaminergic Cell Loss in the Male Sprague-Dawley Rat.

Abstract: 

Photobiomodulation (PBM) provides neuroprotection against dopaminergic cell death and associated motor deficits in rodent and primate models of Parkinson's disease (PD). However, it has not yet been tested in the lipopolysaccharide (LPS) model of PD, which leads to dopaminergic cell death through microglia-evoked neuroinflammation. We investigated whether transcranial PBM could protect against dopaminergic cell death within the substantia nigra in male Sprague-Dawley rats following supranigral LPS injection. PBM fully protected rats from 10µg LPS which would have otherwise caused 15% cell loss, but there was no significant neuroprotection at a 20 µg dose that led to a 50% lesion. Cell loss at this dose varied according to the precise site of injection and correlated with increased local numbers of highly inflammatory amoeboid microglia. Twenty microgram LPS caused motor deficits in the cylinder, adjusted stepping and rotarod tests that correlated with dopaminergic cell loss. While PBM caused no significant improvement at the group level, motor performance on all three tests no longer correlated with the lesion size caused by 20 µg LPS in PBM-treated rats, suggesting extranigral motor improvements in some animals. These results provide support for PBM as a successful neuroprotective therapy against the inflammatory component of early PD, provided inflammation has not reached a devastating level, as well as potential benefits in other motor circuitries.

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PMID: 

Biomed Opt Express. 2019 Aug 1 ;10(8):4003-4017. Epub 2019 Jul 15. PMID: 31452991

Abstract Title: 

Pilot study of transcranial photobiomodulation of lymphatic clearance of beta-amyloid from the mouse brain: breakthrough strategies for non-pharmacologic therapy of Alzheimer's disease.

Abstract: 

In this pilot study, we analyzed effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm) on clearance of beta-amyloid (Aβ) from the mouse brain. The immunohistochemical and confocal data clearly demonstrate the significant reduction of deposition of Aβ plaques in mice after tPBM vs. untreated animals. The behavior tests showed that tPBM improved the cognitive, memory and neurological status of mice with Alzheimer'sdisease (AD). Using of our original method based on optical coherence tomography (OCT) analysis of clearance of gold nanorods (GNRs) from the brain, we proposed possible mechanism underlying tPBM-stimulating effects on clearance of Aβ via the lymphatic system of the brain and the neck. These results open breakthrough strategies for a non-pharmacological therapy of Alzheimer's disease and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying Alzheimer's disease.

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PMID: 

Photochem Photobiol. 2019 Sep 24. Epub 2019 Sep 24. PMID: 31550398

Abstract Title: 

Effect of Photobiomodulation on Repairing Pressure Ulcers in Adult and Elderly Patients: A Systematic Review.

Abstract: 

Evaluation of photobiomodulation therapy (PBMT) in the treatment of pressure ulcers in adults and the elderly. Systematic review, based on the recommendations of the handbook, proposed by Cochrane. The search was carried out in databases, records of randomized clinical trials, list of references cited in the selected articles, as well as a manual search in meetings and specialized journals. A total of 1342 studies were identified, 18 were preselected and 5 were included in this review. Clinical heterogeneity of the participants was observed, in addition to variation in the laser parameters and predominance of studies of low methodological quality. PBMT with the use of laser (658 nm; 4 J cm;50 mw) showed complete wound healing (P 

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PMID: 

Cartilage. 2019 Sep 30:1947603519876338. Epub 2019 Sep 30. PMID: 31569995

Abstract Title: 

Photobiomodulation Therapy Partially Restores Cartilage Integrity and Reduces Chronic Pain Behavior in a Rat Model of Osteoarthritis: Involvement of Spinal Glial Modulation.

