Sesamol improves bone mass in ovary intact growing and adult rats but accelerates bone deterioration in the ovariectomized rats.

Sesamol, an active component in sesame seeds, is known for its health benefits. However, its effect on bone metabolism remains unexplored. The present study aims to investigate the effect of sesamol on growing, adult and osteoporotic skeleton and its mechanism of action. Sesamol at various doses were administered orally to growing, ovariectomized, and ovary-intact rats. Alterations in bone parameters were examined using micro-CT and histological studies. Western blot and mRNA expression from long bones were performed. We further evaluated the effect of sesamol on osteoblast and osteoclast function and its mode of action in the cell culture system. These data showed that sesamol was able to promote peak bone mass in growing rats. However, sesamol had the opposite effect in ovariectomized rats, evident from gross deterioration of trabecular and cortical microarchitecture. Concurrently, it improved the bone mass in adult rats. In vitro results revealed that sesamol enhances the bone formation by stimulating osteoblast differentiation through MAPK, AKT, and BMP-2 signaling. In contrast, it enhances osteoclast differentiation and expression of osteoclast-specific genes in osteoclast differentiation medium. Interestingly, in presence of estrogen, the effect reversed and sesamol decreased osteoclast differentiation, in vitro. Sesamol improves bone microarchitecture in growing and ovary-intact rats, whereas it enhances the bone deterioration in ovariectomized rats. While sesamol promotes bone formation, its opposing effect on the skeleton can be attributed to its dual effect on osteoclastogenesis in presence and absence of estrogen. These preclinical findings suggest a special attention towards the detrimental effect of sesamol in postmenopausal women.

Maternal omega-3 LC-PUFA supplementation programs an improved bone mass in the offspring with a more pronounced effect in females than males at adulthood.

Early balanced nutrition is vital in achieving optimal skeletal mass and its maintenance. Although a lower omega-6 (n-6): omega-3 (n-3) long-chain polyunsaturated fatty acid (LC-PUFA) ratio is strongly linked with bone health, its maternal effect in the programming of the offspring's skeleton remains to be elucidated. Plugged C57BL/6 mice were fed either n-3 LC-PUFA Enriched Diet (LED) or a control diet (C) throughout their gestation and lactation. Offspring born to both the groups were weaned onto C till 6, 12, and 24 weeks of their age. Offspring's skeleton metabolism and serum fatty acid composition was studied. In humans, seventy-five mother-female newborns pairs from term gestation were tested for their maternal LC-PUFA status relationships to venous cord blood bone biomarkers. Offspring of maternal LED supplemented mice exhibited a superior bone phenotype over C, more prominent in females than males. A lower serum n-6/n-3 LC-PUFA in the LED group offspring was strongly associated with blood biomarkers of bone metabolism. Sexual dimorphism evidenced had a strong correlation between offspring's LC-PUFA levels and bone turnover markers in serum. A higher potential for osteoblastic differentiation in both LED offspring genders and reduced osteoclastogenesis in females was cell-autonomous effect. The human cross-sectional study also showed a positive correlation between maternal n-3 PUFA and cord blood markers of bone formation in female newborns at birth. Maternal dietary n-6/ n-3 fat quality determines offspring's bone growth and development. Our data suggest that the skeleton of female offspring is likely to be more sensitive to this early exposure.

Lutein ameliorates high-fat diet-induced obesity, fatty liver, and glucose intolerance in C57BL/6J mice.

Obesity is a multi-factorial metabolic syndrome that increases the risk of cardiovascular diseases, diabetes, and cancer. We recently demonstrated the antiadipogenic efficacy of lutein using a 3 T3-L1 cell culture model. This study aimed to examine the antiobesity efficacy of lutein on high-fat (60% kcal fat) diet-induced C57BL/6J obese mice model. Lutein (300 and 500 µM), Orlistat (30 mg/kg body weight - positive control), and its combination (orlistat, 15 mg/kg body weight+lutein, 300 µM) were administered in high-fat diet (HFD)-fed mice every other day for 24 weeks. The effect on serum and hepatic lipid parameters was estimated using biochemical assay kits. The adipose tissue expression of adipocyte differentiation markers at gene and protein levels was analyzed by RT-PCR and western blotting, respectively. The results showed that lutein administration and drug significantly reduced epididymal and abdominal adipose tissue weights. Further, lutein reduced the serum cholesterol and LDL-C concentration compared to the HFD group. The HFD-induced elevation in the hepatic triglycerides and cholesterol levels were significantly blocked by lutein and its combination with the drug. Similarly, lutein and its drug combination efficiently lowered the HFD-mediated elevated blood glucose levels. Lutein downregulated the expression of CEBP-α, PPAR-γ, and FAS in the epididymal adipose tissue. Thus, supplementation of lutein may control diet-induced obesity and associated complications in the human population.

