Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15% of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18c and 18d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis.

Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.

Adolescent Parvalbumin Expression in the Left Orbitofrontal Cortex Shapes Sociability in Female Mice.

The adolescent social experience is essential for the maturation of the prefrontal cortex in mammalian species. However, it still needs to be determined which cortical circuits mature with such experience and how it shapes adult social behaviors in a sex-specific manner. Here, we examined social-approaching behaviors in male and female mice after postweaning social isolation (PWSI), which deprives social experience during adolescence. We found that the PWSI, particularly isolation during late adolescence, caused an abnormal increase in social approaches (hypersociability) only in female mice. We further found that the PWSI female mice showed reduced parvalbumin (PV) expression in the left orbitofrontal cortex (OFCL). When we measured neural activity in the female OFCL, a substantial number of neurons showed higher activity when mice sniffed other mice (social sniffing) than when they sniffed an object (object sniffing). Interestingly, the PWSI significantly reduced both the number of activated neurons and the activity level during social sniffing in female mice. Similarly, the CRISPR/Cas9-mediated knockdown of PV in the OFCL during late adolescence enhanced sociability and reduced the social sniffing-induced activity in adult female mice via decreased excitability of PV+ neurons and reduced synaptic inhibition in the OFCL Moreover, optogenetic activation of excitatory neurons or optogenetic inhibition of PV+ neurons in the OFCL enhanced sociability in female mice. Our data demonstrate that the adolescent social experience is critical for the maturation of PV+ inhibitory circuits in the OFCL; this maturation shapes female social behavior via enhancing social representation in the OFCL SIGNIFICANCE STATEMENT Adolescent social isolation often changes adult social behaviors in mammals. Yet, we do not fully understand the sex-specific effects of social isolation and the brain areas and circuits that mediate such changes. Here, we found that adolescent social isolation causes three abnormal phenotypes in female but not male mice: hypersociability, decreased PV+ neurons in the left orbitofrontal cortex (OFCL), and decreased socially evoked activity in the OFCL Moreover, parvalbumin (PV) deletion in the OFCL in vivo caused the same phenotypes in female mice by increasing excitation compared with inhibition within the OFCL Our data suggest that adolescent social experience is required for PV maturation in the OFCL, which is critical for evoking OFCL activity that shapes social behaviors in female mice.

Lower Serum Calcium Levels Associated with Disrupted Sleep and Rest-Activity Rhythm in Shift Workers.

Vitamin D deficiency is prevalent in many developed countries, and several studies suggest that vitamin D plays an essential role in brain function. A recent study showed that vitamin D deficiency was closely associated with daytime sleepiness and shorter sleep time. The relationshipbetween vitamin D levels and calcium levels is well established, and calcium level regulates slow-wave sleep generation. It is conceivable that the sleep disturbance in vitamin D deficiency may be due to an altered calcium level. Nonetheless, calcium levels, sleep disturbances, and activity rhythms have not been investigated directly. Therefore, we hypothesized that calcium and vitamin D levels might be important in regulating sleep and activity rhythm, and we analyzed the correlation with calcium levels by actigraphy analysis. Interestingly, a negative correlation was found between calcium level and sleep latency, total sleep time, use of sleep medicine, and daytime dysfunction among shift workers. In contrast, non-shift workers showed a negative correlation between the calcium level and the circadian phase. These findings suggest that low serum calcium levels may disrupt sleep-wake control and rest-activity rhythm, even if they are within the normal range.

Agent Orange Exposure and Prevalence of Self-reported Diseases in Korean Vietnam Veterans / 예방의학회지

OBJECTIVES: The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. METHODS: A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. RESULTS: The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. CONCLUSIONS: Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.

Medical Service Utilization and Trends among Korean Elderly in the Last One Year of Life / 예방의학회지

OBJECTIVES: To analyze medical service utilization and trends among the elderly in the last year of life. METHOD: The subjects of this study were people that had died at the age sixty-five and above between January 1st and June 30th 2000 The names of the deceased and their dates of death were collected from the data of the funeral-expenses-receivers of the National Health Insurance Corporation (NHIC). This data was merged with that of the individual medical expenses of the NHIC. RESULTS: In the first half of 2000, 84.2% of the funeral-expenses-receivers (53, 063) utilized medical services during the year prior to their death; 51.0% (27, 042) were female and 49.0% (26, 021) male. In the last twelve months of life, the medical fees, the number of days receiving medical services and the number of days receiving medicine were 3, 107, 935 Won, 47.88 and 153.21, respectively, for each person. As the age of the groups increased, the level of medical service utilization decreased; the change was more obvious in female group. The level of medical service utilization during the twelve months prior to death drastically increased around the time of death. CONCLUSIONS: This study, from an analysis of the level of medical service utilization prior to death, shows a concentrated volume of medical services during a certain time period prior to death.

