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Metabolic switch from oxidative phosphorylation to aerobic glycolysis, which is also called the Warburg effect, is a hallmark of osteosarcoma (OS) and leads to the enhancement of cell chemoresistance, growth, metastasis, and invasion. Emerging evidence indicates that long non-coding RNA (lncRNA) plays a crucial role in the Warburg effect of cancer cells. Here, we report that lncRNA KCNQ1OT1 was upregulated in OS. Meanwhile, functional experiments demonstrated that the KCNQ1OT1 facilitated proliferation and suppressed apoptosis of OS cells. In addition, KCNQ1OT1 contributed to the Warburg effect by stimulating aldolase A (ALDOA) expression. Furthermore, using bioinformatics analysis, luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay, we identified that KCNQ1OT1 functions as a competing endogenous RNA (ceRNA) by sponging miR-34c-5p, which inhibited ALDOA expression by directly targeting its 3ʹUTR. Taken together, these data identified a key role of KCNQ1OT1 in glucose metabolism reprogramming of OS. Targeting the KCNQ1OT1/miR-34c-5p/ALDOA axis may be a potential therapeutic target in OS treatment.

As a traditional Chinese medicine (TCM) with a usage history of over 2,000 years in China, Spica Schizonepetae possesses definite clinical activity in the treatment of non-small cell lung cancer (NSCLC). However, its active ingredients and mechanism of action remain unclear at present. The further exploration of its active components and underlying mechanism will provide a basis for the development of candidate anti-tumor drugs. Our previous study explored the chemical constituents of Spica Schizonepetae extract (SSE). On this basis, molecular networking technology was applied in analyzing the QTOF-MS/MS data of rat plasma after intragastric administration of SSE using the GNPS database platform. A total of 26 components were found, including 9 proterotype components and 17 metabolites, which revealed the potential active ingredients of SSE. Later, the Lewis lung cancer mouse model was established, and the inhibition rate and histopathological sections were used as the indicators to investigate the anti-tumor effect of SSE, whereas the body weight, survival rate, thymus index and spleen index served as the indicators to explore the pharmacological effects of SSE on improving mouse immunity. The results showed that SSE had comparable anti-tumor efficacy to cisplatin, which enhanced the immunity, improved the quality of life, and extended the survival time of lung cancer mice. Furthermore, human A549 lung tumor cells were selected to explore the mechanism of SSE in treating NSCLC based on cell metabonomics. After data mining by the MPP software, 23 differential endogenous metabolites were identified between SSE and tumor groups. Moreover, results of pathway enrichment analysis using the MetaboAnalyst 4.0 software indicated that these metabolites were mainly enriched in four metabolic pathways (p < 0.1). By adopting the network pharmacology method, the metabolic pathways discovered by cell metabolomics were verified against the ChEMBL, STITCH, UniProt and TCGA databases, and differences in the underlying mechanism between cells and humans were found. It was proved that SSE affected the metabolism of purine, arachidonic acid and histidine to exert the anti-tumor efficacy. Furthermore, the multi-target, multi-pathway, and immunoenhancement mechanism of SSE in anti-tumor treatment was revealed, which provided a scientific basis for new drug development and the rational application of Spica Schizonepetae in clinic.

