Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases ...(HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC‐mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c‐Myc, and nuclear factor‐κB, as well as the extracellular signal‐regulated kinase1/2, phosphatidylinositol 3‐kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.
Pseudorabies (PR), also called Aujeszky’s disease (AD), is a highly infectious viral disease which is caused by pseudorabies virus (PRV). It has been nearly 200 years since the first PR case ...occurred. Currently, the virus can infect human beings and various mammals, including pigs, sheep, dogs, rabbits, rodents, cattle and cats, and among them, pigs are the only natural host of PRV infection. PRV is characterized by reproductive failure in pregnant sows, nervous disorders in newborn piglets, and respiratory distress in growing pigs, resulting in serious economic losses to the pig industry worldwide. Due to the extensive application of the attenuated vaccine containing the Bartha-K61 strain, PR was well controlled. With the variation of PRV strain, PR re-emerged and rapidly spread in some countries, especially China. Although researchers have been committed to the design of diagnostic methods and the development of vaccines in recent years, PR is still an important infectious disease and is widely prevalent in the global pig industry. In this review, we introduce the structural composition and life cycle of PRV virions and then discuss the latest findings on PRV pathogenesis, following the molecular characteristic of PRV and the summary of existing diagnosis methods. Subsequently, we also focus on the latest clinical progress in the prevention and control of PRV infection via the development of vaccines, traditional herbal medicines and novel small RNAs. Lastly, we provide an outlook on PRV eradication.
Porcine circovirus 4 (PCV4), a new circovirus with a distinct relationship to other circoviruses, was identified in 2019 in several pigs with severe clinical disease in Hunan Province, China. To ...investigate the epidemic profile and genetic diversity of the virus, 63 clinical samples were collected from 24 different pig farms in 14 cities in Henan and Shanxi Provinces, China, between February 2018 and December 2019, and the partial Cap gene of PCV4 was amplified by PCR. Among the 63 samples, 16 (25.40%) were positive for PCV4, and 50% (12/24) of the pig farms were positive for PCV4. PCV4 was detected in samples from pigs with different clinical presentations. One PCV4 strain (Henan‐LY1‐2019) was sequenced in this study, and shared 98.4% genomic nucleotide identity with PCV4 strain HNU‐AHG1‐2019 (accession no. MK986820) detected on a pig farm in Hunan Province in 2019. A phylogenetic analysis based on the genomes of Henan‐LY1‐2019 and 31 reference strains showed that the Henan‐LY1‐2019 strain together with PCV4 strain HNU‐AHG1‐2019 was grouped in a relatively independent sub‐branch, and separated from other viruses in the genus Circovirus. The results of this study extend our understanding of the molecular epidemiology of PCV4.
In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective ...role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.
•Irisin is highly expressed in mouse hearts.•FNDC5 deletion aggravated and FNDC5 overexpression ameliorated the left ventricle hypertrophy, remodeling, injury and dysfunction induced by pressure overload.•Irisin supplementation attenuated hypertrophy in Ang II– or phenylephrine-induced cardiomyocytes.•Irisin alleviated cardiomyocyte hypertrophy in vivo and in vitro by inducing beneficial autophagy and autophagy influx via AMPK-ULK1 signaling but independent of mTOR.
Abstract
We performed a radio recombination line (RRL) survey to construct a high-mass star-forming region (HMSFR) sample in the Milky Way based on the all-sky Wide-Field Infrared Survey Explorer ...point-source catalog. The survey was observed with the Shanghai 65 m Tianma radio telescope covering 10 hydrogen RRL transitions ranging from H98
α
to H113
α
(corresponding to the rest frequencies of 4.5–6.9 GHz) simultaneously. Out of 3348 selected targets, we identified an HMSFR sample consisting of 517 sources traced by RRLs; a large fraction of this sample (486) is located near the Galactic Plane (∣
b
∣ < 2°). In addition to the hydrogen RRLs, we also detected helium and carbon RRLs toward 49 and 23 sources, respectively. We crossmatch the RRL detections with the 6.7 methanol maser sources built up in previous works for the same target sample. As a result, 103 HMSFR sources were found to harbor both emissions. In this paper, we present the HMSFR catalog accompanied by the measured RRL line properties and a correlation with our methanol maser sample, which is believed to trace massive stars at earlier stages. The construction of an HMSFR sample consisting of sources in various evolutionary stages indicated by different tracers is fundamental for future studies of high-mass star formation in such regions.
