In Vitro Insights into the Role of 7,8-Epoxy-11-Sinulariolide Acetate Isolated from Soft Coral Sinularia siaesensis in the Potential Attenuation of Inflammation and Osteoclastogenesis.

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the process of bone remodeling. Excessive osteoclast differentiation plays a pivotal role in the pathogenesis of bone diseases such as rheumatoid arthritis and osteoporosis. In the present study, we examined whether 7,8-epoxy-11-sinulariolide acetate (Esa), a marine natural product present in soft coral Sinularia siaesensis, attenuates inflammation and osteoclastogenesis in vitro. The results indicated that Esa significantly inhibited lipopolysaccharide (LPS)-induced inflammation model of RAW264.7 cells and suppressed receptor activator for nuclear factor-κB ligand (RANKL)-triggered osteoclastogenesis. Esa significantly down-regulated the protein expression of iNOS, COX-2, and TNF-α by inhibiting the NF-κB/MAPK/PI3K pathways and reducing the release of reactive oxygen species (ROS) in RAW264.7 macrophages. Besides, Esa treatment significantly inhibited osteoclast differentiation and suppressed the expression of osteoclast-specific markers such as NFATC1, MMP-9, and CTSK proteins. These findings suggest that Esa may be a potential agent for the maintenance of bone homeostasis associated with inflammation.

MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products.

Various diseases, including cancers, age-associated disorders, and acute liver failure, have been linked to the oncogene, MYC. Animal testing and clinical trials have shown that sustained tumor volume reduction can be achieved when MYC is inactivated, and different combinations of therapeutic agents including MYC inhibitors are currently being developed. In this review, we first provide a summary of the multiple biological functions of the MYC oncoprotein in cancer treatment, highlighting that the equilibrium points of the MYC/MAX, MIZ1/MYC/MAX, and MAD (MNT)/MAX complexes have further potential in cancer treatment that could be used to restrain MYC oncogene expression and its functions in tumorigenesis. We also discuss the multifunctional capacity of MYC in various cellular cancer processes, including its influences on immune response, metabolism, cell cycle, apoptosis, autophagy, pyroptosis, metastasis, angiogenesis, multidrug resistance, and intestinal flora. Moreover, we summarize the MYC therapy patent landscape and emphasize the potential of MYC as a druggable target, using herbal medicine modulators. Finally, we describe pending challenges and future perspectives in biomedical research, involving the development of therapeutic approaches to modulate MYC or its targeted genes. Patients with cancers driven by MYC signaling may benefit from therapies targeting these pathways, which could delay cancerous growth and recover antitumor immune responses.

A smart nanoplatform for enhanced photo-ferrotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Emerging therapies, such as ferroptosis mediated cancer therapy and phototherapy, offer new opportunities for HCC treatment. The combination of multiple treatments is often more effective than monotherapy, but many of the current treatments are prone to serious side effects, resulting in a serious decline in patients' quality of life. Therefore, the combination therapy of tumor in situ controllable activation will improve the efficacy and reduce side effects for precise treatment of tumor. Herein, we synthesized a GSH-activatable nanomedicine to synergize photothermal therapy (PTT) and ferrotherapy. We utilized a near-infrared dye SQ890 as both an iron-chelating and a photothermal converter agent, which was encapsulated with a GSH-sensitive polymer (PLGA-SS-mPEG), to attain the biocompatible SQ890@Fe nanoparticles (NPs). In the tumor microenvironment (TME), SQ890@Fe NPs showed a GSH-activated photothermal effect that could increase the Fenton reaction rate. Meanwhile, the depletion of GSH could further increase ferroptosis effect. In turn, the increasing radical generated by ferrotherapy could impair the formation of heat shock proteins (HSPs) which could amplify PTT effects by limiting the self-protection mechanism. Overall, the intelligent nanomedicine SQ890@Fe NPs combines ferrotherapy and PTT to enhance the efficacy and safety of cancer treatment through the mutual promotion of the two treatment mechanisms, providing a new dimension for tumor combination therapy.

Quassinoids from Eurycoma longifolia and their bone formation evaluation in zebrafish, C3H10 cells and silico.

