Development Of Various Tissues Research Articles

Mechanisms of vitamin A metabolism and deficiency in the mammalian and fly visual system

Vitamin A deficiency can cause human pathologies that range from blindness to embryonic malformations. This diversity is due to the lack of two major vitamin A metabolites with very different functions: the chromophore 11-cis-retinal (vitamin A aldehyde) is a critical component of the visual pigment that mediates phototransduction, while the signaling molecule all-trans-retinoic acid regulates the development of various tissues and is required for the function of the immune system.Since animals cannot synthesize vitamin A de novo, they must obtain it either as preformed vitamin A from animal products or as carotenoid precursors from plant sources. Due to its essential role in the visual system, acute vitamin A deprivation impairs photoreceptor function and causes night blindness (poor vision under dim light conditions), while chronic deprivation results in retinal dystrophies and photoreceptor cell death. Chronic vitamin A deficiency is the leading cause of preventable childhood blindness according to the World Health Organization. Due to the requirement of vitamin A for retinoic acid signaling in development and in the immune system, vitamin A deficiency also causes increased mortality in children and pregnant women in developing countries.Drosophila melanogaster is an excellent model to study the effects of vitamin A deprivation on the eye because vitamin A is not essential for Drosophila development and chronic deficiency does not cause lethality. Moreover, genetic screens in Drosophila have identified evolutionarily conserved factors that mediate the production of vitamin A and its cellular uptake. Here, we review our current knowledge about the role of vitamin A in the visual system of mammals and Drosophila melanogaster. We compare the molecular mechanisms that mediate the uptake of dietary vitamin A precursors and the metabolism of vitamin A, as well as the consequences of vitamin A deficiency for the structure and function of the eye.

SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing

Heterozygous de novo missense variants of SRP54 were recently identified in patients with congenital neutropenia (CN) who display symptoms that overlap with Shwachman-Diamond syndrome (SDS). Here, we investigate srp54 knockout zebrafish as the first in vivo model of SRP54 deficiency. srp54−/− zebrafish experience embryonic lethality and display multisystemic developmental defects along with severe neutropenia. In contrast, srp54+/− zebrafish are viable, fertile, and show only mild neutropenia. Interestingly, injection of human SRP54 messenger RNAs (mRNAs) that carry mutations observed in patients (T115A, T117Δ, and G226E) aggravated neutropenia and induced pancreatic defects in srp54+/− fish, mimicking the corresponding human clinical phenotypes. These data suggest that the various phenotypes observed in patients may be a result of mutation-specific dominant-negative effects on the functionality of the residual wild-type SRP54 protein. Overexpression of mutated SRP54 also consistently induced neutropenia in wild-type fish and impaired the granulocytic maturation of human promyelocytic HL-60 cells and healthy cord blood–derived CD34+ hematopoietic stem and progenitor cells. Mechanistically, srp54-mutant fish and human cells show impaired unconventional splicing of the transcription factor X-box binding protein 1 (Xbp1). Moreover, xbp1 morphants recapitulate phenotypes observed in srp54 deficiency and, importantly, injection of spliced, but not unspliced, xbp1 mRNA rescues neutropenia in srp54+/− zebrafish. Together, these data indicate that SRP54 is critical for the development of various tissues, with neutrophils reacting most sensitively to the loss of SRP54. The heterogenic phenotypes observed in patients that range from mild CN to SDS-like disease may be the result of different dominant-negative effects of mutated SRP54 proteins on downstream XBP1 splicing, which represents a potential therapeutic target.

