Analgesic efficacy of median nerve stimulation in mice with chemotherapy-induced peripheral neuropathymodulation of brain-derived neurotrophic factor expression.

OBJECTIVE: Chemotherapeutic agents such as docetaxel (DTX) can trigger chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by unbearable pain. This study was designed to investigate the analgesic effect and related neuronal mechanism of low-frequency median nerve stimulation (LFMNS) on DTX-induced tactile hypersensitivity in mice. METHODS: To produce CIPN, DTX was administered intraperitoneally 4 times, once every 2 d, to male ICR mice. LFMNS was performed on the wrist area, and the pain response was measured using von Frey filaments on both hind paws. Western blot and immunofluorescence staining were performed using dorsal root ganglion and spinal cord samples to measure the expression of brain-derived neurotrophic factor (BDNF). RESULTS: Repeated LFMNS significantly attenuated the DTX-induced abnormal sensory response and suppressed the enhanced expression of BDNF in the DRG neurons and spinal dorsal area. CONCLUSIONS: LFMNS might be an effective non-pharmaceutical option for treating patients suffering from CIPN regulating the expression of peripheral and central BDNF.

Induction of apoptosis in RL95-2 human endometrial cancer cells by combination treatment with docosahexaenoic acid and triacsin C.

Introduction: Docosahexaenoic acid (DHA) supplementation has been reported to negatively correlate with cancer cell proliferation and tumour development in many cancer types. Although cumulative evidence has demonstrated the apoptotic effect and cytotoxicity of DHA against tumour development in many cell types, the precise cellular and biochemical mechanisms of DHA-induced apoptosis in human endometrial cancer cells have not been investigated. Material and methods: MTT assay was performed to confirm the degree of apoptosis by combining treatment with DHA and triacsin C in endometrial cancer cell line. The synergistic effects of triacsin C and DHA were identified by performing flowcytometry and immunoblotting analysis. Results: Combined treatment with DHA and triacsin C significantly induced apoptosis in RL95-2 endometrial carcinoma cells. Combined treatment with 125 µM DHA and 5 µM triacsin C significantly increased the sub-G1 population and apoptotic fragments in endometrial carcinoma cells. It was also demonstrated that DHA and triacsin C induced apoptosis through mitochondrial pathways via caspases-9, -3, and -7 as well as through the extrinsic pathway by activation of caspase-8/BID. Conclusions: Further elucidation of the apoptotic mechanisms involving DHA treatment with ACS ablation could shed light on possible new treatment strategies for endometrial cancer. In addition, further research into the mechanisms of DHA and triacsin C-induced apoptotic mechanisms may lead to the development of therapeutic strategies for endometrial cancer.

Stimulatory effects of wavelength-dependent photobiomodulation on proliferation and angiogenesis of colorectal cancer.

In recent decades, the laser treatment of cancer has been introduced as a promising treatment option. Because of the maldistribution of optical energy and an ambiguous boundary between the normal and tumor tissues, laser irradiation can stimulate residual cancer cells, leading to a cancer regrowth. As photobiomodulation (PBM) is involved in an extensive range of cellular responses, profound comprehension of photo-stimulated mechanisms against the cancer cells is required to establish a safety margin for PBM. Therefore, we aimed to identify the stimulant effects of PBM at various wavelengths against the tumor cells to establish a safety margin for the laser treatment. CT26 murine colon cancer cells were exposed to either 405 (BL), 635 (VIS), or 808 (NIR) nm laser lights at the fluences of 0, 10, 30, and 50 J/cm2. In addition, CT26 tumor-bearing mice were irradiated with BL, VIS, or NIR at a fluence of 30 J/cm2. Both the proliferation and angiogenesis potential of the CT26 cells and tumors were evaluated using the MTT assay, western blot, and immunohistochemistry (IHC) staining analyses. Although cell viability was not statistically significant, BL significantly induced p-ERK upregulation in the CT26 cells, indicating that PBM with BL can stimulate proliferation. In vivo tests showed that the NIR group exhibited the maximum relative tumor volume, and BL yielded a slight increase compared to the control. In the IHC staining and western blot analyses, both BL and NIR increased the expression of EGFR, VEGF, MMP-9, and HIF-1α, which are related to the proliferation and angiogenesis-related factors. Further investigations will be pursued to clarify the molecular pathways that depend on the cancer cell types and laser wavelengths for the establishment of safety guidelines in clinical environments.

