Hypomethylation-associated LINC00987 downregulation induced lung adenocarcinoma progression by inhibiting the phosphorylation-mediated degradation of SND1.

DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.

Is Weak Acid Beneficial for Addressing Checkpoint Inhibitor-Triggered Cancer Hyper Progression in Anti-PD1/PD-L1 Immunotherapies?

Numerous cases of checkpoint inhibitor-triggered cancer hyperprogression have been documented. A previous hypothesis attributes cancer onset to the local buildup of hydrogen chloride, jointly mediated by hydrogen bond donors and acceptors and basic amino acids. The anti-PD1/PD-L1 immunotherapies may have caused a surge of protons or chloride ions for the effective treatment of neoplasm, thus giving rise to the local formation of hydrogen chloride and subsequently cancer hyperprogression in some susceptible individuals. It was postulated that the local strength of acidity is critical for tumor growth and metastasis, as the intake of weak organic acids reduces cancer risks. The anti-PD1/PD-L1 immunotherapies can be integrated with weak organic acids to reduce adverse reactions and generate better anticancer outcomes.

SMBA1, a Bax Activator, Induces Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells.

SMBA1 (small-molecule Bax agonists 1), a small molecular activator of Bax, is a potential anti-tumour agent. In the present study, we investigated the biological effects of SMBA1 on glioblastoma (GBM) cells. SMBA1 reduced the viabilities of U87MG, U251 and T98G cells in a time- and dose-dependent manner. Moreover, treatment with SMBA1 induced cell cycle arrest at the G2/M phase transition, accompanied by the downregulation of Cdc25c and cyclin B1 and the upregulation of p21. SMBA1 also induced apoptosis of GBM cells in a dose-dependent manner. Mechanistically, SMBA1 induced apoptosis via the intrinsic pathway. Silencing of Bax or ectopic expression of Bcl-2 significantly inhibited SMBA1-induced apoptosis. Moreover, SMBA1 inhibited the growth of U87MG xenograft tumours in vivo. Overall, SMBA1 shows anti-proliferative effects against GBM cells through activation of the intrinsic apoptosis pathway.

Circulating/cerebrospinal T lymphocytes as indicators of clinical prognosis in intracerebral hemorrhage: A prospective study.

Secondary injury of cerebral hemorrhage is induced by systemic inflammatory cascades, which are related to perihematomal brain edema, cellular apoptosis, and the disruption of the blood-brain barrier. This study was to specifically elaborate the relationship of circulating/cerebrospinal T lymphocytes and Glasgow Coma Scale (GCS) score at 6 months after intracerebral hemorrhage (ICH). The enrolled patients were divided into 2 groups based on GCS score: the favorable prognosis group (GCS > 12) and unfavorable prognosis group (GCS ≤ 12). T lymphocyte subpopulations were analyzed by flow cytometry. A total of 30 samples of peripheral blood and 17 samples of cerebrospinal fluid were collected and analyzed, including 19 cases and 12 cases in the favorable prognosis group (GCS > 12) respectively. Both CD3+ and CD3+CD4+ T lymphocyte counts on Day 1 after ICH were lower in the peripheral blood of patients with unfavorable prognosis (GCS ≤ 12) (P = .025 and .022, respectively). There were correlation trends between the GCS scores and CD3+ T lymphocyte count (P = .0144), and CD3+CD4+ T lymphocyte count (P = .0135). In cerebrospinal fluid, there was a close correlation between the GCS scores and CD3+CD4+ percentage, CD4+/CD8+ ratio, CD3+ and CD3+CD4+ T lymphocyte counts. The area under the curve of CD4+/CD8+ T lymphocyte ratio was the largest among them (P = .000 and area under the curve = 0.917), with a significantly high specificity and sensitivity (0.917 and 1.000). Based on cerebrospinal fluid samples, the CD4+/CD8+ T lymphocyte ratio on Day 1 after ICH may be a more significant indicator to predict the short-term prognosis at 6 months after ICH.

Synthetic antimicrobial agents inhibit aflatoxin production.

Antimicrobial peptides (AMPs) are biologically active molecules that can eradicate bacteria by destroying the bacterial membrane structure, causing the bacteria to rupture. However, little is known about the extent and effect of AMPs on filamentous fungi. In this study, we synthesized small molecular polypeptides by an inexpensive heat conjugation approach and examined their effects on the growth of Aspergillus flavus and its secondary metabolism. The antimicrobial agents significantly inhibited aflatoxin production, conidiation, and sclerotia formation in A. flavus. Furthermore, we found that the expression of aflatoxin structural genes was significantly inhibited, and the intracellular reactive oxygen species (ROS) level was reduced. Additionally, the antimicrobial agents can change membrane permeability. Overall, our results demonstrated that antimicrobial agents, safe to mammalian cells, have an obvious impact on aflatoxin production, which indicated that antimicrobial agents may be adopted as a new generation of potential agents for controlling aflatoxin contamination.

Local strong acids: A driving force for metastasis.

Carcinogenesis was postulated as the result of the local buildup of strong acids such as hydrogenchloride which may trigger metastasis. A previous study revealed that bicarbonate raised tumor pH and suppressed metastases. The phosphate groups in DNA on neutrophil extracellular traps possess hydrogen bonding capacity and can accept protons. The proteins commonly found in neutrophil extracellular traps such as CCDC25, myeloperoxidase (MPO), histone H3, peptidylarginine deiminase 4 (PAD4) possess basic amino acid content at about 20.2%, 12.8%, 24.3% and 13.0% respectively, which attracts anions such as chloride. The striking 20.2% basic amino acid content in CCDC25 is similar to that of typical oncoproteins. Local hydrogenchloride may be the dominant impetus for metastasis, accounting for the anticancer effects of virtually all weak organic acids, acetic acid and lactic acid in particular.

