As the most significant cause of death worldwide, obesity has become one of the world's most important public health problems, but approved anti-obesity drugs are extremely limited. This article summarizes the feeding control circuits and regulators involved in obesity development, highlight the hypothalamus, melanocortin system and brain-gut peptide actions in this process, and the five US FDA approved anti-obesity medications in long term use, namely phentermine/topiramate, lorcaserin, naltrexone/bupropion, liraglutide and orlistat.
Major depressive syndrome (so-called depression) is a common but serious mental disease that causes low mood. Most patients are treatable, mainly because of high response rates for medicines such as selective serotonin-reuptake inhibitors (SSRIs). However, there are still a considerable number of patients with refractory or drug-resistant depression. On the other hand, recent findings suggest that angiogenesis, i.e., making new blood vessels, could have an important role in the recovery from depressive disorders, at least in part. It has been reported that the brain capillaries are physiologically capable of undergoing angiogenesis upon stimuli such as exercise and SSRIs seem to accelerate brain angiogenesis. Drugs targeting angiogenesis may possibly be another good concept. In addition, the blood brain barrier (BBB), which is a major obstacle for drug development for the central nervous system, would be circumvented. Here I summarize the reports that relate angiogenesis to a cure for major depression and discuss some of the potential molecular targets.
Whole brain radiation therapy for the treatment of tumors can sometimes cause cognitive impairment. Memory deficits were noted in up to 50% of treated patients over a short period of several months. In addition, an increased rate of dementia in young patients has been noted over the longer term, i.e. years. A deficit in neurogenesis after irradiation has been postulated to be the main cause of cognitive decline in patients, but recent data on irradiation therapy for limited parts of the brain appear to indicate other possibilities. Irradiation can directly damage various types of cells other than neuronal stem cells. However, this paper will focus on injury to brain vasculature leading to cognitive decline since vessels represent a better therapeutic target for drug development than other cells in the brain because of the blood-brain barrier.
Tenascin C (TNC) is an extracellular matrix glycoprotein involved in osteogenesis and bone mineralization. In a previous study, we identified TNC protein located in the matrix vesicles (MVs) of osteoblasts. MVs are determinant in the mineralization formation. Therefore, we hypothesize whether TNC can modulate osteoblast mineralization via MVs. In this study, we demonstrated that the expression level of TNC was increased with osteoblast differentiation of osteoblast-like SaOS2 cells, and down-regulation of TNC expression by siRNA could significantly inhibit SaOS2 differentiation toward osteoblasts and mineralization as evidenced by decreases in ALP activity, mineralized nodule formation, calcium deposition, and down-regulation of osteogenic marker genes ALP, and COL1A1. Furthermore, we validated that TNC located in the MVs of mineralized SaOS2 cells, and that down-regulation of TNC could decrease MVs mineralization ability in vitro, and the decrease of MVs mineralization ability was not associated with annexins. In conclusion, in this study, we extended the role of TNC during osteogenesis previous progresses, and that supported TNC as an important functional MVs component in modulating osteoblast mineralization.
The pH, osmotic pressure (cryoscopy), viscosity, squeeze force, spray angle, and spraying frequency of nasal spray containing ketotifen fumarate (1 brand-name product and 8 generic products) were measured. Based on the results of pH measurement, all products were weakly acidic (4.0 to 5.1). For all products, the osmotic pressure ratio to physiological saline was approximately 1. The viscosity of various products ranged from approximately 1.0 to 1.5 mPa·s. The spray angle of drug solution differed among the products: minimum, 46 degrees (Sawai and Fusachol); and maximum, 68.7 degrees (Sekiton). In particular, TOA, Sawai, Fusachol, and TYK showed significantly smaller angles compared to Zaditen (brand-name product). Container properties varied among the products: minimum squeeze force, 19.0 N (Sekiton); and maximum squeeze force, 43.1 N (Sawai). Based on these results, although all the above products are identical in dosage form and active ingredient, the differences in pharmaceutical properties, such as container operations and drug-solution spraying/attachment, may markedly influence patients' subjective opinions.
Detrimental effects of ionizing radiation (IR) are observed at the doses above 1 Gy. Treatment modalities are available up to doses of 6 Gy including bonemarrow transplantation and administration of antibiotics. However, exposure to IR doses above 8 Gy results in gastro-intestinal (GI) syndrome characterised by denudated villi, apoptosis of crypt cells and elevated inflammatory responses. Multiple strategies have been employed to investigate novel agents to protect against IR induced injury. Since cellular redox homeostasis plays a pivotal role in deciding the cell fate, present study was undertaken to explore the potential of 1,4-naphthoquinone (NQ), a pro-oxidant, to ameliorate IR induced GI syndrome. NQ protected INT 407 cells against IR induced cell death of intestinal epithelial cells in vitro. NQ induced perturbation in cellular redox status and induced the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Thiol antioxidant and inhibitors of Nrf2 pathway abrogated the radioprotection offered by NQ. Further, knocking down Nrf2 rescind the NQ mediated protection against IR induced cell death. In conclusion, NQ protects against IR radiation induced GI syndrome in vitro by perturbing cellular redox and activating Nrf2 pathway. This is the first report highlighting the potential of a pro-oxidant to ameliorate IR induced GI injury.