Osteosarcoma (OS) is the most common primary malignant neoplasm of the bone. Recent studies have indicated that the inhibitory effects of microRNA (miR)‐324‐3p could affect the development of numerous cancers. However, its biological roles and underlying mechanisms in OS progression remain unexplored. In this study, miR‐324‐3p expression was markedly reduced in OS cell lines and tissues. Functionally, miR‐324‐3p overexpression suppressed OS progression and was involved in the Warburg effect. Mechanistically, miR‐324‐3p negatively regulated phosphoglycerate mutase 1 (PGAM1) expression by targeting its 3′‐UTR. Moreover, high expression of PGAM1 promoted OS progression and aerobic glycolysis, which were associated with inferior overall survival in patients with OS. Notably, the tumor suppressor functions of miR‐324‐3p were partially recovered by PGAM1 overexpression. In summary, the miR‐324‐3p/PGAM1 axis plays an important role in regulating OS progression by controlling the Warburg effect. Our results provide mechanistic insights into the function of miR‐324‐3p in glucose metabolism and subsequently on the progression of OS. Targeting the miR‐324‐3p/PGAM1 axis could be a promising molecular strategy for the treatment of OS. The main novel finding of this study was that miR‐324‐3p expression was markedly reduced in OS and miR‐324‐3p regulated OS growth via targeting PGAM1‐mediated aerobic glycolysis. Thus, targeting the miR‐324‐3p/PGAM1 axis is a promising OS treatment strategy.

Cancer stem-like cells (CSCs) contribute to cancer metastasis, drug resistance and tumor relapse, yet how amino acid metabolism promotes CSC maintenance remains exclusive. Here, we identify that proline synthetase PYCR1 is critical for breast cancer stemness and tumor growth. Mechanistically, PYCR1-synthesized proline activates cGMP-PKG signaling to enhance cancer stem-like traits. Importantly, cGMP-PKG signaling mediates psychological stress-induced cancer stem-like phenotypes and tumorigenesis. Ablation of PYCR1 markedly reverses psychological stress-induced proline synthesis, cGMP-PKG signaling activation and cancer progression. Clinically, PYCR1 and cGMP-PKG signaling components are highly expressed in breast tumor specimens, conferring poor survival in breast cancer patients. Targeting proline metabolism or cGMP-PKG signaling pathway provides a potential therapeutic strategy for breast patients undergoing psychological stress. Collectively, our findings unveil that PYCR1-enhanced proline synthesis displays a critical role in maintaining breast cancer stemness.

Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila ( A. muciniphila ), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila , butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.

Background: Rheumatoid arthritis (RA) is related to several pivotal susceptibility genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes. Although the connection between polymorphisms of CTLA-4 and CD86 genes in different populations of RA have been studied extensively, the results are controversial. Objective: To clarify the correlation in the Chinese Han population between CTLA-4, CD80/86 , and CD28 gene polymorphisms, and RA susceptibility. Methods: A case-control study (574 RA patients and 804 controls) was conducted to determine the correlation between CTLA-4 rs231775 and rs16840252 gene polymorphisms, CD86 rs17281995 gene polymorphisms, and the risk of RA for the Chinese Han population. Furthermore, an additional meta-analysis, including three single nucleotide polymorphisms (SNPs) ( CTLA-4 rs231775, CTLA-4 rs3087243, and CTLA-4 rs5742909) from 32 citations, including 43 studies, 24,703 cases and 23,825 controls was performed to elucidate the relationship between known SNPs in the CTLA-4 genes and RA for more robust conclusions. Results: The results showed that CTLA-4 rs231775 gene polymorphism decreased the RA risk (GA vs. AA, OR = 0.77, P = 0.025), whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA susceptibility. Stratification analyses by RF, ACPA, CRP, ESR, DAS28, and functional class identified significant associations for CTLA-4 rs231775 and rs16840252 gene polymorphisms in the RF-positive and RF-negative groups. A meta-analysis of the literature on CTLA-4 gene polymorphisms and RA risk revealed that the risk of RA was decreased by CTLA-4 rs231775 gene polymorphisms. Conclusions: The CTLA-4 rs231775 gene polymorphism decreased the risk of RA, whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA risk. A meta-analysis indicated that CTLA-4 rs231775 and rs3087243 gene polymorphisms decreased the risk of RA. To support these analytical results, additional clinical cases should be investigated in further studies.

