2021 Vol. 35, No. 1
Neurological and neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS) in the brain. Inhibiting nNOS benefits a variety of neurological and neuropsychiatric disorders, including stroke, depression and anxiety disorders, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, chronic pain, and drug addiction. Due to critical roles of nNOS in learning and memory and synaptic plasticity, direct inhibition of nNOS may cause severe side effects. Importantly, interactions of several proteins, including post-synaptic density 95 (PSD-95), carboxy-terminal PDZ ligand of nNOS (CAPON) and serotonin transporter (SERT), with the PSD/Disc-large/ZO-1 homologous (PDZ) domain of nNOS have been demonstrated to influence the subcellular distribution and activity of the enzyme in the brain. Therefore, it will be a preferable means to interfere with nNOS-mediated protein-protein interactions (PPIs), which do not lead to undesirable effects. Herein, we summarize the current literatures on nNOS-mediated PPIs involved in neurological and neuropsychiatric disorders, and the discovery of drugs targeting the PPIs, which is expected to provide potential targets for developing novel drugs and new strategy for the treatment of neurological and neuropsychiatric disorders.
Previous studies have demonstrated that Chinese lung adenocarcinoma (LUAD) patients have unique genetic characteristics, however, the specific genomic features relating to the development and treatment of LUAD in the Chinese population are not fully understood. Here, we applied the ultra-deep targeted sequencing to 66 Chinese LUAD samples, accompanied by comparative analysis with 162 Caucasian LUAD in The Cancer Genome Atlas. We focused on the 68 recurrently mutated genes and results revealed that the panel-based tumor mutational burden (pTMB) is significantly higher in the Chinese LUAD (P=0.0017). Additionally, the percentage of smoking-associated C>A transversion is significantly lower in Chinese LUAD (15.5%vs. 39.7%, P=5.69×10−27), while C>T transition is more frequent in Chinese LUAD (35.8%vs. 25.7%, P=2.67×10−5), which indicated the ethnic difference in mutation types. Notably, novel driver genes (GNAS and JAK1) that are peculiar to Chinese LUAD were identified, and a more convergent distribution of mutations was observed in the Chinese cohort (P=0.012) compared with scattered mutations in Caucasian LUAD. Our results present a distinct genomic profile of Chinese LUAD compared to Caucasians LUAD and elucidate the ethnic difference in mutation distribution besides the type and rate.
Colorectal cancer (CRC) is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients. In this study, mRNA microarray datasets GSE113513, GSE21510, GSE44076, and GSE32323 were obtained from the Gene Expression Omnibus (GEO) and analyzed with bioinformatics to identify hub genes in CRC development. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Gene ontology (GO) and KEGG analyses were performed through the DAVID database. STRING database and Cytoscape software were used to construct a protein-protein interaction (PPI) network and identify key modules and hub genes. Survival analyses of the DEGs were performed on GEPIA database. The Connectivity Map database was used to screen potential drugs. A total of 865 DEGs were identified, including 374 upregulated and 491 downregulated genes. These DEGs were mainly associated with metabolic pathways, pathways in cancer, cell cycle and so on. The PPI network was identified with 863 nodes and 5817 edges. Survival analysis revealed that HMMR, PAICS, ETFDH, and SCG2 were significantly associated with overall survival of CRC patients. And blebbistatin and sulconazole were identified as candidate drugs. In conclusion, our study found four hub genes involved in CRC, which may provide novel potential biomarkers for CRC prognosis, and two potential candidate drugs for CRC.
There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression. However, the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown. Here, we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs). More importantly, we found that inhibition of glutaminolysis by bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) impeded PGCLC specialization, but the impediment could be rescued by addition of α-ketoglutarate (αKG), the intermediate metabolite of oxidative phosphorylation and glutaminolysis. Moreover, adding αKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3K27me3 demethylation. Thus, our study reveals the importance of metabolite αKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.
Protein ubiquitination is essential for diverse cellular functions including spermatogenesis. The tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activity, are highly conserved in mammals. They are involved in important cellular processes such as embryonic development, immunity, and fertility. Our previous studies indicated that Trim69, a testis-specific expressed TRIM family gene, potentially participates in the spermatogenesis by mediating testicular cells apoptosis. In this study, we investigated the biological functions of Trim69 in male mice by established Trim69 knockout mice with CRISPR/Cas9 genomic editing technology. Here, we reported that the male Trim69 knockout mice had normal fertility. The adult knockout mice have shown that the appearance of testes, testis/body weight ratios, testicular histomorphology, and the number and quality of sperm were consistent with wild-type mice. These results indicated that the E3 ubiquitin ligase protein Trim69 was not essential for male mouse fertility, and it might be compensated by other TRIM family members such as Trim58 in Trim69-deficiency testis. This study would help to elucidate the functions of tripartite motif protein family and the regulation of spermatogenesis.
To evaluate if valproic acid (VPA) therapy is associated with vitamin D deficiency among infants and toddlers with epilepsy, a cross-sectional clinical study was conducted in 25 children with epilepsy taking VPA. Blood levels of calcium, phosphorus, alkaline phosphatase, and 25-hydroxy vitamin D [25(OH)D] and plasma VPA level were measured at 1- to 3-month intervals. At the initial and final measurements, vitamin D deficiency or insufficiency was recognized in 8 (32%) and 12 (42%), respectively. In girls, a decreasing trend in serum 25(OH)D levels (P<0.05) was observed. Polytherapy had a significant negative effect on the longitudinal change of 25(OH)D (P<0.05) in girls. In conclusion, our study indicates that a high proportion of girls after VPA therapy had hypovitaminosis D.
Postdural puncture headache (PDPH) is an incapacitating complication that can occur following spinal anesthesia and with inadvertent dural puncture during epidural anesthesia. We present a case of a 32-year-old G2P1 female who was admitted for induction of labor and received epidural catheter placement for analgesia. After an inadvertent dural puncture and development of a PDPH, the patient was offered conservative measures for the first 48 hours without improvement. An epidural blood patch (EBP) was placed achieving only moderate relief. Two days later, a second EBP was performed and the patient developed severe back pain which radiated bilaterally to her buttocks. Magnetic resonance imaging (MRI) demonstrated the presence of blood in the intrathecal space. This could be the cause of sacral radiculitis, an uncommon complication of an EBP. This suggests that EBPs could potentially cause neurologic symptoms which may be more common than people previously thought. As complicated outcomes have followed both conservative and aggressive management, MRI can be an early diagnostic tool in such cases and a multidisciplinary approach should be taken.
After type A acute aortic dissection (AAD) repair or modified Bentall procedure, uncontrollable bleeding from the anastomotic sites of the fragile dissected tissues or aortic root area is a critical situation to a cardiac surgeon. For postoperative care, lots of blood transfusion with strict monitoring on the patient all night and subsequent reoperation for the bleeding control is usually needed. We managed to make contained local compression of upper half of the heart, from upper part of the right ventricle to just above the innominate vein, using bovine pericardium with closing both sides of transverse sinus in two cases of uncontrolled postoperative bleeding (bleeding from distal anastomotic site in type-A AAD and valve sitting site in modified Bentall procedure). Even though reoperations for the removal of packed gauges were done in both cases 2 days later, postoperative courses at intensive care unit were very smooth with little need for transfusion. This kind of contained local compression trial could be a useful strategy for dealing with the malignant uncontrollable bleeding from the fragile aortic tissue or root area after acute dissection or aortic root repair.