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PubMed2002

Novel mechanisms in accelerated vascular calcification in renal disease patients.

PURPOSE OF REVIEW: Vascular calcification occurs more often and earlier in patients with end-stage renal disease than in normal controls. It is a regulated biological process following many of the cellular and molecular programs in osteogenesis. This review summarizes some of the regulatory mechanisms that may explain its severity in renal patients. RECENT FINDINGS: A subpopulation of cells from arteries and cardiac valves produce a mineralizing matrix and undergo osteoblastic differentiation. Osteogenic differentiation regulators are found in calcified but not normal arteries. Phosphate levels have dramatic effects on vascular calcification in vitro, through a sodium phosphate transporter signaling molecular changes. Atherogenic oxidized lipids promote osteoblastic differentiation of vascular cells and inhibit bone mineralization. In uremic patients, the severity of dyslipidemia corresponds with the progression of vascular calcification. Oxidative stress and inflammatory mediators may underlie the effects of oxidized lipids. In dialysis patients, the degree of cardiac valvular calcification corresponds with levels of C-reactive protein. Genetic factors may also contribute. Polymorphisms of the inflammatory adhesion molecule, E-selectin, associate with coronary calcification in young women. Mice deficient in matrix GLA protein, which inhibits bone morphogenetic protein activity, develop complete ossification of the aorta, presumably as a result of unopposed osteogenic activity on vascular mesenchyme. Since matrix GLA protein function requires gamma-carboxylation of its glutamate residues by a vitamin K dependent carboxylase, warfarin treatment may affect vascular calcification by blocking vitamin K and hence matrix GLA protein activity. SUMMARY: These findings indicate that vascular calcification is regulated both positively and negatively by a wide variety of mechanisms affecting patients with renal disease.

Animals↗
PubMed2001

Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice.

The role of NF-kappaB-inducing kinase (NIK) in cytokine signaling remains controversial. To identify the physiologic functions of NIK, we disrupted the NIK locus by gene targeting. Although NIK-/- mice displayed abnormalities in both lymphoid tissue development and antibody responses, NIK-/- cells manifested normal NF-kappaB DNA binding activity when treated with a variety of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin-beta (LTbeta). However, NIK was selectively required for gene transcription induced through ligation of LTbeta receptor but not TNF receptors. These results reveal that NIK regulates the transcriptional activity of NF-kappaB in a receptor-restricted manner.

Animals↗
PubMed2006

Atp7a determines a hierarchy of copper metabolism essential for notochord development.

The critical developmental and genetic requirements of copper metabolism during embryogenesis are unknown. Utilizing a chemical genetic screen in zebrafish, we identified small molecules that perturb copper homeostasis. Our findings reveal a role for copper in notochord formation and demonstrate a hierarchy of copper metabolism within the embryo. To elucidate these observations, we interrogated a genetic screen for embryos phenocopied by copper deficiency, identifying calamity, a mutant defective in the zebrafish ortholog of the Menkes disease gene (atp7a). Copper metabolism in calamity is restored by human ATP7A, and transplantation experiments reveal that atp7a functions cell autonomously, findings with important therapeutic implications. The gene dosage of atp7a determines the sensitivity to copper deprivation, revealing that the observed developmental hierarchy of copper metabolism is informed by specific genetic factors. Our data provide insight into the developmental pathophysiology of copper metabolism and suggest that suboptimal copper metabolism may contribute to birth defects.

Adenosine Triphosphatases↗
PubMed2026

The novel adipokine Placin regulates glucose homeostasis via insulin secretion and IGF1 receptor signaling.