The Efficacy and Safety of RET-selective Inhibitors for Cancer Patients

The rearrangement during transfection (RET) encodes a receptor tyrosine kinase (RTK), which is involved in the development of various tissues and cells. The rearrangements and mutations of RET contribute to the development of a variety of human malignancies. Therefore, RET alterations are novel therapeutic targets. Inhibitors for RET and other kinases have been approved for the treatment of RET-altered tumors and have demonstrated their benefits for some types of cancer patients in clinics. However, due to off-target effects, these inhibitors have some adverse effects and dose-limiting toxicity. Therefore, long-term treatment with these inhibitors has potential limitations. Novel highly selective inhibitors (pralsetinib and selpercatinib) that target the RET pathway are well tolerated and have significant and long-lasting antitumor activity. They have been accelerated for approval by the FDA. This article will focus on the role of highly selective inhibitors targeting the RET and their efficacy and safety in therapy for RET-associated cancers.

Comprehensive Analysis and Expression Profiling of PIN, AUX/LAX, and ABCB Auxin Transporter Gene Families in Solanum tuberosum under Phytohormone Stimuli and Abiotic Stresses

Simple SummaryIn this study, we provide comprehensive information on auxin transporter gene families in potato, including basic parameters, chromosomal distribution, phylogeny, co-expression network analysis, gene structure, tissue-specific expression patterns, subcellular localization, transcription analysis under exogenous hormone stimuli and abiotic stresses, and cis-regulatory element prediction. The responsiveness of auxin transporter family genes to auxin and polar auxin transport inhibitors implied their possible roles in auxin homoeostasis and redistribution. Additionally, the differential expression levels of auxin transporter family genes in response to abscisic acid and abiotic stresses suggested their specific adaptive mechanisms on tolerance to various environmental stimuli. Promoter cis-regulatory element description analyses indicated that a number of cis-regulatory elements within the promoters of auxin transporter genes in potato were targeted by relevant transcription factors to respond to diverse stresses. We are confident that our results provide a foundation for a better understanding of auxin transporters in potato, as we have demonstrated the biological significance of this family of genes in hormone signaling and adaption to environmental stresses.Auxin is the only plant hormone that exhibits transport polarity mediated by three families: auxin resistant (AUX) 1/like AUX1 (LAX) influx carriers, pin-formed (PIN) efflux carriers, and ATP-binding cassette B (ABCB) influx/efflux carriers. Extensive studies about the biological functions of auxin transporter genes have been reported in model plants. Information regarding these genes in potato remains scarce. Here, we conducted a comprehensive analysis of auxin transporter gene families in potato to examine genomic distributions, phylogeny, co-expression analysis, gene structure and subcellular localization, and expression profiling using bioinformatics tools and qRT-PCR analysis. From these analyses, 5 StLAXs, 10 StPINs, and 22 StABCBs were identified in the potato genome and distributed in 10 of 18 gene modules correlating to the development of various tissues. Transient expression experiments indicated that three representative auxin transporters showed plasma membrane localizations. The responsiveness to auxin and auxin transport inhibitors implied their possible roles in mediating intercellular auxin homoeostasis and redistribution. The differential expression under abscisic acid and abiotic stresses indicated their specific adaptive mechanisms regulating tolerance to environmental stimuli. A large number of auxin-responsive and stress-related cis-elements within their promoters could account for their responsiveness to diverse stresses. Our study aimed to understand the biological significance of potato auxin transporters in hormone signaling and tolerance to environmental stresses.

Petiolar Anatomy as an Aid in Taxonomy of the Genus Ixora L. (Rubiaceae)

The present authors investigated petiolar anatomy of 12 species of the genus Ixora L. (Rubiaceae). The petioles (in T.S.) are horse shoe-shaped, planoconvex or circular in outline. They are usually winged and channeled adaxially. The extent of development of various tissues and their distribution, besides the cell inclusions, are observed. The vasculature is resolved into a conspicuous central arc, besides few other vascular bundles. The central arc is horse shoe-shaped, heart-shaped, circular, lunar or crescent shaped. The vascular arcs or bundles are capped abaxially by few sclerenchymatous layers, except few. The shapes of petiole, petiolar wings, features of epidermis, patterns of vascular supply and association of sclerenchyma with it, cell contents, etc. are thought systematically important. All these features are employed to prepare a key helping identification of the taxa investigated.

Bcl11b/Ctip2 in Skin, Tooth, and Craniofacial System.

