Identification of lactate-related subgroups and prognostic model in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that exhibits elevated glycolytic capacity. Lactate, as a byproduct of glycolysis, is considered a major oncometabolite that plays an important role in oncogenesis and remodeling of the tumor microenvironment. However, the potential roles of lactate in TNBC are not yet fully understood. In this study, our goal was to identify prognosis-related lactate genes (PLGs) and construct a lactate-related prognostic model (LRPM) for TNBC. METHODS: First, we applied lactate-related genes to classify TNBC samples using a hierarchical clustering algorithm. Then, we performed the log-rank analysis and the least absolute shrinkage and selection operator analysis to screen PLGs and construct the LRPM. The biological functions of the identified PLGs in TNBC were investigated using CCK8 assay and clone formation assay. Finally, we constructed a nomogram based on the lactate-risk score and tumor clinical stage. We used the operating characteristic curve and decision curve analysis to evaluate the predictive capability of the nomogram. RESULTS: Our results showed that the TNBC samples could be classified into two subgroups with different survival probabilities. Three genes (NDUFAF3, CARS2 and FH), which can suppress TNBC cell proliferation, were identified as PLGs. Moreover, the LRPM and nomogram exhibited excellent predictive performance for TNBC patient prognosis. CONCLUSION: We have developed a novel LRPM that enables risk stratification and identification of poor molecular subtypes in TNBC patients, showing great potential in clinical practice.

The Beneficial Role of Exercise on Treating Alzheimer's Disease by Inhibiting ß-Amyloid Peptide.

Alzheimer's disease (AD) is associated with a very large burden on global healthcare systems. Thus, it is imperative to find effective treatments of the disease. One feature of AD is the accumulation of neurotoxic ß-amyloid peptide (Aß). Aß induces multiple pathological processes that are deleterious to nerve cells. Despite the development of medications that target the reduction of Aß to treat AD, none has proven to be effective to date. Non-pharmacological interventions, such as physical exercise, are also being studied. The benefits of exercise on AD are widely recognized. Experimental and clinical studies have been performed to verify the role that exercise plays in reducing Aß deposition to alleviate AD. This paper reviewed the various mechanisms involved in the exercise-induced reduction of Aß, including the regulation of amyloid precursor protein cleaved proteases, the glymphatic system, brain-blood transport proteins, degrading enzymes and autophagy, which is beneficial to promote exercise therapy as a means of prevention and treatment of AD and indicates that exercise may provide new therapeutic targets for the treatment of AD.

The involvement of NLRP3 inflammasome in the treatment of neurodegenerative diseases.

In an ageing society, neurodegenerative diseases have attracted attention because of their high incidence worldwide. Despite extensive research, there is a lack of conclusive insights into the pathogenesis of neurodegenerative diseases, which limit the strategies for symptomatic treatment. Therefore, better elucidation of the molecular mechanisms involved in neurodegenerative diseases can provide an important theoretical basis for the discovery of new and effective prevention and treatment methods. The innate immune system is activated during the ageing process and in response to neurodegenerative diseases. Inflammasomes are multiprotein complexes that play an important role in the activation of the innate immune system. They mediate inflammatory reactions and pyroptosis, which are closely involved in neurodegeneration. There are different types of inflammasomes, although the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is the most common inflammasome; NLRP3 plays an important role in the pathogenesis of neurodegenerative diseases. In this review, we will discuss the mechanisms that are involved in the activation of the NLRP3 inflammasome and its crucial role in the pathology of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. We will also review various treatments that target the NLRP3 inflammasome pathway and alleviate neuroinflammation. Finally, we will summarize the novel treatment strategies for neurodegenerative disorders.