High-Dose Vitamin C Prevents Secondary Brain Damage After Stroke via Epigenetic Reprogramming of Neuroprotective Genes.

Vitamin C has recently been identified as an epigenetic regulator by activating ten-eleven translocases (TETs), enzymes involved in generating DNA hydroxymethylcytosine (5hmC). Currently, we investigated whether high-dose vitamin C promotes neuroprotection through epigenetic modulation of 5hmC, if there are sex-specific differences in outcome, and the therapeutic potential of vitamin C in stroke-related comorbidities in adult mice. Post-stroke treatment with ascorbate (reduced form), but not dehydroascorbate (oxidized form), increased TET3 activity and 5hmC levels and reduced infarct following focal ischemia. Hydroxymethylation DNA immunoprecipitation sequencing showed that ascorbate increased 5hmC across the genome and specifically in promoters of several stroke pathophysiology-related genes, particularly anti-inflammatory genes. Ascorbate also decreased markers of oxidative stress, mitochondrial fragmentation, and apoptosis in cortical peri-infarct neurons and promoted motor and cognitive functional recovery in both sexes via TET3. Furthermore, post-stroke ascorbate treatment reduced infarct volume and improved motor function recovery in aged, hypertensive and diabetic male and female mice. Delayed ascorbate treatment at 6 h of reperfusion was still effective at reducing infarct volume and motor impairments in adult mice. Collectively, this study shows that post-stroke treatment with high-dose ascorbate protects the brain through epigenetic reprogramming and may function as a robust therapeutic against stroke injury.

Annual Prevalence, Health Expenditures, and Co-Morbidities Trend of Iron Deficiency Anemia in Korea: National Health Insurance Service Data from 2002 to 2013.

Despite improvements in nutritional status, iron deficiency anemia (IDA) remains a debilitating nutritional problem worldwide. We estimate annual IDA prevalence rates by sex and age and the trends therein in Korea. We also calculate the health expenditures of IDA and its co-morbidities by analyzing claims data in the National Health Information Database from 2002 to 2013. All analyses were performed based on diagnosis codes of IDA (D50, D50.0, D50.8, and D50.9) regardless of whether IDA was the principal or a coexisting disease. Trends in IDA prevalence rates were evaluated by calculating annual percent changes (APCs) in prevalence. The health expenditures of IDA were calculated based on the direct medical costs (outpatient and hospitalization costs, pharmaceutical costs) and direct non-medical costs (travel costs). The overall IDA prevalence in both sexes increased approximately 2.3-fold from 2002 to 2013; the APC was +7.6%. In females, the prevalence of IDA was highest in aged 30-39 and 40-49 years. The APC was highest in those aged <10 years (+18.2%), followed by those aged ≥80 (+14.7%) and 70-79 (+9.8%) years. In males, the prevalence rates were highest in aged <10 years, followed by those aged ≥60 years. The APC was highest in those aged <10 years (+19.1%), followed by those aged ≥80 years (+10.5%). The total health expenditures increased 2.8-fold during 12 years. Diseases of the respiratory or gastrointestinal tract were the most prevalent co-morbidities in both males and females. The annual prevalence of IDA continues to rise in association with adverse health expenditures and co-morbidities in spite of improvements in nutritional status. Most importantly, infants and young children, the elderly, and females aged 30-49 years are at highest risk of IDA. A national, prospective, and well-organized effort to improve iron status and to manage IDA is required.

Eckol from Ecklonia cava Suppresses Immunoglobulin E-mediated Mast Cell Activation and Passive Cutaneous Anaphylaxis in Mice.

