Association of histone modification with the development of schizophrenia.

Schizophrenia, influenced by genetic and environmental factors, may involve epigenetic alterations, notably histone modifications, in its pathogenesis. This review summarizes various histone modifications including acetylation, methylation, phosphorylation, ubiquitination, serotonylation, lactylation, palmitoylation, and dopaminylation, and their implications in schizophrenia. Current research predominantly focuses on histone acetylation and methylation, though other modifications also play significant roles. These modifications are crucial in regulating transcription through chromatin remodeling, which is vital for understanding schizophrenia's development. For instance, histone acetylation enhances transcriptional efficiency by loosening chromatin, while increased histone methyltransferase activity on H3K9 and altered histone phosphorylation, which reduces DNA affinity and destabilizes chromatin structure, are significant markers of schizophrenia.

A Radical Approach for Asymmetric α-C-H Addition of N-Sulfonyl Benzylamines to Aldehydes.

Efficient synthesis of enantioenriched amines is of great importance due to their significant synthetic and biological applications. Photoredox-mediated asymmetric α-amino C(sp3)-H functionalization offers an atom-economical and sustainable approach to access chiral amines. However, the development of analogous reactions is in its early stages, generally affording chiral amines with a single stereocenter. Herein, we present a novel synergistic triple-catalysis approach for the asymmetric α-C-H addition of readily available N-sulfonyl amines to aldehydes under mild conditions. This method allows for the efficient synthesis of a diverse array of valuable ß-amino alcohols bearing vicinal stereocenters. Unlike previous reports, our protocol employs a radical approach using earth-abundant Cr catalysis. Quinuclidine plays a dual role by facilitating highly selective hydrogen-atom transfer to generate α-amino radicals and promoting the dissociation of the Cr-O bond, which is crucial for the overall catalytic cycle as evidenced by control, NMR, and DFT experiments. Preliminary mechanistic studies, including radical trapping, nonlinear effect, Stern-Volmer plot, kinetic isotope effect, and Hammett plot, offer valuable insights into the reaction pathway.

Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis.

The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.

Catalytic Enantioconvergent Allenylation of Aldehydes with Propargyl Halides.

α-Allenol is a versatile synthon in organic synthesis. The catalytic asymmetric synthesis of α-allenols from readily available starting materials remains a prominent challenge, especially when simultaneous control over axial and central chirality is required. Herein, we describe the Cr-catalyzed enantioconvergent allenylation of aldehydes with racemic propargyl halides to rapidly access a wide range of chiral α-allenols with adjacent axial and central chiralities. This method features excellent regio-, diastereo- and enantioselectivity control with broad substrate scope, and provides facile access to all four stereoisomers when allied with a Mitsunobu reaction. Preliminary mechanistic studies support radical-based reaction pathways. The synthetic utility is demonstrated by the application in late-stage functionalization and the formal total synthesis of (+)-varitriol.

Chiral Electron-Rich PNP Ligand with a Phospholane Motif: Structural Features and Application in Asymmetric Hydrogenation.

Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand, the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging diaryl ketones: up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining step.

Intramolecular asymmetric reductive amination: synthesis of enantioenriched dibenz[c,e]azepines.

An Ir-catalyzed intramolecular asymmetric reductive amination (ARA) of bridged biaryl derivatives has been described. Using this unprecedented approach, synthetically useful dibenz[c,e]azepines containing both central and axial chiralities are obtained with excellent enantiocontrol (up to 97% ee). This methodology represents a rare example of enantioselective chemocatalytic synthesis of chiral dibenz[c,e]azepines featuring a broad substrate scope, and their synthetic utilities are exhibited by derivatizing the products into a chiral amino acid derivative and chiral phosphoramidite ligands, which display excellent enantiocontrol in Rh-catalyzed asymmetric hydrogenation of α-dehydroamino acid derivatives. Remarkably, our method is also applicable to enantioselectively synthesize an allocolchicine analogue.

Effects of Beclin 1 overexpression on aggressive phenotypes of colon cancer cells.

Beclin 1 is involved in autophagy, differentiation, apoptosis and cancer progression, and functions as a haploinsufficient tumor suppressor gene. The aim of the present study was to elucidate the function of Beclin 1 in colon cancer. A Beclin 1-expressing plasmid was transfected into HCT-15 and HCT-116 cells, and the phenotypes and associated molecules were determined. Beclin 1 transfectants were subcutaneously injected into nude mice to determine tumor growth, and proliferation and apoptosis levels using Ki-67 immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively. Beclin 1 overexpression inhibited viability as determined using a Cell Counting Kit-8 assay, inhibited migration and invasion as determined using a wound healing assay or Transwell assay, and lamellipodia formation by filamentous actin staining, induced autophagy as determined using electron microscopy, and light chain 3B (LC-3B) expression, and apoptosis as determined using Annexin V staining in the two cell lines (P<0.05). Beclin 1 induced G2 arrest of HCT-15 transfectants as determined using propidium iodide staining (P<0.05), whereas HCT-116 transfectants were arrested in G1 phase (P<0.05). The two transfectants exhibited increased expression of c-Myc, cyclin D1, ß-catenin, insulin-response element 1 and 78 kDa glucose-regulated protein compared with the control and mock cells as determined using the reverse transcription-quantitative polymerase chain reaction (P<0.05). Beclin 1 overexpression upregulated LC-3B and cyclin-dependent kinase 4 expression, but downregulated cyclin E expression of the cancer cell lines as determined using western blot analysis (P<0.05). Beclin 1 expression in vivo significantly suppressed the proliferation of colon cancer cells in xenograft models via inducing apoptosis by TUNEL, and inhibiting proliferation by Ki-67 expression (P<0.05). Beclin 1 overexpression may reverse aggressive phenotypes and suppress colon cancer tumor growth, and be employed as a target molecule for gene therapy of patients with colon cancer.