High glycine content in TDP-43: a potential culprit in limbic-predominant age-related TDP-43 encephalopathy.

Numerous risk factors for heart disease or dementia harbor over 10% valine plus glycine content. Interestingly, TDP-43 contains 6.0% valine and 13.3% glycine, and the buildup of this protein in the brains of patients with limbic-predominant age-related TDP-43 encephalopathy has dire consequences. The two γ-methyl groups in valine enable hyperconjugation, which enhances the van der Waals interaction between its side group and the carbonyl carbon. This extends the C=O bond length, and this weakened C=O bond augments the secondary chemical bonding of the carbonyl oxygen atom to cations. This, in turn, promotes the formation and buildup of insoluble and rigid salts such as calcium oxalate, which is postulated to be a major cause of heart disease. Similarly, the long C=O bond length in glycine results in a weakened C=O bond with an enhanced affinity toward cations and the formation of insoluble salts. Further, several prion proteins possess a high glycine content of approximately 20%. The insoluble calcium salts produced may promote aggregate formation via secondary chemical bonding between calcium and glycine, as well as between calcium and valine. Chemical and biochemical insights will help us to better understand the etiology of disorders linked to protein aggregates.

A Solo Dance or a Tango?

Previous studies have identified genetic factors and Epstein-Barr virus underlying nasopharyngeal carcinoma. A hypothesis postulated that the local buildup of HCl, mediated by hydrogen bond donors and acceptors and basic amino acids, causes cancer. Nasopharyngeal carcinoma incidences are high in the humid southern coastal China, Southeast Asia, and Mediterranean regions, but not in the noncoastal and nonhumid southern Yunnan Province, China, and nonhumid Central China. The nearly saturated humidity in the Huinan period in Guangdong can trigger the expression of proteins with extensive hydrogen bonding to protons, augmenting the formation of HCl that is mutagenic. Given that the Epstein-Barr virus carries high content of hydrogen bond donors and acceptors, the moist environment in the nasal cavity may enable the virus to colonize the site, compounding pertinent investigations as both virus and high humidity are likely to trigger carcinogenesis. Therefore, the phenomena of exceptionally high humidity in regions with high nasopharyngeal cancer rates warrant further investigations.

Cellular States and Secondary Chemical Bonding: A Biochemical View of Major Human Diseases.

Nasopharyngeal carcinoma is prevalent in hot and humid areas such as south coastal China and Southeast Asia, but not in the non-coastal southern Chinese Yunnan Province. Secondary chemical bonding may underlie such phenomena. Cancer may be caused by strong acids such as HCl, whereas insoluble and rigid salts such as calcium oxalate are the potential causative factors of heart disease and the Alzheimer disease. The weak organic acids produced by plants counteract strong acids and dissolve insoluble salts, therefore boasting dual roles in disease prevention and treatments. The aforementioned perspective sheds light on the underlying mechanism of human disorders and opens new avenues in the interventions of numerous diseases.

The potential long-term neurological improvement of early hyperbaric oxygen therapy on hemorrhagic stroke in the diabetics.

AIMS: Although Hyperbaric oxygen therapy (HyperBOT) attract our attention successfully these days, it is still full of controversy on the treatment of acute stroke. The aim of this study is to assess the potential long-term neurological consequences and safety of using HyperBOT on intracerebral hemorrhage (ICH) in the diabetics. METHODS: In this prospective, randomized controlled trial, 79 diabetes patients suffering from acute ICH were randomized to treat for 60 min in a monoplace hyperbaric chamber pressurized with pure oxygen to 2.5-atm absolute (ATA) in the HyperBOT group or 1.5 ATA in the normobaric oxygen therapy (NormBOT) group, which was performed as control. Both short-term and long-term neurological consequences were studied and compared in each group on National Institutes of Health Stroke Scale [NIHSS], Barthel Index, modified Rankin Scale [mRS] and Glasgow Outcome Scale [GOS]. The related complications or side-events of all patients were recorded as well at the final follow-up of six months after onset. RESULTS: No distinct difference was observed between each group at one month follow-up. However, in the long-term follow-up of six months, a higher frequency of patients in the HyperBOT group resulted into good outcome with a relative high neurological consequence compared with the NormBOT group (Barthel Index: 85.1% versus 65.6%, P = 0.080; mRS: 89.4% versus 68.8%, P = 0.045; GOS: 83.0% versus 62.5%, P = 0.073; NIHSS: 80.9% versus 56.2%, P = 0.035). CONCLUSIONS: Early HyperBOT was found to be safe and effective with regards to the long-term neurological outcome of diabetic patients suffering from ICH.

How Hepatitis B virus causes cirrhosis and liver cancer.

Hepatitis B virus is a major pathogen infecting the liver, causing high morbidity and mortality worldwide, particularly in developing countries. The mechanism underlying progression from infections of Hepatitis B virus to cirrhosis and liver cancer is not fully determined. Here we propose that the HBV X protein traps protons and Cl-, and induces the expression of collagen in the liver, which forms potent hydrogen bonds with trapped protons. The presence of collagen in the liver marks the progression to fibrosis. The X protein and collagen concertedly build up HCl locally, triggering disease advances to liver cancer in some patients with liver cirrhosis. The hypothesis can be tested in Hepatitis B primate model with the administration of calcium and weak acids to ascertain physiological changes and monitor tumorigenesis rate. The experiments will pave the way for better intervention of human infections with Hepatitis B virus.