Eckol, a precursor compound belonging to the dibenzo-1,4-dioxin class of phlorotannins, is a phloroglucinol derivative that exerts various activities. In the present study, we investigated the antiallergic effects of eckol isolated from the marine brown algae, Ecklonia cava using immunoglobulin E (IgE)/bovine serum albumin (BSA)-stimulated mouse bone marrow-derived cultured mast cells (BMCMC) and a mouse model of anaphylaxis. Eckol inhibited IgE/BSA-induced BMCMC degranulation by reducing ß-hexosaminidase release. A flow cytometric analysis revealed that eckol decreases FcεRI expression on cell surface and IgE binding to the FcεRI in BMCMC. Moreover, eckol suppressed the production of the cytokines, interleukin (IL)-4, IL-5, IL-6, and IL-13 and the chemokine, thymus activation-regulated chemokine (TARC) by downregulating, IκB-α degradation and NF-κB nuclear translocation. Furthermore, it attenuated the passive cutaneous anaphylactic reaction induced by IgE/BSA-stimulation in the ear of BALB/c mice. These results suggest that eckol is a potential therapeutic candidate for the prevention and treatment of allergic disorders.

Subacute Combined Degeneration Caused by Nitrous Oxide Intoxication: A Report of Two Cases.

We report two cases of subacute combined degeneration (SCD) caused by nitrous oxide (N2O) gas intoxication, which is rarely reported in Korea. Two patients recreationally inhaled N2O gas daily for several months. They presented with paresthesia of limbs, voiding difficulty, and gait disturbance. The initial vitamin B12 levels were normal or decreased, but homocysteine levels of the two patients were increased. Magnetic resonance imaging of the cervical spine showed T2-weighted hyperintensity in the bilateral dorsal columns of the cervical spinal cord. Electromyography and somatosensory evoked potential tests for both patients suggested posterior column lesion of the spinal cord combined with sensorimotor polyneuropathy. According to these findings, we concluded that the two patients had SCD. The patient's symptoms partially improved after cessation of N2O gas inhalation and the receiving of vitamin B12 supplementation therapy. As the incidence of recreational N2O gas inhalation is increasing in Korea, physicians must be alert to the N2O induced SCD in patients presenting with progressive myelopathy.

Improvement in neurogenesis and memory function by administration of Passiflora incarnata L. extract applied to sleep disorder in rodent models.

Recently, there have been reports that chronic insomnia acts as an insult in the brain, causing memory loss through the production of ROS, inflammation, and, Alzheimer's disease if persistent. Insomnia remains the leading cause of sleep disturbance and as such has serious implications for public health. Patients with Alzheimer's disease are also known to suffer from severe sleep disturbance. Meanwhile, vitexin is a key ingredient in Passiflora incarnata L (passion flower, PF) extract, which is known to help with sleep. This medicinal plant has been used as a folk remedy for sedation, anxiety and sleep since centuries ago, but the standardization work has not been done and the extent of the effect has not been clearly demonstrated. For this reason, we tried to test the possibility that repeated administration of PF could improve the memory by promoting hippocampal neurogenesis at the DBA/2 mice known have inherited sleep disorders, as well as preventive effects of Alzheimer's disease. Here, we found that vitexin, which is the main bioactive component of ethanol extracts from leaves and fruits (ratio; 8:2) of PF, confirmed the improvement of neurogenesis (DCX) of DBA/2 mice repeated PF oral administration by immunohistochemistry (IHC) and western blot analysis. PF-treated group showed increased the neurotrophic factor (BDNF) in the hippocampus compared with that of vehicle-treated group, but the inflammation markers Iba-1 (microglial marker) and COX-2 were inconsistent between the groups. However, we found COX-2 signal is essential for hippocampal neurogenesis according to the additional IHC experiments using COX-2 inhibitor and pIkappaB have shown. In addition, although prescription sleeping pills have been reported to show significant changes in appetite and metabolic rate from time to time, no changes in the feeding behavior, body weight, metabolic rate and body composition of the animals were observed by administration of PF. Interestingly, we found that short-term oral administration of PF displayed improved memory according to the water maze test. Quantitative analysis of Tau protein, which is a marker of Alzheimer's disease, was performed in the SD rats and DBA/2 mice by repeated PF oral administration and pTau/Tau values were significantly decreased in PF-treated group than vehicle-treated group. In conclusion, our results suggest that PF lead high hippocampal neurogenesis in the animals even in inherited sleep-disturbed animals. The increased hippocampal neurogenesis functionally enhanced memory and learning functions by repeated PF oral administration. These results identify PF as a potential therapy for enhancing memory functions and prevention of Alzheimer's disease through actions on the hippocampus.