While genome-wide association studies have linked the human PLAC9 gene to body mass index, its physiological function remains largely unexplored. This study identifies PLAC9 as a novel adipokine that is enriched in the stromal vascular fraction of adipose tissue. Its circulating levels correlate with key metabolic dysregulation markers in humans and mice. We utilized gain- and loss-of-function approaches in diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mouse models to demonstrate that PLAC9 is a critical regulator of systemic metabolism. Notably, knockdown of endogenous PLAC9 exacerbated metabolic impairments, while its overexpression significantly mitigated DIO-associated metabolic dysregulation. Additionally, recombinant PLAC9 protein administration alleviated hyperglycemia in insulin-resistant and insulin-deficient models. Mechanistically, PLAC9 potentiated calcium-dependent insulin secretion in pancreatic beta cells, promoted glucose uptake in the liver and skeletal muscle, and upregulated hepatic Ghr and Igf1 levels to facilitate glucose homeostasis. Based on these hormone-like properties, we propose renaming the protein Placin. Collectively, these findings establish Placin as a promising therapeutic target, offering translational potential for the management of both type 2 and type 1 diabetes.

Animals↗
PubMed2004

Carbohydrate deficient glycoprotein syndrome type Ia.

Carbohydrate deficient glycoprotein syndromes (CDG) are inherited multisystem disorders characterized by the abnormal glycosylation of a number of serum glycoproteins. CDG-Ia results from deficiency of phosphomannomutase that catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate in the cytosol. We report a case of CDG-Ia in an 11-month-old girl with developmental delay, failure to thrive, inverted nipples and abnormal fat pads. The abnormal pattern of transferrin glycosylation and phosphomannomutase activity assay confirmed the diagnosis of CDG type Ia. Unfortunately, an efficient treatment is still not available for CDG type Ia patients. This is the first report of a Taiwanese patient with this syndrome.

Adipose Tissue↗
PubMed2006

Tandem mass neonatal screening in Taiwan--report from one center.

BACKGROUND/PURPOSE: Neonatal screening using tandem mass spectrometry (MS/MS) started in Taiwan in 2000. We evaluated the efficacy of this system by analyzing the frequency of diseases and the outcome of the patients identified. METHODS: Between August 2001 and July 2004, 199, 922 neonates were screened for 10 amino acids and acylcarnitines using MS/MS in a single center. RESULTS: In total, 29 cases of inborn errors of metabolism were detected. The overall prevalence was one per 6894 births. The most common inborn error found was 3-methylcrotonyl CoA carboxylase deficiency (10 cases, 34.5%), but none of the cases needed aggressive treatment. There were two cases of type I glutaric aciduria, two cases of maple syrup urine disease, and one case of type II citrullinemia, and early therapeutic intervention was effective for all of them. CONCLUSION: We found that MS/MS neonatal screening was valuable in the early diagnosis of severe and treatable inborn errors of metabolism such as organic acidemias and urea cycle disorders. It also detected less severe disorders that required only observation.

Amino Acids↗
PubMed1995

Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family.

The maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. Bcl-2 inaugurated a new category of oncogenes, regulators of cell death. The Bcl-2 gene was identified at the chromosomal breakpoint of t(14;18) bearing B cell lymphomas. Bcl-2 proved unique by blocking programmed cell death rather than promoting proliferation. In adults, Bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress Bcl-2 demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two unexpected pathologies resulting from cell death, polycystic kidney disease and hair hypopigmentation. The latter is a potential oxidant injury from the melanin biosynthetic pathway. A family of Bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with Bcl-2 and promotes cell death. The ratio of family members, such as Bcl-2/Bax, determines the survival or death of cells following an apoptotic stimulus.

Amino Acid Sequence↗
PubMed2006

Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.

The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4(PHAII) mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.

Animals↗
PubMed2005

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair.

DNA mismatch repair (MMR) is essential in the surveillance of accurate transmission of genetic information, and defects in this pathway lead to microsatellite instability and hereditary nonpolyposis colorectal cancer (HNPCC). Our previous study raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1. Here, we show that hMRE11 deficiency leads to significant increase in MSI for both mono- and dinucleotide sequences. Furthermore, RNA-interference-mediated hMRE11-knockdown in HeLa cells results in MMR deficiency. Analysis of seven HNPCC-associated hMLH1 missense mutations located within the hMRE11-interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near-complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction. These findings indicate that hMRE11 represents a functional component of the MMR pathway and the disruption of hMLH1-hMRE11 interaction could be an alternative molecular explanation for hMLH1 mutations in a subset of HNPCC tumours.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Regulation of pulmonary fibrosis by chemokine receptor CXCR3.

