Effect of calcium phosphate compound (MZF-CaP) with and without fluoride in preventing bone loss in ovariectomized rats

Zinc (Zn) has been shown to inhibit osteoclast differentiation, promote osteoblast activity, and enhance the bone formation. Zinc-containing calcium phosphate (Zn-TCP) implanted in rabbit femoral defect was demonstrated to stimulate bone formation. Other studies demonstrated that calcium phosphate compounds (MZF-CaP) incorporating magnesium (Mg2+), zinc and fluoride (F-) when administered either by injection or orally were effective in preventing bone loss (osteoporosis) induced by estrogen deficiency (ovariectomy) in a rat model. The objective of the present study was to investigate the preventive effect of similar compound, with F (MZF-CaP-L, MZF-CaP-H) and without F (MZ-CaP-L), when injected in ovariectomized (OVX) rats. MZF-CaP-L and MZ-CaP-L were prepared by precipitation at 90oC and MZF-CaP-H was prepared by sintering MZF-CaP-L at 900oC. The release of the ions from acidic buffer was determined. Suspensions of Zn-TCP, MZF-CaP-H, MZF-CaP-L and MZ-CaP-L (617 μg in 0.2 ml of 1% sodium alginate saline solution) were injected intramuscularly under anesthesia into 5-week-old OVX rats on Zn-deficient diet. One week after surgery, bone mineral density (BMD) and bone mineral content (BMC) of the rat femurs were measured using X-ray CT. The injections and X-ray CT and Zn ion plasma measurements were repeated every week for 12 weeks. The rats were sacrificed and the femurs removed after 12 weeks. Bone mechanical strength was evaluated using the three-point bending test. MZ-CaP-L (without F), compared to the other compounds, showed the highest increase in the Zn2+ ion plasma concentration, and the highest BMD, BMC and mechanical strength

Effect of calcium phosphate compound (MZF-CaP) with and without fluoride in preventing bone loss in ovariectomized rats

Zinc (Zn) has been shown to inhibit osteoclast differentiation, promote osteoblast activity, and enhance the bone formation. Zinc-containing calcium phosphate (Zn-TCP) implanted in rabbit femoral defect was demonstrated to stimulate bone formation. Other studies demonstrated that calcium phosphate compounds (MZF-CaP) incorporating magnesium (Mg2+), zinc and fluoride (F-) when administered either by injection or orally were effective in preventing bone loss (osteoporosis) induced by estrogen deficiency (ovariectomy) in a rat model. The objective of the present study was to investigate the preventive effect of similar compound, with F (MZF-CaP-L, MZF-CaP-H) and without F (MZ-CaP-L), when injected in ovariectomized (OVX) rats. MZF-CaP-L and MZ-CaP-L were prepared by precipitation at 90oC and MZF-CaP-H was prepared by sintering MZF-CaP-L at 900oC. The release of the ions from acidic buffer was determined. Suspensions of Zn-TCP, MZF-CaP-H, MZF-CaP-L and MZ-CaP-L (617 μg in 0.2 ml of 1% sodium alginate saline solution) were injected intramuscularly under anesthesia into 5-week-old OVX rats on Zn-deficient diet. One week after surgery, bone mineral density (BMD) and bone mineral content (BMC) of the rat femurs were measured using X-ray CT. The injections and X-ray CT and Zn ion plasma measurements were repeated every week for 12 weeks. The rats were sacrificed and the femurs removed after 12 weeks. Bone mechanical strength was evaluated using the three-point bending test. MZ-CaP-L (without F), compared to the other compounds, showed the highest increase in the Zn2+ ion plasma concentration, and the highest BMD, BMC and mechanical strength

Functional Overload Enhances Satellite Cell Properties in Skeletal Muscle

Skeletal muscle represents a plentiful and accessible source of adult stem cells. Skeletal-muscle-derived stem cells, termed satellite cells, play essential roles in postnatal growth, maintenance, repair, and regeneration of skeletal muscle. Although it is well known that the number of satellite cells increases following physical exercise, functional alterations in satellite cells such as proliferative capacity and differentiation efficiency following exercise and their molecular mechanisms remain unclear. Here, we found that functional overload, which is widely used to model resistance exercise, causes skeletal muscle hypertrophy and converts satellite cells from quiescent state to activated state. Our analysis showed that functional overload induces the expression of MyoD in satellite cells and enhances the proliferative capacity and differentiation potential of these cells. The changes in satellite cell properties coincided with the inactivation of Notch signaling and the activation of Wnt signaling and likely involve modulation by transcription factors of the Sox family. These results indicate the effects of resistance exercise on the regulation of satellite cells and provide insight into the molecular mechanism of satellite cell activation following physical exercise

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Solution Structure of Molecular Associations Investigated Using NMR for Polysaccharides: Xanthan/Galactomannan Mixtures