The Clinical Effects of Dendropanax Morbifera on Postmenopausal Symptoms: Review Article.

Postmenopausal women aged 50s generally experience gradual changes in body such as decline in antioxidant and estrogen levels as the body ages. To overcome these aging-associated changes, the needs for health functional foods are increasing. Dendropanax morbifera (DM) have antioxidant effects, anti-inflammatory against cancer cells, antidiabetic, and antiatherogenic effect which are associated with postmenopausal symptoms. We analyzed clinical effects of DM on aging-related symptoms by reporting their antioxidant, anticancer and inflammatory activity, etc. and their bioactivity. Data sources EMBASE, SCOPUS, PubMed, Web of Science, and Google Scholar databases were searched up to August 2016 for studies investigating medicinal plants in prevention and treatment of diabetes. The search terms were "Dendropanax morbifera". The reference lists of articles were also reviewed for additional relevant studies. Extracts of DM have various efficacy such as antioxidant, anti-cancer, anti-inflammatory activity and anti-thrombotic effect.

Role Identification of Passiflora Incarnata Linnaeus: A Mini Review.

Some species of traditional herbal medicine has a history of use, most traditional natural herbs have been used for various diseases such as diabetes, hypertension, and obesity. Among them, Passiflora incarnata L. is a traditional natural medicine, flowers as well as berries, roots, and leaves have been used as a medicine. It has been used as a natural medicine for the treatment of insomnia and anxiety for a longtime in Europe, and it has been used primarily for sedation tea in North America. Moreover, Passiflora incarnata L. is widely used anti-asthmatic, analgesic and sedation in Brazil. In other words, Passiflora incarnata L. has been used to treat a sedative, dysmenorrhea, insomnia, cancer, etc. in many countries. Present review of the plants showed a wide range of pharmacological activity in anxiolytic relax the clinical disease, such as anti-inflammatory, anxiety and antioxidant. In addition, Passiflora incarnata L. affects menopause symptoms such as vasomotor symptoms, insomnia, and depression. This review aims to provide the latest information on specific functional components of Passiflora incarnata L. especially the results of clinical trials will provide new insights into opportunities for the future development of natural medicines and doors will be used for purposes of analysis.

Premenstrual syndrome: A mini review.

Premenstrual syndrome (PMS) is characterized by recurrent, moderate-to-severe affective, physical, and behavioral symptoms that develop during the luteal menstrual cycle and disappear within a few days of menstruation. Premenstrual dysphoric disorder (PMDD) is a severe and disabling condition that can affect personal relationships and occupational activities. PMS occurs in 30-40% of reproductive-age females; PMDD affects 3-8% of this population. Although the etiology of PMS is unclear, several theories suggest increased sensitivity to normal hormonal changes and neurotransmitter abnormalities. The diagnostic method of PMS is the Daily Record of Severity of Problems, which women with PMS can use to self-report several symptoms and their severity. Although combined oral contraceptives and serotonergic antidepressants are effective drugs, each is a different option for treating PMS/PMDD. Serotonergic antidepressants are the drugs of choice for improving both physical and mood symptoms. Combined oral contraceptives appear to primarily improve physical symptoms. Clinicians should consider each patient's situation individually. Other treatment options include lifestyle modification, cognitive behavioral therapy, and herbal medicine (e.g., chasteberry).

Effect of Korean Red Ginseng as an adjuvant treatment for women with residual symptoms of major depression.