CXC chemokine receptor 3 (CXCR3) is the receptor for the IFN-gamma-inducible C-X-C chemokines MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11. CXCR3 is expressed on activated immune cells and proliferating endothelial cells. The role of CXCR3 in fibroproliferation has not been investigated. We examined the role of CXCR3 in pulmonary injury and repair in vivo. CXCR3-deficient mice demonstrated increased mortality with progressive interstitial fibrosis relative to WT mice. Increased fibrosis occurred without increased inflammatory cell recruitment. CXCR3 deficiency resulted in both a reduced early burst of IFN-gamma production and decreased expression of CXCL10 after lung injury. We identified a relative deficiency in lung NK cells in the unchallenged CXCR3-deficient lung and demonstrated production of IFN-gamma by WT lung NK cells in vivo following lung injury. The fibrotic phenotype in the CXCR3-deficient mice was significantly reversed following administration of exogenous IFN-gamma or restoration of endogenous IFN-gamma production by adoptive transfer of WT lymph node and spleen cells. Finally, pretreatment of WT mice with IFN-gamma-neutralizing Ab's enhanced fibrosis following lung injury. These data demonstrate a nonredundant role for CXCR3 in limiting tissue fibroproliferation and suggest that this effect may be mediated, in part, by the innate production of IFN-gamma following lung injury.

Adoptive Transfer↗
PubMed2005

The effect of transformation on the virulence of Streptococcus pneumoniae.

Although pneumococcus is one of the most frequently encountered opportunistic pathogen in the world, the mechanisms responsible for its infectiveness have not yet been fully understood. In this paper, we have attempted to characterize the effects of pneumococcal transformation on the pathogenesis of the organism. We constructed three transformation-deficient pneumococcal strains, which were designated as Nos. 1d, 2d, and 22d. The construction of these altered strains was achieved via the insertion of the inactivated gene, comE, to strains 1, 2 and 22. We then conducted a comparison between the virulence of the transformation-deficient strains and that of the wild-type strains, via an evaluation of the ability of each strain to adhere to endothelial cells, and also assessed psaA mRNA expression, and the survival of hosts after bacterial challenge. Compared to what was observed with the wild-type strains, our results indicated that the ability of all of the transformation-deficient strains to adhere to the ECV304 cells had been significantly reduced (p < 0.05), the expression of psaA mRNA was reduced significantly (p < 0.05) in strains 2d and 22d, and the median survival time of mice infected with strains 1d and 2d was increased significantly after intraperitoneal bacterial challenge (p < 0.05). The results of our study also clearly indicated that transformation exerts significant effects on the virulence characteristics of S. pneumoniae, although the degree to which this effect is noted appears to depend primarily on the genetic background of the bacteria.

Adhesins, Bacterial↗
PubMed2006

Bid-independent mitochondrial activation in tumor necrosis factor alpha-induced apoptosis and liver injury.

The death receptor apoptosis pathway is intimately connected with the mitochondrial apoptosis pathway. Bid is a BH3-only pro-death Bcl-2 family protein and is the major molecule linking the two pathways. Bid-mediated mitochondrial activation occurs early and is responsible for the prompt progress of tumor necrosis factor alpha (TNF-alpha)-induced apoptosis. However, in both cultured cells and animal models of TNF-alpha-induced injury, later-phase Bid-independent mitochondrial activation could be demonstrated. Consequently, bid-deficient mice are still susceptible to endotoxin-induced liver injury and mortality. Notably, embryonic hepatocyte apoptosis and lethality caused by TNF-alpha in the absence of p65relA cannot be rescued by the simultaneous deletion of bid. Further studies indicate that multiple mechanisms including reactive oxygen species, JNK, and permeability transition are critically involved in Bid-independent mitochondrial activation. Inhibition of these events suppresses TNF-alpha-induced mitochondrial activation and apoptosis in bid-deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondrial activation upon TNF-alpha stimulation. While the Bid-mediated mechanism is rapid and potent, the Bid-independent mechanism progresses gradually and involves multiple players. The critical involvement of Bid-independent mitochondrial activation in TNF-alpha-induced apoptosis demands the intervention of TNF-alpha-mediated tissue injury via multiple avenues.