The involvement of NLRP3 inflammasome in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and it is characterised by progressive deterioration in cognitive and memory abilities, which can severely influence the elderly population's daily living abilities. Although researchers have made great efforts in the field of AD, there are still no well-established strategies to prevent and treat this disease. Therefore, better clarification of the molecular mechanisms associated with the onset and progression of AD is critical to provide a theoretical basis for the establishment of novel preventive and therapeutic strategies. Currently, it is generally believed that neuroinflammation plays a key role in the pathogenesis of AD. Inflammasome, a multiprotein complex, is involved in the innate immune system, and it can mediate inflammatory responses and pyroptosis, which lead to neurodegeneration. Among the various types of inflammasomes, the NLRP3 inflammasome is the most characterised in neurodegenerative diseases, especially in AD. The activation of the NLRP3 inflammasome causes the generation of caspase-1-mediated interleukin (IL)-1ß and IL-18 in microglia cells, where neuroinflammation is involved in the development and progression of AD. Thus, the NLRP3 inflammasome is likely to be a crucial therapeutic molecular target for AD via regulating neuroinflammation. In this review, we summarise the current knowledge on the role and regulatory mechanisms of the NLRP3 inflammasome in the pathogenic mechanisms of AD. We also focus on a series of potential therapeutic treatments targeting NLRP3 inflammasome for AD. Further clarification of the regulatory mechanisms of the NLRP3 inflammasome in AD may provide more useful clues to develop novel AD treatment strategies.

Disulfiram as a potent metallo-ß-lactamase inhibitor with dual functional mechanisms.

We report a promising NDM-1 inhibitor, disulfiram, which can covalently bind to NDM-1 by forming an S-S bond with the Cys208 residue. Its copper-containing metabolite in vivo, Cu(DTC)2, also inactivated NDM-1 through oxidizing the Zn(ii) thiolate site of the enzyme, therefore exhibiting dual functional inhibitory potential against B1 and B2 subclass MßLs.

Combining proton and silaborane-based superhalogen anions - an effective route to new superacids as verified via systematic DFT calculations.

Based on systematic DFT calculations, silaborane-based superhalogen anions, which obey the Wade-Mingos rule, are shown to be capable of giving rise to superacids via their combination with protons. Compared to previous carborane-based systems, the acidities of the composites here are stronger in both the gas phase and solution phase. Thus, the potential of candidates based on silaborane could be greater than those based on carborane in the search for ultra-strong acidic systems. Within a given group, a higher superhalogen anion vertical electron detachment energy (VDE) generally leads to stronger acidity. This consistency arises from the dominant role of the VDE, as established through the decomposition of the gas-phase acidity into different contributions. Thus, constructing superacids from superhalogens is a rational route whose future should be positive. Besides the VDE, other effects, i.e., the deformation energy (DE) and bond dissociation energy (BDE), could also be crucial, especially in terms of the differences between the acidities of composites belonging to different groups. A comparison between the results in the gas phase and solution phase indicates that complete calculations of both gas-phase ΔGacid and solution-phase pKa values are necessary to obtain an unbiased description of the acidity. The solvation free energies of the participants in the deprotonation process, especially the conjugate acid, are responsible for the discrepancies between gas phase and solution phase behavior.

Exploring the structure, bonding and stability of noble gas compounds promoted by superhalogens. A case study on HNgMX3 (Ng = Ar-Rn, M = Be-Ca, X = F-Br) via combined high-level ab initio and DFT calculations.

A series of complexes (HNgMX3), formed from superhalogen MX3 (M = Be-Ca, X = F-Br) noble gas (Ar-Rn) and the hydrogen atom, were investigated via combined high-level ab initio and DFT calculations. The high vertical electron detachment energy (VDE) of the superhalogen part will lead to charge transfer from the noble gas hydride to it. This charge transfer gives rise to attractive ionic interaction between the two components and to the existence of these complexes as local minima on the potential energy surface eventually. However, the VDE value of the superhalogen part is not always monotonically correlated with the thermodynamic/kinetic stability of the whole complexes. Therefore the superhalogen itself might not be enough to provide information for the correct prediction of the properties of the whole composites. Although there are exothermic channels of dissociation, the existence of energy barrier might ensure the existence of these Ng hydrides under certain conditions. Our analysis indicates the existence of two important factors, functioning in opposite directions, for the energy barriers along the exothermic channel. To achieve a high energy barrier, the attractive interaction between superhalogen and the H atom in the TS, which lowers the barrier, needs to be suppressed effectively. An understanding of the superhalogen-based composites will provide valuable information on the functional properties and potential application of superhalogens. The details of the interaction between different parts of these composites should be one of the areas of focus in these studies.