INTRODUCTION: Around 20% of patients with major depression experience residual symptoms. Ginseng has shown potential antidepressant effects in some animal studies and in patients with stress-related somatic symptoms. Therefore, we investigated the effectiveness and tolerability of Korean Red Ginseng adjuvant treatment in patients with residual symptoms of major depression. METHODS: In this eight-week prospective study, 35 female outpatients aging from 18 to 65 years (45.1 ± 9.5), who were remitted from major depression with residual symptoms, were given Korean Red Ginseng at doses of 3 g/day. The Depression Residual Symptom Scale (DRSS) and Montgomery-Åsberg Depression Rating Scale (MADRS) were administrated to evaluate depressive symptoms. The general severity of symptoms was assessed by a clinician using the Clinical Global Impressions Scale for Severity (CGI-S). The Depression and Somatic Symptom Scale (DSSS) was also used to evaluate somatic symptoms in the subjects. This trial is registered at Clinical.gov, number NCT01496248. RESULTS: Subjects reported significant decrease in depressive symptoms on the DRSS (P < 0.05) and MADRS (P < 0.01) decreased significantly over the eight-week period. The scores on the CGI-S, an objective measurement of symptoms, showed significant improvement in the severity of illness (P < 0.001). Somatic symptoms on the DSSS also attenuated significantly during the study period (P < 0.05). DISCUSSION: These results suggest that Korean Red Ginseng is efficacious as an adjuvant treatment for patients experiencing residual symptoms of major depression. Future placebo-controlled research is required to confirm our results.

Anti-obesity phenotypic screening looking to increase OBR cell surface expression.

The leptin receptor, OBR, is involved in the regulation of whole-body energy homeostasis. Most obese people are resistant to leptin and do not respond to the hormone. The prevention and reversal of leptin resistance is one of the major current goals of obesity research. We showed previously that increased OBR cell surface expression concomitantly increases cellular leptin signaling and prevents obesity development in mice. Improvement of OBR cell surface expression can thus be considered as an interesting anti-obesity therapeutic strategy. To identify compounds that increase the surface expression of OBR, we developed a cell-based, phenotypic assay to perform a high-content screen (HCS) against a library of 50,000 chemical compounds. We identified 67 compounds that increased OBR cell surface expression with AC50 values in the low micromolar range and no effect on total OBR expression and cellular toxicity. Compounds were classified into 16 chemical clusters, of which 4 potentiated leptin-promoted signaling through the JAK2/STAT3 pathway. In conclusion, development of a robust phenotypic screening approach resulted in the discovery of four new scaffolds that demonstrate the desired biological activity and could constitute an original therapeutic solution against obesity and associated disorders.

Identification of two HIV inhibitors that also inhibit human RNaseH2.

A total of 140,000 compounds were screened in a targetfree cell-based high throughput assay against HIV-1 infection, and a subset of 81 promising compounds was identified. Secondary screening of these 81 compounds revealed two putative human RNaseH2 inhibitors, RHI001 and RHI002, with IC50 value of 6.8 µM and 16 µM, respectively. RHI002 showed selective activity against human RNaseH2 while RHI001 inhibited HIV-RNaseH, E. coli RNaseH, and human RNaseH1 with IC50 value of 28.5 µM, 7.9 µM, and 31.7 µM, respectively. Kinetic analysis revealed that both inhibitors had non-competitive inhibitor-like properties. Because RNaseH2 is involved in the etiology of Aicardi-Goutier syndrome and has been suggested as an anticancer drug target, small molecule inhibitors modulating its activity would be useful for investigating the cellular function of this molecule.

Identification of a novel sulfonamide non-nucleoside reverse transcriptase inhibitor by a phenotypic HIV-1 full replication assay.

Classical target-based, high-throughput screening has been useful for the identification of inhibitors for known molecular mechanisms involved in the HIV life cycle. In this study, the development of a cell-based assay that uses a phenotypic drug discovery approach based on automated high-content screening is described. Using this screening approach, the antiviral activity of 26,500 small molecules from a relevant chemical scaffold library was evaluated. Among the selected hits, one sulfonamide compound showed strong anti-HIV activity against wild-type and clinically relevant multidrug resistant HIV strains. The biochemical inhibition, point resistance mutations and the activity of structural analogs allowed us to understand the mode of action and propose a binding model for this compound with HIV-1 reverse transcriptase.