Ctip2/Bcl11b is a zinc finger transcription factor with dual action (repression/activation) that couples epigenetic regulation to gene transcription during the development of various tissues. It is involved in a variety of physiological responses under healthy and pathological conditions. Its role and mechanisms of action are best characterized in the immune and nervous systems. Furthermore, its implication in the development and homeostasis of other various tissues has also been reported. In the present review, we describe its role in skin development, adipogenesis, tooth formation and cranial suture ossification. Experimental data from several studies demonstrate the involvement of Bcl11b in the control of the balance between cell proliferation and differentiation during organ formation and repair, and more specifically in the context of stem cell self-renewal and fate determination. The impact of mutations in the coding sequences of Bcl11b on the development of diseases such as craniosynostosis is also presented. Finally, we discuss genome-wide association studies that suggest a potential influence of single nucleotide polymorphisms found in the 3’ regulatory region of Bcl11b on the homeostasis of the cardiovascular system.

The role of Hippo-YAP signaling in squamous cell carcinomas.

The Hippo‐YAP pathway regulates organ size, tissue homeostasis, and tumorigenesis in mammals. In response to cell density, external mechanical pressure, and/or other stimuli, the Hippo core complex controls the translocation of YAP1/TAZ proteins to the nucleus and thereby regulates cell growth. Abnormal upregulation or nuclear localization of YAP1/TAZ occurs in many human malignancies and promotes their formation, progression, and metastasis. A key example is squamous cell carcinoma (SCC) genesis. Many risk factors and crucial signals associated with SCC development in various tissues accelerate YAP1/TAZ accumulation, and mice possessing constitutively activated YAP1/TAZ show immediate carcinoma in situ (CIS) formation in these tissues. Because CIS onset is so rapid in these mutants, we propose that many SCCs initiate and progress when YAP1 activity is sustained and exceeds a certain oncogenic threshold. In this review, we summarize the latest findings on the roles of YAP1/TAZ in several types of SCCs. We also discuss whether targeting aberrant YAP1/TAZ activation might be a promising strategy for SCC treatment.

Identification and effect of Zf-AD-containing C2H2 zinc finger genes on BmNPV replication in the silkworm (Bombyx mori)

Zf-AD-containing C2H2 zinc -finger genes (ZAD) are uniquely present and have lineage-specific expansion in arthropods. Arthropods are also the hosts of Baculoviruses. We studied the possible relationship between the lineage-specific expansion of ZAD genes and arthropod–Baculovirus co-evolution. We used the silkworm (Bombyx mori) as a model. We identified 73 ZAD genes (BmZAD) in the silkworm. Sequence-based similarity analysis showed that nine clusters involving 28 BmZADs may have undergone species-specific expansion in the silkworm. Expression pattern analysis showed that the BmZADs were divided into five groups. Group I comprised 10 genes with high expression in multiple tissues, suggesting that BmZADs may play roles in the development of various tissues. We identified six BmZADs that could be induced by the Nucleopolyhedrovirus (BmNPV). Among them, BmZAD69 expression is capable of responding to BmNPV infection, and the ZAD domain is indispensable for the function of BmZAD69 in BmNPV replication. We also detected a 3 bp deletion at 1.7 kb upstream of BmZAD69, which may make it more sensitive to BmNPV infection, and thus elevate the BmNPV resistance in Qiufeng_N, a strain with strong virus resistance. These data suggest that BmZADs may be involved in BmNPV infection and that ZAD genes may play a role in arthropod–Baculovirus co-evolution.