Dysregulated cellular proliferation represents a hallmark feature across all cancers. Aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, independent of mitogenic signaling, engenders uncontrolled breast cancer cell proliferation. Consequently, the advent of CDK4/6 inhibition has constituted a pivotal milestone in the realm of targeted breast cancer therapy. The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) has emerged as the foremost therapeutic modality for patients afflicted with hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced breast cancer. At present, the Food and Drug Administration (FDA) has sanctioned various CDK4/6i for employment as the primary treatment regimen in HR + /HER2- breast cancer. This therapeutic approach has demonstrated a substantial extension of progression-free survival (PFS), often amounting to several months, when administered alongside endocrine therapy. Within this comprehensive review, we systematically evaluate the utilization strategies of CDK4/6i across various subpopulations of breast cancer and explore potential therapeutic avenues following disease progression during application of CDK4/6i therapy.

Pramlintide, an approved analog of amylin, is responsible for regulating the physiology of energy homeostasis. The goals of this study were to investigate the roles of pramlintide in the regulation of cell survival and matrix metabolism, and further explore their underlying mechanisms, in human nucleus pulposus (NP) cells. NP cells were treated with different concentrations of pramlintide in normoxic or hypoxic conditions. Cell viability, LAC concentration, calcium concentration, mitochondrial membrane potential (ΔΨm), MMPs proteins, and apoptotic related proteins were detected. The results indicate that pramlintide could improve NP cell proliferation, glycolytic activity, and the ECM synthesis under hypoxia, which is evident from the increased precipitation of proteoglycans; increased expression of AGG, Col2, and SOX9 proteins; and decreased expression of MMP3, MMP9, and MMP13 proteins, which are Ca2+-dependent enzymes. And, pramlintide could facilitate the survival of NP cells through mitochondrial-mediated, Bcl-2/caspase-3-dependent apoptosis. In addition, activation of AKT-AMPK/mTOR signaling pathway is also observed by the treatment. These findings demonstrate that pramlintide may play a pivotal role in reversing intervertebral disk degeneration and may relieve the impairment of ECM metabolism and NP cells survival through mitochondrial-dependent apoptotic signaling pathway, thus offering a novel potential pharmacological treatment strategy.

Loop subdivision is a significant surface scheme with wide applications in fields like computer graphics and wavelet. As a type of stationary scheme, Loop subdivision cannot adjust the limit surface directly. In this paper, we present a new way to solve this problem by proposing a symmetric non-stationary Loop subdivision based on a suitable iteration. This new scheme can be used to adjust the limit surfaces freely and thus can generate surfaces with different shapes. For this new scheme, we show that it is C2 convergent in the regular part of mesh and is at least tangent plane continuous at the limit positions of the extraordinary points. Additionally, we present a non-uniform generalization of this new symmetric non-stationary subdivision so as to locally control the shape of the limit surfaces. More interestingly, we present the limit positions of the initial points, both for the symmetric non-stationary Loop subdivision and its non-uniform generalization. Such limit positions can be used to interpolate the initial points with different valences, generalizing the existing result. Several numerical examples are given to illustrate the performance of the new schemes.

Primary histiocytic sarcoma of the central nervous system is a rare lymphohematopoietic tumor originating from histiocytes. Here we report such a case with somatic mutation. Based on imaging studies, a 24-year-old woman presented with a homogeneously enhancing lesion in the right parietal lobe region and without other organ involvement. Histological analysis showed that the pleomorphic tumor cells were loosely arranged, and the neoplastic cells are characterized by abundant eosinophilic cytoplasm, highly atypical nuclei, and prominent nucleoli. The lesional cells were immunoreactive with antibodies against -CD68KP1, CD163 focally, lysozyme, and BRAF V600E. NGS-based genetic profiling revealed a pathogenic somatic (p.R196*) mutation. Additionally, (p.V600E), (p.V561D), (p.H437Q, VUS), and (p.E2343A, VUS) mutations were detected. However, the tumor did not respond to apatinib and anlotinib treatment, and the patient died 10 months after the initial diagnosis.