[Homer protein expression after focal brain contusion in rats].

OBJECTIVE: To investigate Homer protein expression after focal brain contusion and explore the relationship between expression and injury time. METHODS: Focal brain contusion in rats was established and Homer protein expression in brain at different injury intervals after contusion was detected by immunohistochemistry and Western blotting. RESULTS: A small amount of Homer positive expression cells were detected in control group, sham operated group and experimental group (0.5 h after contusion). The amount of Homer positive expression cells increased after 3 h and reached peak 12 h after contusion. The amount of positive cells continued to decrease 1 d after contusion and to the base level 7 d after contusion. Homer protein expression based on immunohistochemistry and Western blotting had statistical difference among adjacent groups. CONCLUSION: Expression of Homer protein near the focal contusion area shows time dependence after brain contusion in rats.

[Expression of matrix metalloproteinase-3 after brain contusion in rats].

OBJECTIVE: To investigate the expression of matrix metalloproteinase-3 after brain contusion and its applicability for estimating the age of brain contusion. METHODS: Rats had been divided into three groups: control group, sham operation group and brain contusion group. The expression of matrix metalloproteinase-3 at different time was detected by immunohistochemistry and Western blot. RESULTS: By the immunohistochemistry, no staining was observed in control and sham operation groups. The positive staining of MMP-3 appeared 6 hours after contusion, increased gradually in 24 hours and peaked 5 days after contusion, then started to decrease, 14 days after contusion still could be observed. By the Western blot analysis, no expression of MMP-3 was detected in control and sham groups. The positive staining of MMP-3 appeared 6 hours after contusion, increased gradually and maximized 5 days after contusion, then started to decrease, 14 days after contusion still could be found. CONCLUSION: Time-order expression of MMP-3 could be used for estimating the age of brain contusion in forensic pathology.

Study on changes of MMP-3 expression after brain contusion in rats.

To investigate the mechanism and to explore the applicability of MMP-3 (matrix metalloproteinase-3) to determine the age of brain contusion, expression of MMP-3 was studied by immunochemistry and Western blot techniques on model of brain contusion in rats. Brain contusion was performed by falling weight in adult male Sprague-Dawley rats after anesthetized with diethyl ether, then maintained with 2% pentobarbital sodium (30 mg/kg). Samples were collected at 6 and 12 h, 1, 3, 5, 7, 10 and 14 days after the contusion. Histopathological examination and immunostaining of MMP-3 were conducted using paraffin sections. Protein of MMP-3 bands was visualized by ECL kit in Western blot. Result showed that: No staining in control and sham operation group. The staining of MMP-3 positive appeared 6 h after contusion, and it becomes stronger 24 h after contusion, the staining reached the maximum at 5 days post-contusion, then it decrease, positive staining could still be observed at 14 days after contusion. No MMP-3 expression was detected in control and sham group by Western blot analysis. Brain contusion caused the appearance of a band of 45 ku molecular weight, which corresponds to an active form of MMP-3. Conclusions were drew that there is no expression of MMP-3 in normal brain, that the expression of MMP-3 appears 6h after TBI, and that there is a relationship between the expression of MMP-3 and the time course after TBI, and MMP-3 would be used as an indicator for estimating the age of traumatic brain contusion in forensic pathology.

[Animal model of grading skeletal muscle contusion due to blunt impact in rats].

OBJECTIVE: To establish a new animal model of grading skeletal muscle contusions that could be controllable and repetitive. METHODS: The rats' gastrocnemius was injured by a new weight-dropping device designed. The force acting on gastrocnemius with a comparatively constant duration and inducing elastic deformation of the gastrocnemius was expressed with velocity (v) and deformation (DF). Instant velocity was changed to create gastrocnemius contusions. Pathological changes of gastrocnemius were graded by the gross and histological examinations of 39 rats. RESULTS: At low level of impact (v: 2 m/s, DF: 5.5 mm), mild injuries were detected in epimysium and superficial layer of gastrocnemius. At moderate level of impact (v: 2.5 m/s, DF: 6.5 mm), the injuries were observed in epimysium and whole gastrocnemius. At high level of impact (v: 3 m/s, DF: 7.5 mm), severe injuries were seen deeper to soleus with more extensive skeletal muscle damage. CONCLUSION: Grading of skeletal muscle blunt force contusion is created by parameter of velocity and muscle deformation. The model could be used for further research on skeletal muscle contusions.