Maternal high-cholesterol diet negatively programs offspring bone development and downregulates hedgehog signaling in osteoblasts.

Cholesterol is one of the essential intrauterine factors required for fetal growth and development. Maternal high cholesterol levels are known to be detrimental for offspring health. However, its long-term effect on offspring skeletal development remains to be elucidated. We performed our studies in two strains of mice (C57BL6/J and Swiss Albino) and human subjects (65 mother-female newborn dyads) to understand the regulation of offspring skeletal growth by maternal high cholesterol. We found that mice offspring from high-cholesterol-fed dams had low birth weight, smaller body length, and delayed skeletal ossification at the E18.5 embryonic stage. Moreover, we observed that the offspring did not recover from the reduced skeletal mass and exhibited a low bone mass phenotype throughout their life. We attributed this effect to reduced osteoblast cell activity with a concomitant increase in the osteoclast cell population. Our investigation of the molecular mechanism revealed that offspring from high-cholesterol-fed dams had a decrease in the expression of ligands and proteins involved in hedgehog signaling. Further, our cross-sectional study of human subjects showed a significant inverse correlation between maternal blood cholesterol levels and cord blood bone formation markers. Moreover, the bone formation markers were significantly lower in the female newborns of hypercholesterolemic mothers compared with mothers with normal cholesterolemic levels. Together, our results suggest that maternal high cholesterol levels deleteriously program offspring bone mass and bone quality and downregulate the hedgehog signaling pathway in their osteoblasts.

Ethanolic extract from the root and leaf of Sida cordifolia promotes osteoblast activity and prevents ovariectomy-induced bone loss in mice.

BACKGROUND: Sida cordifolia is traditionally found in the Indian system of medicine, well known for its medicinal and nutritional properties among local natives. PURPOSE: The present study aims to investigate the osteo-protective effect of root and leaf ethanolic extract of S. cordifolia (RE and LE) and its underlying mechanism. METHODS: Antioxidant activity of RE and LE was assessed. Total phenolic and flavonoid content were determined. HPLC profiling of RE and LE was performed to examine the polyphenol content. The effect of RE and LE on osteoblast cells proliferation, differentiation, mineralization, and expression of the protein associated with osteogenesis were evaluated using primary calvarial osteoblast culture. Skeletal effects of RE and LE of S. cordifolia were investigated in C57BL/6J ovariectomized mice. Micro CT was employed to evaluate the alteration in trabecular and cortical bone microarchitecture. Histology studies were performed on the isolated vertebra. qPCR analysis and western blotting was done to check the key bone markers. RESULTS: RE and LE showed a potent antioxidant activity, owing to a notable polyphenol content. Both RE and LE did not alter the cell viability but significantly increased the osteoblast cell proliferation, differentiation, and mineralization. Moreover, they enhanced the mRNA expression of osteogenic genes. Both RE and LE stimulated the activation of ERK, AKT, and CREB. Both RE and LE had no direct effect on osteoclastogenesis, but both increased Opg/Rankl ratio expression in osteoblast cells. Both RE and LE at 750 mg/kg/day significantly improved the trabecular and cortical microarchitecture of femur and tibia by increasing bone mineral density, bone volume fraction, trabecular number, and trabecular thickness, and decreasing trabecular separation and structural model index in ovariectomized mice. Furthermore, vertebral histology of lumbar vertebrae revealed that RE and LE significantly enhance the vertebral bone mass and exert osteo-protective effects by stimulating osteoblast function and inhibiting osteoclast function. CONCLUSION: In conclusion, both RE and LE stimulate osteoblast differentiation through activating ERK, AKT, and CREB signalling pathways and indirectly inhibits osteoclast differentiation. RE and LE also improve the trabecular and cortical microarchitecture of ovariectomized mice, making it a promising agent to prevent postmenopausal bone loss.

Efficacy of Citrus maxima fruit segment supplemented paranthas in STZ induced diabetic rats.