Animals↗
PubMed1997

[Effects of different form calcium on growth and tissue calcium level in rats].

In order to solve the problem of calcium deficiency and to look for economic and efficient source of calcium, the effects of calcium carbonate, active calcium and calcium lactate on growth, development and tissue calcium level in rats were compared. Fifty-six 3-week old weaning rats were fed with calcium deficient diet (containing vitamin D 500 IU per kg diet) for 3 weeks, and then were divided into four groups randomly with 14 rats in each group, half male and half female. The diet of control group (A) was the basic diet, while the three experiment diets were supplemented with calcium carbonate (B), active calcium (C) and calcium lactate (D) (3000 mg calcium per kg diet), respectively. The experiment term was 12 weeks. The results showed that the body weight and length of calcium supplemented group were significantly higher than that of control group (P<0.05). Among the calcium supplemented groups, no significant differences were observed except the difference of body length between the group D and the group A in female. Calcium deficiency dramatically hindered the development with reduced dietary intake and decreased food consumption efficiency. The calcium levels in plasma, red blood cells and liver were significantly higher in the supplemented groups than that in the control group (P<0.05), however, there was no difference among the supplemented groups. No significant difference of calcium levels in muscle and heart was observed among all groups. Based on needs for reaching the RDA with additional 400 mg/d from present calcium status in Chinese population, the calcium carbonate is the most economic one and the ideal calcium source for supplementation.

Animals↗
PubMed2006

Significant increase of glycolytic flux in Torulopsis glabrata by inhibition of oxidative phosphorylation.

This study was aimed at increasing the glycolytic flux of the multivitamin-auxotrophic yeast Torulopsis glabrata by disturbing oxidative phosphorylation. We examined two different strategies to impede oxidative phosphorylation. The first strategy was disruption of the activity of the electron transfer chain (ETC), by either of two approaches. One was separately adding, at 10 mg L1, specific inhibitors of complex I (rotenone) or of the bc1 complex (antimycin A) to the culture broth of T. glabrata CCTCC M202019, which resulted in significantly decreased intracellular ATP levels (43% and 27.7%) and significantly increased rates of glucose consumption (qs) and pyruvate production (qp); another approach was breeding a respiratory-deficient mutant RD-16, in which cytochromes aa3 and b in the ETC were deleted after ethidium bromide mutagenesis, to reduce the ETC activity constitutively. The second strategy was inhibiting F0F1-ATP synthase with 0.05 mM oligomycin. Also, a neomycin-resistant mutant with 65% decreased F0F1-ATPase activity was studied. With the two strategies, the specific activity of phosphofructokinase (R2=0.9971), the average specific glucose consumption rate (R2=0.9967) and the average specific pyruvate production rate (R2=0.965) were closely correlated with the intracellular ATP level, all of them being increased at a lower intracellular ATP level.

Adenosine Triphosphate↗
PubMed2003

Relationship between lymph node sinuses with blood and lymphatic metastasis of gastric cancer.