In vitro and in vivo immunostimulatory effects of hot water extracts from the leaves of Artemisia princeps Pampanini cv. Sajabal.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia princeps Pampanini (Asteraceae) is used as a traditional medicine to immune function-related diseases, such as dysmenorrhea, inflammation, cancer, and ulcers. AIM OF THE STUDY: The purpose of this study is to evaluate the immunostimulatory effects of the hot water extract from the leaves of Artemisia princeps Pampanini (WAPP) in recombinant interferon-γ (rIFN-γ)-primed RAW 264.7 macrophages and in cyclophosphamide (20mg/kg, i.p.)-induced immunosuppressed Sprague-Dawley rats. MATERIALS AND METHODS: RAW 264.7 macrophages were treated with WAPP and production and expressions of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) via nuclear factor-κB (NF-κB) were detected by immunoassay, western blot, qRT-PCR and reporter gene assay. In addition, in vivo immunomodulatory activity was studied by cyclophosphamide-induced myelosuppression in rats. RESULTS: In rIFN-γ-primed RAW 264.7 macrophages, pretreatment with WAPP increased the productions of nitric oxide (NO) and tumor necrosis factor-α (TNF-α),and increased the expressions of inducible nitric oxide synthase (iNOS) at the protein level and of iNOS and TNF-α at the mRNA level. Molecular data revealed that WAPP upregulated the transcriptional activity and translocation of nuclear factor-κB (NF-κB) by activating inhibitory kappa B-α (IκB-α) degradation and phosphorylation. Furthermore, WAPP upregulated the phosphorylations of p38 MAP kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2). In cycloheximide-induced immunosuppressed rats, pretreatment with WAPP (100, 200, or 400mg/kg, p.o.) increased the serum levels of albumin and globulin, and reduced immobility times. CONCLUSION: Our results suggest that upregulations of the expressions of iNOS and TNF-α via the activations of NF-κB and MAPK are responsible for the immunostimulatory effects of WAPP.

A new labdane diterpenoid with anti-inflammatory activity from Thuja orientalis.

UNLABELLED: ETHONOPHARMACOLOGICAL RELEVANCE: Thuja orientalis (L) ENDL (Cupressaceae) is an evergreen arbor that is distributed throughout Northeast Asia. This plant has been used as a traditional medicine for the treatment of various inflammatory diseases such as dermatitis, gout and chronic tracheitis. AIM OF THE STUDY: To isolate the active principles responsible for the anti-inflammatory activities of Thuja orientalis and to disclose their mechanism of action in lipopolysaccharide (LPS)-stimulated macrophages. MATERIALS AND METHODS: The methanolic leaves and stem extracts of the Thuja orientalis were successively fractionated into EtOAc, n-BuOH and the remaining aqueous fractions. The EtOAc soluble fraction, which exhibited significant inhibitory activity on LPS-induced nitric oxide (NO) production, was followed by successive activity-guided chromatography to yield seven diterpenoids. The anti-inflammatory properties of active constituents were evaluated by RT-PCR, Western blotting and reporter gene assay in cell culture system. RESULTS: A new labdane diterpene, 15-nor-14-oxolabda-8(17),13(16)-dien-19-oic acid (1), and six known diterpenoids (2-7) were isolated from the EtOAc extracts of Thuja orientalis. The isolated compounds 1-7 were evaluated for the inhibitory activity of LPS-induced NO production in RAW264.7 macrophage cells. Compound 1 was the most potent among the isolated compounds for the inhibition of LPS-induced NO production (IC501: 3.56µM). Compound 1 reduced the production of pro-inflammatory mediators and suppressed the expression of the inflammatory enzymes of iNOS and COX-2. In addition, compound 1 attenuated the LPS-induced transcriptional activity of NF-κB by the inhibition of inhibitory-κBα degradation, and suppressed the activity of extracellular signal regulated kinase (ERK). CONCLUSIONS: This study demonstrates that a new labdane diterpene from Thuja orientalis inhibits the inflammatory responses by the suppression of NF-κB activity and ERK phosphorylation. This compound might be a valuable candidate for the development of anti-inflammatory drugs.