Abstract: 

OBJECTIVE: Chronic pain associated with osteoarthritis (OA) often leads to reduced function and engagement in activities of daily living. Current pharmacological treatments remain relatively ineffective. This study investigated the efficacy of photobiomodulation therapy (PBMT) on cartilage integrity and central pain biomarkers in adult male Wistar rats.DESIGN: We evaluated the cartilage degradation and spinal cord sensitization using the monoiodoacetate (MIA) model of OA following 2 weeks of delayed PBMT treatment (i.e., 15 days post-MIA). Multiple behavioral tests and knee joint histology were used to assess deficits related to OA. Immunohistochemistry was performed to assess chronic pain sensitization in spinal cord dorsal horn regions. Furthermore, we analyzed the principal components related to pain-like behavior and cartilage integrity.RESULTS: MIA induced chronic pain-like behavior with respective cartilage degradation. PBMT had no effects on overall locomotor activity, but positive effects on weight support (= 0.001; effect size [ES] = 1.01) and mechanical allodynia (= 0.032; ES = 0.51). Greater optical densitometry of PBMT-treated cartilage was evident in superficial layers (= 0.020; ES = 1.34), likely reflecting the increase of proteoglycan and chondrocyte contents. In addition, PBMT effects were associated to decreased contribution of spinal glial cells to pain-like behavior (= 0.001; ES = 0.38).CONCLUSION: PBMT during the chronic phase of MIA-induced OA promoted cartilage recovery and reduced the progression or maintenance of spinal cord sensitization. Our data suggest a potential role of PBMT in reducing cartilage degradation and long-term central sensitization associated with chronic OA.

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PMID: 

J Biophotonics. 2019 Sep 30:e201900204. Epub 2019 Sep 30. PMID: 31568634

Abstract Title: 

Photobiomodulation therapy in knee osteoarthritis reduces oxidative stress and inflammatory cytokines in rats.

Abstract: 

Knee osteoarthritis (OA) is a chronic disease that causes pain and gradual degeneration of the articular cartilage. In this study, MIA-induced OA knee model was used in rats to test the effects of the photobiomodulation therapy (PBM). We analyzed the inflammatory process (pain and cytokine levels), and its influence on the oxidative stress and antioxidant capacity. Knee OA was induced by monosodium iodoacetate (MIA) intra-articular injection (1.5 mg/50μL) and the rats were treated with eight sessions of PBM 3 days/week (904 nm, 6 or 18 J/cm). For each animal, mechanical and cold hyperalgesia and spontaneous pain were evaluated; biological analyses were performed in blood serum, intra-articular lavage, knee structures, spinal cord and brainstem. Cytokine assays were performed in knee, spinal cord and brainstem samples. The effects of the 18 J/cmdose of PBM were promising in reducing pain and neutrophil activity in knee samples, together with reducing oxidative stress damage in blood serum and spinal cord samples. PBM improved the antioxidant capacity in blood serum and brainstem, and decreased the knee pro-inflammatory cytokine levels. Our study demonstrated that PBM decreased oxidative damage, inflammation and pain. Therefore, this therapy could be an important tool in the treatment of knee OA.

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PMID: 

Injury. 2019 Nov ;50(11):1853-1867. Epub 2019 Sep 21. PMID: 31585673

Abstract Title: 

Photobiomodulation therapy (PBMT) in bone repair: A systematic review.

Abstract: 

BACKGROUND: Photobiomodulation therapy (PBMT) using low-level laser influences the release of several growth factors involved in the formation of epithelial cells, fibroblasts, collagen and vascular proliferation, besides accelerating the synthesis of bone matrix due to the increased vascularization and lower inflammatory response, with significant increase of osteocytes in the irradiated bone. Considering its properties, beneficial effects and clinical relevance, the aim of this review was to analyze the scientific literature regarding the use of PBMT in the process of bone defect repair.METHODS: Electronic search was carried out in PubMed/MEDLINEand Web of Science databases with combination of the descriptors low-level laser therapy AND bone repair, considering the period of publication until the year 2018.RESULTS: The literature search identified 254 references in PubMed/MEDLINE and 204 in Web of Science, of which 33 and 4 were selected, respectively, in accordance with the eligibility requirements. The analysis of researches showed articles using PBMT in several places of experimentation in the subjects, different types of associated biomaterials, stimulatory effects on cell proliferation, besides variations in the parameters of use of laser therapy, mainly in relation to the wavelength and density of energy. Only four articles reported that the laser did not improve the osteogenic properties of a biomaterial.CONCLUSIONS: Many studies have shown that PBMT has positive photobiostimulatory effects on bone regeneration, accelerating its process regardless of parameters and the use of biomaterials. However, standardization of its use is still imperfect and should be better studied to allow correct application concerning the utilization protocols.

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