AIM: To elucidate the relationship between lymph node sinuses with blood and lymphatic metastasis of gastric cancer. METHODS: Routine autopsy was carried out in the randomly selected 102 patients (among them 100 patients died of various diseases, and 2 patients died of non-diseased reasons), their superficial lymph nodes locating in bilateral necks (include supraclavicle), axilla, inguina, thorax, and abdomen were sampled. Haematoxylin-Eosin staining was performed on 10 % formalin-fixed and paraffin-embedded lymph node tissue sections (5 um). The histological patterns of the lymph sinuses containing blood were observed under light microscope. The expression of CD31, a marker for endothelial cell, was detected both in blood and non-blood containing lymph node sinuses with the method of immunohistochemistry. RESULTS: Among the 1 322 lymph nodes sampled from the autopsies of 100 diseased cases, lymph node sinuses containing blood were found in 809 lymph nodes sampled from 91 cases, but couldn't be seen in the lymph nodes sampled from the non-diseased cases. According to histology, we divided the blood containing lymph node sinuses into five categories: vascular-opening sinus, blood-deficient sinus, erythrophago-sinus, blood-abundant sinus, vascular-formative sinus. Immunohistochemical findings showed that the expression of CD31 was strongly positive in vascular-formative sinuses and some vascular-opening sinuses while it was faint in blood-deficient sinuses, erythrophago-sinuses and some vascular-opening sinuses. It was almost negative in blood-abundant sinus and non-blood containing sinus. CONCLUSION: In the state of disease, the phenomenon of blood present in the lymph sinus is not uncommon. Blood could possibly enter into the lymph sinuses through the lymphaticovenous communications between the veins and the sinuses in the node. Lymph circulation and the blood circulation could communicate with each other in the lymph node sinuses. The skipping and distal lymphatic metastasis of gastric cancer may have some connection with the blood containing lymph node sinuses.

Adolescent↗
PubMed2006

Redirection of the NADH oxidation pathway in Torulopsis glabrata leads to an enhanced pyruvate production.

This study aimed at increasing the pyruvate productivity of a multi-vitamin auxotrophic yeast Torulopsis glabrata by redirecting NADH oxidation from adenosine triphosphate (ATP)-production pathway (oxidative phosphorylation pathway) to non-ATP production pathway (fermentative pathway). Two respiratory-deficient mutants, RD-17 and RD-18, were screened and selected after ethidium bromide (EtBr) mutagenesis of the parent strain T. glabrata CCTCC M202019. Compared with the parent strain, cytochrome aa (3) and b in electron transfer chain (ETC) of RD-18 and cytochrome b in RD-17 were disrupted. As a consequence, the activities of key ETC enzymes of the mutant RD-18, including F(0)F(1)-ATP synthase, complex I, complex I + III, complex II + III, and complex IV, decreased by 22.2, 41.6, 53.1, 23.6, and 84.7%, respectively. With the deficiency of cytochromes in ETC, a large amount of excessive cytosolic NADH was accumulated, which hampered the further increase of the glycolytic flux. An exogenous electron acceptor, acetaldehyde, was added to the strain RD-18 culture to oxidize the excessive NADH. Compared with the parent strain, the concentration of pyruvate and the glucose consumption rate of strain RD-18 were increased by 26.5 and 17.6%, respectively, upon addition of 2.1 mM of acetaldehyde. The strategy for increasing the glycolytic flux in T. glabrata by redirecting the NADH oxidation pathway may provide an alternative approach to enhance the glycolytic flux in yeast.

Adenosine Triphosphate↗
PubMed2006

Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation.

Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca2+, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis.

Animals↗
PubMed2026

DREAMS illuminates spatial DNA and RNA modification landscapes.

DNA and RNA modifications regulate gene expression and RNA processing, but their spatial organization in complex tissues remains elusive. Here we developed DNA RNA Elements Areal Mass Spectrometry (DREAMS), a mass spectrometry imaging platform that spatially maps diverse nucleic acid modifications simultaneously. Applying DREAMS to TET-deficient mouse brains (Tet1&#x394;/&#x394; and triple Tet1/2/3&#x394;/&#x394;), we uncover TET1's unexpected role in modulating N1-methyladenosine (m1A), a pivotal RNA modification. While DREAMS reveals broad modification landscapes altered across TET knockouts, we identify TET1-mediated changes in m1A that correlate with transcriptome alterations. Our work establishes DREAMS as a transformative tool for spatial epigenomics/epitranscriptomics and suggests that TET enzymes could influence multiple DNA and RNA modifications with potential gatekeeping roles in nucleic acid regulation.

Animals↗