Paired box 9 regulates VSMC phenotypic transformation, proliferation, and migration via sonic hedgehog

AimsVascular smooth muscle cells (VSMCs) play a crucial role in the progression of atherosclerosis. Paired box 9 (Pax9) is a member of the Pax gene family which participates in the development of various tissues and organs. However, the effect of Pax9 on atherosclerosis and VSMCs and the underlying mechanisms remain unclear. Main methodsWestern blotting was performed to assess Pax9 expression in atherosclerosis and VSMCs. Pax9 siRNA and overexpression plasmid were constructed to explore the biological function. Cell proliferation assay, phalloidin staining, and Transwell assay, accompanied by the sonic hedgehog (Shh) signaling pathway antagonist, cyclopamine (5 μM) and agonist, SAG (100 nM), were used to evaluate the VSMC phenotype, proliferation, and migration, as well as explore the associated mechanisms. Key findingsWe first discovered Pax9 to be significantly increased in atherosclerotic mice and platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs. Pax9 knockdown inhibited the phenotypic transformation, proliferation, and migration of VSMCs, whereas the opposite effect was observed when Pax9 was overexpressed. Next, we established that Shh was activated in PDGF-BB-induced VSMCs. Moreover, Pax9 overexpression further activated Shh and exacerbated the phenotypic transformation, proliferation, and migration of PDGF-BB-induced VSMCs. These changes were effectively inhibited by treatment with the Shh signaling pathway antagonist. Consistently, Pax9 knockdown down-regulated Shh expression and inhibited the phenotypic transformation, proliferation, and migration of PDGF-BB-induced VSMCs. Treatment with the Shh signaling pathway agonist prevented these changes. SignificancePax9 regulated VSMC phenotypic transformation, proliferation, and migration via Shh, which may represent a novel target for the treatment of atherosclerosis.

Gene coexpression network analysis and tissue-specific profiling of gene expression in jute (Corchorus capsularis L.)

BackgroundJute (Corchorus spp.), belonging to the Malvaceae family, is an important natural fiber crop, second only to cotton, and a multipurpose economic crop. Corchorus capsularis L. is one of the only two commercially cultivated species of jute. Gene expression is spatiotemporal and is influenced by many factors. Therefore, to understand the molecular mechanisms of tissue development, it is necessary to study tissue-specific gene expression and regulation. We used weighted gene coexpression network analysis, to predict the functional roles of gene coexpression modules and individual genes, including those underlying the development of different tissue types. Although several transcriptome studies have been conducted on C. capsularis, there have not yet been any systematic and comprehensive transcriptome analyses for this species.ResultsThere was significant variation in gene expression between plant tissues. Comparative transcriptome analysis and weighted gene coexpression network analysis were performed for different C. capsularis tissues at different developmental stages. We identified numerous tissue-specific differentially expressed genes for each tissue, and 12 coexpression modules, comprising 126 to 4203 genes, associated with the development of various tissues. There was high consistency between the genes in modules related to tissues, and the candidate upregulated genes for each tissue. Further, a gene network including 21 genes directly regulated by transcription factor OMO55970.1 was discovered. Some of the genes, such as OMO55970.1, OMO51203.1, OMO50871.1, and OMO87663.1, directly involved in the development of stem bast tissue.ConclusionWe identified genes that were differentially expressed between tissues of the same developmental stage. Some genes were consistently up- or downregulated, depending on the developmental stage of each tissue. Further, we identified numerous coexpression modules and genes associated with the development of various tissues. These findings elucidate the molecular mechanisms underlying the development of each tissue, and will promote multipurpose molecular breeding in jute and other fiber crops.

Transcription levels and prognostic significance of the NFI family members in human cancers.

BackgroundThe nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX, which are important in the development of various tissues and organs in mammals. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers. However, the expression levels and distinctive prognostic values of the NFI family remain poorly explored in most cancers.Materials and MethodsIn the present study, the differences in mRNA expression of the NFI family in various cancers were investigated using the Oncomine and TCGA databases, and the mRNA expression, genetic alteration and DNA methylation of the NFI family members in various cancers were examined using cBioPortal for Cancer Genomics. In addition, the prognostic significance of the NFI family was assessed in multiple cancers using the Kaplan–Meier plotter (KM plotter) and SurvExpress databases.ResultsThe mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression. Although NFIX expression was not downregulated in kidney, colorectal and prostate cancers. Furthermore, NFIB expression was upregulated in gastric cancer. Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers. Decreased expression levels of NFIA, NFIB and NFIC were associated with poor overall survival (OS) in head and neck cancer. Low mRNA expression of NFIA and NFIB was significantly associated with OS and first progression in lung adenocarcinoma, but not in lung squamous cell carcinoma. In addition, potential correlations between NFI family members and survival outcomes were also observed in liver, esophageal, kidney and cervical cancer.ConclusionThe results from the present study indicated certain members of the NFI family could be promising therapeutic targets and novel prognostic biomarkers for human cancers.