Porcine circovirus 4 (PCV4), a novel circovirus, was first discovered in April 2019 in Hunan Province of China. At present, PCV4 infection has been detected in China and South Korea. However, until ...2019, there was little information about its circulating status and genetic characteristics. To further clarify the origin and prevalence of PCV4, a total of 152 clinical samples collected from 49 different swine farms of 15 cities in Henan Province of China from 2011 to 2021 were tested for the presence of PCV4 by qPCR, and the complete genome of PCV4 strains was amplified from the positive samples and sequenced. Among these samples, 45.39% (69/152) were positive for PCV4 and 86.67% (13/15) of the cities and 67.35% (33/49) of the swine farms were positive for PCV4. The genome sequences of 15 PCV4 strains were obtained, of which two PCV4 strains (HN‐ZMD‐201212 and HN‐XX‐201212) were achieved from archival samples in 2012, indicating that PCV4 has been circulating for at least 10 years in Henan Province of China. The phylogenetic analysis showed that 15 PCV4 strains in our study together with PCV4 strain HNU‐AHG1‐2019 were clustered into an identical but separate evolutionary branch, with genomic identity ranging from 98.2% to 98.8%. Our research further provides significant epidemiological information on PCV4 in China, which will help understand the origin and genetic characteristics of this new virus.
Hepatitis B virus (HBV) X protein, HBx, interacts with anti-apoptotic Bcl-2 and Bcl-xL proteins through its BH3-like motif to promote HBV replication and cytotoxicity. Here we report the crystal ...structure of HBx BH3-like motif in complex with Bcl-xL where the BH3-like motif adopts a short α-helix to snuggle into a hydrophobic pocket in Bcl-xL via its noncanonical Trp120 residue and conserved Leu123 residue. This binding pocket is ~2 Å away from the canonical BH3-only binding pocket in structures of Bcl-xL with proapoptotic BH3-only proteins. Mutations altering Trp120 and Leu123 in HBx impair its binding to Bcl-xL in vitro and HBV replication in vivo, confirming the importance of this motif to HBV. A HBx BH3-like peptide, HBx-aa113-135, restores HBV replication from a HBx-null HBV replicon, while a shorter peptide, HBx-aa118-127, inhibits HBV replication. These results provide crucial structural and functional insights into drug designs for inhibiting HBV replication and treating HBV patients.
The peeled stems of Syringa pinnatifolia(SP) is a representative Mongolian folk medicine with the effects of anti-depression, heat clearance, pain relief, and respiration improvement. It has been ...clinically used for the treatment of coronary heart disease, insomnia, asthma, and other cardiopulmonary diseases. As part of the systematic study on pharmacological substances of SP, 11 new sesquiterpenoids were isolated from the terpene-containing fractions of the ethanol extract of SP by liquid chromatography-mass spectrometry(LC-MS) and proton nuclear magnetic resonance(~1H-NMR) guided isolation methods. The planar structures of the sesquiterpenoids were identified by MS, 1D NMR, and 2D NMR data analysis, and were named pinnatanoids C and D(1 and 2), and alashanoids T-ZI(3-11), respectively. The structure types of the sesquiterpenoids included pinnatane, humulane, seco-humulane, guaiane, carryophyllane, seco-erimolphane, isodaucane, and other types. However, limited to the low content of compounds, the existence
The 2b proteins encoded by cucumovirus act as post‐transcriptional gene silencing suppressors to counter host defence during infection. Here we report the crystal structure of Tomato aspermy virus 2b ...(TAV2b) protein bound to a 19 bp small interfering RNA (siRNA) duplex. TAV2b adopts an all α‐helix structure and forms a homodimer to measure siRNA duplex in a length‐preference mode. TAV2b has a pair of hook‐like structures to recognize simultaneously two α‐helical turns of A‐form RNA duplex by fitting its α‐helix backbone into two adjacent major grooves of siRNA duplex. The conserved π‐stackings between tryptophan and the 5′‐terminal base of siRNA duplex from both ends enhance the recognition. TAV2b further oligomerizes to form a dimer of dimers through the conserved leucine‐zipper‐like motif at its amino‐terminal α‐helix. Biochemical experiments suggest that TAV2b might interfere with the post‐transcriptional gene silencing pathway by directly binding to siRNA duplex.
Abstract
We report a survey of excited-state hydroxyl (ex-OH) masers at the 4.7 and 6.0 GHz transitions toward a sample consisting of 3348 massive star-forming region candidates selected from the ...all-sky Wide-field Infrared Survey Explorer point-source catalog. The survey was conducted with the Shanghai Tianma Radio Telescope. In total, 6, 9, and 30 sources were detected with the ex-OH masers at the 4766, 6031, and 6035 MHz transitions, respectively. Among them, one 4766 MHz, one 6031 MHz, and five 6035 MHz ex-OH maser sources are newly identified. A series of statistical analyses derived that the ex-OH masers were detected efficiently toward the subsamples associated with both the 6.7 GHz CH
3
OH maser and radio recombination lines (RRLs), whereas compared to the CH
3
OH masers, the ex-OH masers are more likely to be produced toward the sources with stronger 22
μ
m band emission. A significant luminosity correlation is found between the ex-OH masers and RRLs. In addition, we found that the magnetic field strength of most sources with the 6.7 GHz CH
3
OH maser was stronger relative to that of sources without the CH
3
OH maser. Combined with these, it demonstrates that the ex-OH maser is associated with more evolved star-forming regions, likely associated with thicker dust envelopes. Meanwhile, the ex-OH masers might be a potential tracer for measuring the Galactic magnetic field information on the large-scale views using their Zeeman pairs.
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