Monoclonal antibodies (mAbs) are needed for the quantitation of environmental allergens for precise diagnosis and immunotherapy. In this study, we produced and purified monoclonal antibodies against Der f 2, one of the major allergens of the house dust mite Dermatophagoides farina, in order to develop an assay for the detection of this allergen. BALB/c mice were immunized four times with the protein Der f 2 together with an adjuvant after which splenocytes were collected and fused with SP2/0 (myeloma cells) in the presence of polyethylene glycol (PEG). The fused cells were selected in the presence of Hypoxanthine-Aminopterin-Thymidine (HAT) and then Hypoxanthine-Thymidine (HT) medium. Positive cells were screened with ELISA and subcloned by limited dilution at least three times to achieve stable mAb-producing clones. Four stable mAb-producing clones were obtained. One clone with IgG1 isotype and another with IgG2b isotype were chosen to produce large amounts of mAb by inoculation of the cells into the abdominal cavity of mice. Ascites were collected and the mAbs were purified using protein A affinity chromatography. Testing of the ascites by ELISA showed the titration of IgG1 and IgG2b to be higher than 1/106 dilution. The specificity of both antibodies was confirmed by immunoblotting. Thus, we produced two mAb clones against Der f 2 that can be used to create a precise quantitative method to identify allergen components in dust samples and facilitate further study in Der f 2 component-resolved diagnosis (CRD).
To find a novel influenza inhibitor targeting the endonuclease activity of influenza A virus polymerase acidic protein (PA), which is essential for the acquisition of primers for viral mRNA transcription, seven Kampo extracts were tested in vitro for their ability to inhibit endonuclease activity of the recombinant PA protein that was expressed and purified from Escherichia coli. The Kampo medicines Kakkonto, Shosaikoto, Saikokeishito, Keishito, Maobushisaishinto, and Maoto, but not Chikujountanto, inhibited PA endonuclease activity in a dose-dependent manner. Our results indicate that Kampo medicines are good sources providing a structural lead for optimization of an influenza endonuclease inhibitor.
An 81-year-old woman visited a local clinic due to chest pain and a skin induration on the right precordia. She had a history of right breast cancer, and she had undergone a mastectomy and radiation therapy 10 years prior. Computed tomography (CT) imaging of the chest demonstrated a lobular mass that involved the right anterior thoracic wall and partially extruded from the thoracic cavity into the subcutaneous tissue. The tumor was surgically excised, and pathological analyses yielded a diagnosis of angiosarcoma. Five months after the operation, CT imaging showed multiple masses on the right pleura, indicating a local relapse and pleural dissemination of the angiosarcoma. Systemic chemotherapy composed of nanoparticle albumin-bound paclitaxel (nab-PTX) (80 mg/m2) was delivered weekly. After 4 courses of chemotherapy, the tumors regressed remarkably. Nab-PTX may be an effective treatment option for recurrent or metastatic angiosarcoma.
Infiltration is a frequent complication of infusion therapy. We previously demonstrated the usefulness of infrared thermography as an objective method of detecting infiltration in healthy people. However, whether thermography can detect infiltration in clinical settings remains unknown. Therefore, we report two cases where thermography was useful in detecting infiltration at puncture sites. In both cases, tissue changes were verified ultrasonographically. The patients were a 56-year-old male with cholangitis and a 76-year-old female with hepatoma. In both cases, infiltration symptoms such as swelling and erythema occurred one day after the insertion of a peripheral intravenous catheter. Thermographic images from both patients revealed low-temperature areas spreading from the puncture sites; however, these changes were not observed in other patients. The temperature difference between the low-temperature areas and their surrounding skin surface exceeded 1.0°C. Concurrently, ultrasound images revealed that tissues surrounding the vein had a cobblestone appearance, indicating edema. In both patients, subcutaneous tissue changes suggested infiltration and both had low-temperature areas spreading from the puncture sites. Thus, subcutaneous edema may indicate infusion leakage, resulting in a decrease in the temperature of the associated skin surface. These cases suggest that infrared thermography is an effective method of objectively and noninvasively detecting infiltration.