GSK2 stabilizes OFP3 to suppress brassinosteroid responses in rice.

Brassinosteroids (BRs) are a class of phytohormones that modulate several important agronomic traits in rice (Oryza sativa). GSK2 is one of the critical suppressors of BR signalling and targets transcription factors such as OsBZR1 and DLT to regulate BR responses. Here, we identified OFP3 (OVATE FAMILY PROTEIN 3) as an interactor of both GSK2 and DLT by yeast-two-hybrid screening and demonstrated that OFP3 plays a distinctly negative role in BR responses. While knockout of OFP3 promoted rice seedling growth, overexpression of OFP3 led to strong BR insensitivity, which resulted in reduced plant height, leaf angle, and grain size. Interestingly, both BR biosynthetic and signalling genes had decreased expression in the overexpression plants. OFP3 overexpression also enhanced the phenotypes of BR-deficient mutants, but largely suppressed those of BR-enhanced plants. Moreover, treatment with either BR or bikinin, a GSK3-like kinase inhibitor, induced OFP3 depletion, whereas GSK2 or brassinazole, a BR synthesis inhibitor, promoted OFP3 accumulation. Furthermore, OFP3 exhibited transcription repressor activity and was able to interact with itself as well as additional BR-related components, including OFP1, OSH1, OSH15, OsBZR1, and GF14c. Importantly, GSK2 can phosphorylate OFP3 and enhance these interactions. We propose that OFP3, as a suppressor of both BR synthesis and signalling but stabilized by GSK2, incorporates into a transcription factor complex to facilitate BR signalling control, which is critical for the proper development of various tissues.

The role of histone deacetylase 4 during chondrocyte hypertrophy and endochondral bone development.

Chondrocyte hypertrophy represents a crucial turning point during endochondral bone development. This process is tightly regulated by various factors, constituting a regulatory network that maintains normal bone development. Histone deacetylase 4 (HDAC4) is the most well-characterized member of the HDAC class IIa family and participates in different signalling networks during development in various tissues by promoting chromatin condensation and transcriptional repression. Studies have reported that HDAC4-null mice display premature ossification of developing bones due to ectopic and early-onset chondrocyte hypertrophy. Overexpression of HDAC4 in proliferating chondrocytes inhibits hypertrophy and ossification of developing bones, which suggests that HDAC4, as a negative regulator, is involved in the network regulating chondrocyte hypertrophy. Overall, HDAC4 plays a key role during bone development and disease. Thus, understanding the role of HDAC4 during chondrocyte hypertrophy and endochondral bone formation and its features regarding the structure, function, and regulation of this process will not only provide new insight into the mechanisms by which HDAC4 is involved in chondrocyte hypertrophy and endochondral bone development, but will also create a platform for developing a therapeutic strategy for related diseases.Cite this article: Bone Joint Res. 2020;9(2):82–89.

A novel MEF2C mutation in lymphoid neoplasm diffuse large B-cell lymphoma promotes tumorigenesis by increasing c-JUN expression.