Although the intermolecular nuclear Overhauser effect (NOE) signal was valuable to elucidate molecular association structure, it could not always be observed for associated molecules due to the short spin–spin relaxation time <i>T</i>₂ in NMR measurements, especially for high molar mass systems. While almost no study has been reported for high molar mass polymers (>1 × 10⁶), especially for polysaccharide–polysaccharide interactions, NOE signals were observed for the first time between two different types of polysaccharides, xanthan and galactomannan (locust bean gum), forming a synergistic gel, as a direct evidence of intermolecular binding of polysaccharides. The NOE peak was found between pyruvic acid in xanthan and anomeric proton of mannose of galactomannan. This NOE signal was observed only when mixing time >0.5 s, indicating indirect NOEs caused by spin diffusion. Therefore, this NOE could not be used to construct the molecular models. However, it is a direct evidence for the binding between two different types of polysaccharide to elucidate the synergistic gelation. This NOE signal was observed only for low molar mass galactomannans (1.4 × 10⁴). <i>T</i>₂ of pyruvate methyl drastically decreased at low temperatures in the presence of synergistic interaction, suggesting that pyruvate group at terminal end of side chain in xanthan plays an essential role in synergistic interaction

The regulation of stem cell aging by Wnt signaling

Aging is an inevitable physiological process that leads to the dysfunction of various tissues, and these changes may contribute to certain diseases, and ultimately death. Recent research has discovered biological pathways that promote aging. This review focuses on Wnt signaling, Wnt is a highly conserved secreted signaling molecule that plays an essential role in the development and function of various tissues, and is a notable factor that regulates aging. Although Wnt signaling influences aging in various tissues, its effects are particularly prominent in neuronal tissue and skeletal muscle. In neuronal tissue, neurogenesis is attenuated by the downregulation of Wnt signaling with aging. Skeletal muscle can also become weaker with aging, in a process known as sarcopenia. A notable cause of sarcopenia is the myogenic-to-fibrogenic transdifferentiation of satellite cells by excessive upregulation of Wnt signaling with aging, resulting in the impaired regenerative capacity of aged skeletal muscle. However, exercise is very useful for preventing the age-related alterations in neuronal tissue and skeletal muscle. Upregulation of Wnt signaling is implicated in the positive effects of exercise, resulting in the activation of neurogenesis in adult neuronal tissue and myogenesis in mature skeletal muscle. Although more investigations are required to thoroughly understand age-related changes and their biological mechanisms in a variety of tissues, this review proposes exercise as a useful therapy for the elderly, to prevent the negative effects of aging and maintain their quality of life

Diabetes and Stem Cell Function

Diabetes mellitus is one of the most common serious metabolic diseases that results in hyperglycemia due to defects of insulin secretion or insulin action or both. The present review focuses on the alterations to the diabetic neuronal tissues and skeletal muscle, including stem cells in both tissues, and the preventive effects of physical activity on diabetes. Diabetes is associated with various nervous disorders, such as cognitive deficits, depression, and Alzheimer’s disease, and that may be caused by neural stem cell dysfunction. Additionally, diabetes induces skeletal muscle atrophy, the impairment of energy metabolism, and muscle weakness. Similar to neural stem cells, the proliferation and differentiation are attenuated in skeletal muscle stem cells, termed satellite cells. However, physical activity is very useful for preventing the diabetic alteration to the neuronal tissues and skeletal muscle. Physical activity improves neurogenic capacity of neural stem cells and the proliferative and differentiative abilities of satellite cells. The present review proposes physical activity as a useful measure for the patients in diabetes to improve the physiological functions and to maintain their quality of life. It further discusses the use of stem cell-based approaches in the context of diabetes treatment

Effects of Excess Essential Amino Acids in Low Protein Diet on Abdominal Fat Deposition and Nitrogen Excretion of the Broiler Chicks

Two experiments were conducted to determine whether the excess essential amino acids in low protein diets affects the performance, nitrogen excretion and abdominal fat deposition of broiler chicks. Essential amino acids were classified into seven groups, (1)branched-chain amino acid (BCAA ; leucine+isoleucine+valine) (2)hydroxy amino acid (Thr ; threonine) (3)sulfur-containing amino acid (Met ; methionine) (4)aromatic amino acid (AAA ; phenylalanine+Tyrosine) (5)basic amino acid (BAA ; lysine+arginine) (6)glycine (Gly) (7)tryptophan (Trp) and were supplemented to low crude protein (19% CP) diet at the level of 150% (Experiment 1) and 200% (Experiment 2) of the Japanese Feeding Standard requirement. Seven amino acids supplemented diets, low CP and control (21% CP) diets were fed to 7-day-old chicks for 14 days. Body weight gain of the chicks fed the low CP and amino acids supplemented diets were did not differ among the treatments. Significant reduction in feed intake compared to the control diet were not seen in excess amino acids supplemented diets. Low CP and amino acids supplemented diets significantly increased abdominal fat weight than the control diet in experiment 1, however in experiment 2, compared to the control diet, abdominal fat weight were significantly higher in chicks fed the Gly and Trp supplemented diet among the groups. Nitrogen excreted were not reduced in chicks fed the low CP diets. These results show that the supplementation of excess amino acids to the low CP diet had little effect on abdominal fat deposition of broiler chicks in 1 to 3 wks of age