A Study on the Association between Healthcare Utilization and the Burden of Families Caring for the Elderly in the Last 6 Months of Life / 예방의학회지

OBJECTIVE: To investigate the relationship between medical expenses and the burden of families caring for the elderly in the last 6 months of life, and to evaluate the factors relating to the burden of family caregivers. METHODS: The families of 301 persons older than 65 years, who died between 1 July and 31 December 2001, and were registered in Resident-based- Health Insurance Programs in Seoul, were interviewed. The medical expenses and length of stay among the elderly were collected from Korean Health Insurance Corporations. RESULTS: 31 percents of the elderly had no medical expenses in the last 6 months of life. On average, the objective burden (4.92) was higher than the subjective burden (3.35). Families caring for male elderly had a higher burden. With increasing age at death, the objective burden was significantly increased. The burden on a family seemed to be influenced more by the family income than the property of the elderly. With increasing total health care costs, the objective burden on the family caregivers was significantly increased, but with increasing medical expenses, the subjective burden was significantly decreased. CONCLUSION: An association between healthcare utilization and burden on families was observed. The reason for the decreasing subjective burden when medical expenses were decreased was unclear. Further research will be needed.

Intake Increased the GallStone Formation in Guinea Pigs Due to High Oral Calcium Intake

Oral calcium supplementation has been recommended for prevention of osteoporosis in postmenopausal women. However experimental studies have suggested that oral calcium supplementation may increase the biliary calcium concentration and the incidence of gallstone formation in some animals. We designed an experiment to establish the effect of oral calcium supplementation in Guinea pigs. Nineteen Guinea pigs were divided into 2 groups. Group I (n=10) was fed with normal water, and group II (n=9) was fed with calcium-containing water(oscal 1000 mg/250 ml normal water). After 6 weeks, all animal were sacrifised, and the presence of gallstones was examined by inspection. Gallbladder bile and blood also were sampled. Gallstones were not found in group I, but in group II, gallstones were observed in five animals (56%). The level of calcium, bile acid, phospholipid, cholesterol, and bilirubin in the gallbladder bile was the same for both group I and group II. The levels of calcium and cholesterol in the serum was also the same for these two groups, but the level of bilirubin was remarkably lower group II than in group I. Oral calcium supplementation increased gallstone formation in guinea pigs, but there was no difference in the level of calcium in the bile composition. This present study could not confirm that oral calcium supplementation increased biliary calcium and then the incidence of gallstone formation in Guinea pigs. We think that the increase of biliary calcium after oral calcium supplementation is not the sole fator in gallstone formation and that other factors may be involved.

Intake Increased the GallStone Formation in Guinea Pigs Due to High Oral Calcium Intake

Oral calcium supplementation has been recommended for prevention of osteoporosis in postmenopausal women. However experimental studies have suggested that oral calcium supplementation may increase the biliary calcium concentration and the incidence of gallstone formation in some animals. We designed an experiment to establish the effect of oral calcium supplementation in Guinea pigs. Nineteen Guinea pigs were divided into 2 groups. Group I (n=10) was fed with normal water, and group II (n=9) was fed with calcium-containing water(oscal 1000 mg/250 ml normal water). After 6 weeks, all animal were sacrifised, and the presence of gallstones was examined by inspection. Gallbladder bile and blood also were sampled. Gallstones were not found in group I, but in group II, gallstones were observed in five animals (56%). The level of calcium, bile acid, phospholipid, cholesterol, and bilirubin in the gallbladder bile was the same for both group I and group II. The levels of calcium and cholesterol in the serum was also the same for these two groups, but the level of bilirubin was remarkably lower group II than in group I. Oral calcium supplementation increased gallstone formation in guinea pigs, but there was no difference in the level of calcium in the bile composition. This present study could not confirm that oral calcium supplementation increased biliary calcium and then the incidence of gallstone formation in Guinea pigs. We think that the increase of biliary calcium after oral calcium supplementation is not the sole fator in gallstone formation and that other factors may be involved.