Diffuse large B-cell lymphoma (DLBCL) is the most aggressive non-Hodgkin lymphoma (NHL), accounting for about 31% of the newly diagnosed NHL worldwide. Although approximately 60% of patients who initially received a standard R-CHOP treatment likely have a 3-year event-free survival, many patients become refractory or relapsed due to the genetic heterogeneity of this malignancy. Hence, new treatment strategies are urgently needed. MEF2C, a member of the MEF2 transcription factor family gene, plays great important roles involved in the development of various tissues and the pathogenesis of lymphoma. However, the exact functions and molecular mechanisms of MEF2C in DLBCL are not fully investigated. By Sanger sequencing, we identified a novel point mutation of MEF2C at the p.N389 site in DLBCL patient, which was further validated by several DLBCL cell lines. Intriguingly, we found that the p.N389S mutation did not influence MEF2C expression, protein stability, and subcellular distribution, but enhanced its transcriptional activity. Furthermore, we demonstrated that MEF2C p.N389S mutation promotes DLBCL cell proliferation, cellular adhesion, and tumor formation in nude mice. On mechanism, our data revealed that MEF2C p.N389S mutation increases c-JUN expression, and c-JUN regulation mediated the oncogenic function of MEF2C p.N389S mutation on DLBCL cells. Our finding may provide a significant insight into the DLBCL and a compelling therapy target for this disease treatment.

Requirement of activating transcription factor 5 for murine fetal liver erythropoiesis.

Activating transcription factor 5 (ATF5) is necessary for the development of various tissues, particularly under stress. Dysfunctions of ATF5 have been shown to be involved in many diseases. The exact function of ATF5 is tissue-specific, and its role in erythropoiesis is still unknown. We here employed the loss of function strategy to investigate the role of ATF5 in murine erythropoiesis. We found that knockdown of Atf5 impaired the proliferation of fetal liver erythroid progenitors. Furthermore, erythroid differentiation was inhibited by ATF5 deficiency. Our study suggests that ATF5 may be a potential therapeutic target for treating blood diseases with ineffective erythropoiesis.

Notch signaling inhibition induces G0/G1 arrest in murine Leydig cells.

As a highly evolutionarily conserved signaling pathway, Notch widely participates in cell-fate decisions and the development of various tissues and organs. In male reproduction, research on the Notch signaling pathway has mainly concentrated on germ cells and Sertoli cells. Leydig cells are the primary producers of testosterone and play important roles in spermatogenesis and maintaining secondary sexual characteristics. In this study, we used TM3 cells, a murine adult Leydig cell line, to investigate the expression profiles of Notch receptors and ligands and observe the effect of Notch signaling on the proliferation of TM3 cells. We found that Notch 1-3 and the ligands Dll-1 and Dll-4 were expressed in TM3 cells, Notch 1-3 and the ligand Dll-1 were expressed in testis interstitial Leydig cells, and Notch signaling inhibition suppressed the proliferation of TM3 cells and induced G0/G1 arrest. Inhibition of Notch signaling increased the expression of p21Waf1/Cip1 and p27. Overall, our results suggest that Notch inhibition suppresses the proliferation of TM3 cells and P21Waf1/Cip1 , and p27 may contribute to this process.

Aliskiren, Fosinopril, and Their Outcome on Renin-Angiotensin-Aldosterone System (RAAS) in Rats with Thyroid Dysfunction.