The study was conducted to investigate the efficacy of Citrus maxima (Pomelo) fruit segments fortified paranthas compared to pomelo juice and naringin in streptozotocin-induced diabetic rats. The animals were divided into nine groups, Groups 1 to 3: negative control; Group 4: diabetic control; Groups 5 through 8: treatments with pomelo juice, naringin, plain paranthas, and pomelo supplemented paranthas; and Group 9 was positive control metformin. The groups were monitored for weight, oral glucose tolerance, insulin tolerance, bioavailability, biochemical parameters, and histopathological studies. Based on the result the group treated with paranthas fortified with pomelo fruit segment (Group 8) showed 19% of overall weight gain, approximately 50% reduction in plasma glucose level and improved serum protein (5.70 g/dl) and serum insulin (8.54 ng/ml) level as compared against diabetic control. The treatments had effectively lowered the level of liver enzyme and lipids (except HDL) in the serum along with the improved renal function. The group treated with pomelo juice and pomelo supplemented paranthas exhibited marked tolerance to the glucose and insulin similar to the positive control. Therefore, the antidiabetic activity was found to be more pronounced in the order of pomelo juice > fortified paranthas > naringin. Since pomelo juice is bitter and astringent in nature, the fruit can be better utilized in the form of fortified paranthas, which exerts antidiabetic effect similar to the positive control metformin. Hence, paranthas supplemented with pomelo fruit segments (bioactives-rich) aids in the reducing the risk of diabetes and can be recommended to gain nutritional benefits for normal and diabetic populations.

Maternal high protein-diet programs impairment of offspring's bone mass through miR-24-1-5p mediated targeting of SMAD5 in osteoblasts.

Maternal nutrition is crucial for the offspring's skeleton development and the onset of osteoporosis later in life. While maternal low protein diet has been shown to regulate bone mass negatively, the effect of a high protein diet (HP) remains unexplored. Here, we found that C57BL/6 mice fed with HP delivered offspring with decreased skeletal mineralization at birth and reduced bone mass throughout their life due to a decline in their osteoblast maturation. A small RNA sequencing study revealed that miR-24-1-5p was highly upregulated in HP group osteoblasts. Target prediction and validation studies identified SMAD-5 as a direct target of miR-24-1-5p. Furthermore, mimic and inhibitor studies showed a negative correlation between miR-24-1-5p expression and osteoblast function. Moreover, ex vivo inhibition of miR-24-1-5p reversed the reduced maturation and SMAD-5 expression in the HP group osteoblasts. Together, we show that maternal HP diminishes the bone mass of the offspring through miR-24-1-5p.

Sesaminol induces brown and beige adipocyte formation through suppression of myogenic program.

Adipocytes are key players in maintaining energy homeostasis and are classified into two different categories: white and brown adipocytes. While white adipocytes store energy as triacylglycerols in lipid droplets, brown adipocytes combust excess chemical energy and release in the form of heat through uncoupled respiration. This characteristic phenomenon of brown fat attracts researchers and pharmacological industries to view brown fat as one of the potential therapeutic targets for obesity and associated metabolic disease. In the current study, we investigated the effect of a small molecule, sesaminol (SML) on brown fat activity and found that SML induces the thermogenic program in primary white adipocytes as well as chow diet fed mice. In particular, SML treatment to mice elevated mitochondrial complex proteins and the rate of oxygen consumption in brown and white fat. Administration of SML to high fat diet (HFD) challenged mice decreased weight gain, adiposity and cholesterol levels along with an increase of brown fat gene program in brown and white fat. Mechanistically, SML repressed the myogenic gene program in C2C12 myoblasts and increased all mitochondrial marker genes as appeared in brown adipose cells. Together, our results demonstrate that SML stimulates brown adipose function and protects mice against diet-induced weight gain.

The antioxidant effect of mulberry and jamun fruit wines by ameliorating oxidative stress in streptozotocin-induced diabetic Wistar rats.

Polyphenols act by scavenging reactive oxygen species during oxidative stress and hence are useful in the treatment of metabolic disorders including diabetes. This study describes the effect of polyphenol rich mulberry and jamun wines fed to streptozotocin-induced diabetic rats. To male adult Wistar rats, divided into groups (n = 10 per group) intraperitoneal injection was administered with streptozotocin at 38 mg per kg body weight for inducing diabetes. After confirmation of diabetes, rats divided into groups were fed each day with 5.7 milliliter per kg body weight of mulberry, jamun, white and red grape wines for 6 weeks. One group of animals received resveratrol at 20 mg per kg body weight. After six weeks of treatment, blood glucose, urinary profile, lipid profile, plasma, liver, kidney, brain and eye antioxidant enzyme activities, lipid peroxidation, non-esterified fatty acids (NEFA) and hepatic glutathione (GSH) content were determined. Though wine and resveratrol feeding did not improve the glycemic status of diabetic rats, increases in antioxidant enzymes and GSH content accompanied by reduced NEFA and lipid peroxidation were observed. The kidneys and brains of resveratrol fed rats showed significant reduction in malondialdehyde equivalents, exhibited an improved antioxidant status of tissues and an increased glutathione content. The findings suggested that the wines can ameliorate the consequences of diabetes due to their antioxidants.