Background and Objectives Thyroid hormones have an important role in the growth and development of various tissues including the kidney, which is the major site of renin release and the consequent angiotensin and aldosterone formation. Therefore any derangement in thyroid function can result in abnormal functioning in the renin-angiotensin-aldosterone system. The current study was undertaken to find the impact of using a direct renin inhibitor (Aliskiren) and an angiotensin-converting enzyme inhibitor (Fosinopril) on the components of the renin-angiotensin-aldosterone system (RAAS) in rats with thyroid dysfunctions. Method Forty-two male albino rats were divided into three subgroups. First group (6 rats) served as control. Second group (18 rats) served as hyperthyroid group (6 rats positive control, 6 rats given Aliskiren, and 6 rats given Fosinopril). Third group (18 rats) served as hypothyroid group (6 rats positive control, 6 rats given Aliskiren, and 6 rats given Fosinopril). Induction of hyperthyroidism and hypothyroidism was done through daily oral administration of L-Thyroxine and Propylthiouracil, respectively. On day 40 of the study, the rats were sacrificed and blood was collected for estimation of renin, angiotensin I, angiotensin II, aldosterone, TSH, T3, and T4. The collected blood samples were also used for estimation of levels blood urea, serum creatinine, liver enzymes, and serum electrolytes. Blood pressure and urine collection were done on days 1 and 40. The collected urine was used for estimation of urine flow, sodium excretion, and potassium excretion rates. Results In hypothyroid induced rats, serum renin level dropped as expected, while the use of Aliskiren and Fosinopril on these hypothyroid rats raised renin level due to the feedback mechanism. Both angiotensin I and II were significantly (P <0.05) lower than normal levels in the hypothyroid rats, unlike the level of aldosterone, which was higher than normal level. There was nonsignificant lowering in BP (systolic, diastolic, and mean BP) in the hypothyroid rats. Treatment of these rats with Aliskiren and Fosinopril did not lower the blood pressure more than normal when compared to the hypothyroid group. The hypothyroid rats also showed a decrease in level of serum creatinine. In hyperthyroid rats, there was a rise in levels of serum renin, angiotensin II, and aldosterone; nevertheless, the increase in angiotensin I level was significant. The use of Aliskiren and Fosinopril increased the level of renin nonsignificantly (decreased angiotensin I significantly). Hyperthyroid rats showed a significant increase in systolic, diastolic, and mean blood pressure. Both Aliskiren and Fosinopril increased urine flow, Na+ excretion, and K+ excretion rates. Aliskiren was better at reducing the high blood pressure. Conclusion Aliskiren and Fosinopril in hyperthyroid rats decreased serum angiotensin I, angiotensin II, and aldosterone. Blockade of renin and inhibition of angiotensin-converting enzyme both resulted in a rebound increase in level of renin in hypothyroid rats. Aliskiren is better at controlling blood pressure in hyperthyroid rats. Urine flow, sodium excretion, and potassium excretion rates were improved by the use of Aliskiren and Fosinopril in hyperthyroid rats.

Genome-wide analysis of the callose enzyme families of fertile and sterile flower buds of the Chinese cabbage (Brassicarapa L. ssp. pekinensis).

Callose is a β‐1,3‐glucan commonly found in higher plants that plays an important role in regulating plant pollen development. It is synthesized by glucan synthase‐like (GSL) and is degraded by the enzyme endo‐1,3‐β‐glucosidase. However, genome‐wide analyses of callose GSL and endo‐1,3‐β‐glucosidase enzymes in fertile and sterile flower buds of Chinese cabbage have not yet been reported. Here, we show that delayed callose degradation at the tetrad stage may be the main cause of microspore abortion in Chinese cabbage with nuclear sterility near‐isogenic line ‘10L03’. Fifteen callose GSLs and 77 endo‐1,3‐β‐glucosidase enzymes were identified in Chinese cabbage. Phylogenetic, gene structural and chromosomal analyses revealed that the expansion occurred due to three polyploidization events of these two gene families. Expression pattern analysis showed that the GSL and endo‐1,3‐β‐glucosidase enzymes are involved in the development of various tissues and that the genes functionally diverged during long‐term evolution. Relative gene expression analysis of Chinese cabbage flowers at different developmental stages showed that high expression of the synthetic enzyme BraA01g041620 and low expression of AtA6‐homologous genes (BraA04g008040, BraA07g009320, BraA01g030220 and BraA03g040850) and two other genes (BraA10g020080 and BraA05g038340) for degrading enzymes in the meiosis and tetrad stages may cause nuclear sterility in the near‐isogenic line ‘10L03’. Overall, our data provide an important foundation for comprehending the potential roles of the callose GSL and endo‐1,3‐β‐glucosidase enzymes in regulating pollen development in Chinese cabbage.

GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone.

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1‐1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC.

Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3.

BackgroundProtein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.MethodsPancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.ResultsPrmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.ConclusionPRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.