Phytochemicals with bone formation potential in traditional medicines captured more and more attentions due to their advantages to bone loss and fewer side effects. As a famous aphrodisiac phytomedicine, Eurycoma longifolia (EL) has acquired general recognition in improving male sexual health, and thus been considered as traditional medicine for the treatment of androgen-deficient osteoporosis. Although the aqueous extract of EL had been proved to be beneficial to bone loss, the active constituents and the mechanisms underlying the effects are still obscure. The current study performed a chemical investigation on the roots of EL, which resulted in the isolation and identification of ten quassinoids (EL-1-EL-10), and then conducted their osteogenic activity evaluations in vivo zebrafish model with or without dexamethasone (Dex) and in vitro C3H10 cell model. The result displayed that most tested concentrations of EL-1-EL-5 could significantly increase the mineralization areas and integrated optical densities (IODs) of skull in both zebrafish model. The majority tested concentrations of EL-1-EL-5 could also improve the mRNA expression of early osteogenic associated genes ALPL, Runx2a, Sp7 in zebrafish model without Dex, but only a few could accelerate the mRNA expression of late osteogenic associated genes OCN. These results suggested the ability of EL-1-EL-5 to increase bone formation mainly by accelerating osteogenic differentiation at the early stage. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking study, implied that the effects of the quassinoids (EL-1-EL-5) on the enhancement of bone formation might be related with improving the content and the activity of androgen through binding with CYP19A, SHBG and AKR1C2, and activating bone metabolism-related ANDR target genes and signal pathways by combining with ANDR directly. Although the assumptions are in silico model-based and further in vitro and in vivo validations are still necessary, we provided a new perspective to explore the potential of EL to be used as an alternative treatment for not only androgen-deficient osteoporosis, but also estrogen-deficient bone loss, by combining with SHBG.

Immunomodulatory potential of natural products from herbal medicines as immune checkpoints inhibitors: Helping to fight against cancer via multiple targets.

Immunotherapy sheds new light to cancer treatment and is satisfied by cancer patients. However, immunotoxicity, single-source antibodies, and single-targeting stratege are potential challenges to the success of cancer immunotherapy. A huge number of promising lead compounds for cancer treatment are of natural origin from herbal medicines. The application of natural products from herbal medicines that have immunomodulatory properties could alter the landscape of immunotherapy drastically. The present study summarizes current medication for cancer immunotherapy and discusses the potential chemicals from herbal medicines as immune checkpoint inhibitors that have a broad range of immunomodulatory effects. Therefore, this review provides valuable insights into the efficacy and mechanism of actions of cancer immunotherapies, including natural products and combined treatment with immune checkpoint inhibitors, which could confer an improved clinical outcome for cancer treatment.

Anti-Osteogenic Effect of Danshensu in Ankylosing Spondylitis: An in Vitro Study Based on Integrated Network Pharmacology.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by abnormal bone metabolism, with few effective treatments available. Danshensu [3-(3,4-dihydroxy-phenyl) lactic acid) is a bioactive compound from traditional Chinese medicine with a variety of pharmacologic effects. In the present study, we investigated the pharmacologic effect and molecular mechanism of Danshensu in AS. Potential targets of Danshensu were identified in four drugs-genes databases; and potential pharmacologic target genes in AS were identified in three diseases-genes databases. Differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database. Overlapping targets of Danshensu and AS were determined and a disease-active ingredient-target interaction network was constructed with Cytoscape software. Enrichment analyses of the common targets were performed using Bioconductor. To test the validity of the constructed network, an in vitro model was established by treating osteoblasts from newborn rats with low concentrations of tumor necrosis factor (TNF)-α. Then, the in vitro model and AS fibroblasts were treated with Danshensu (1-10 µM). Osteogenesis was evaluated by alkaline phosphatase staining and activity assay, alizarin red staining, quantitative PCR, and western blotting. We identified 2944 AS-related genes and 406 Danshensu targets, including 47 that were common to both datasets. The main signaling pathways associated with the targets were the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. A low concentration of TNF-α (0.01 ng/ml) promoted the differentiation of osteoblasts; this was inhibited by Danshensu, which had the same effect on AS fibroblasts but had the opposite effect on normal osteoblasts. Danshensu also decreased the phosphorylation of JNK and ERK in AS fibroblasts. There results provide evidence that Danshensu exerts an anti-osteogenic effect via suppression of JNK and ERK signaling, highlighting its therapeutic potential for the treatment of AS.

Anticancer effects of asiatic acid against doxorubicin-resistant breast cancer cells via an AMPK-dependent pathway in vitro.

BACKGROUND AND PURPOSE: Asiatic acid is one of the active compounds isolated from Centella asiatica and has been used to treat many diseases, including hypertension, pulmonary fibrosis, and cancer. It exhibits anticancer effects in many cancers, such as ovarian, lung and colon cancer; however, its anticancer effects in breast cancer and the underlying mechanism are not fully understood. Chemoresistance is often induced after the use of chemotherapy, and it is a challenging problem in cancer therapy. The effects of asiatic acid on chemoresistance in breast cancer have never been studied. Therefore, the aim of the present study was to examine the anticancer effects of asiatic acid in doxorubicin-resistant breast cancer MCF-7 cells. METHODS: The cells were incubated with asiatic acid at 0-160 µM for 2-24 h. Cell viability and cytotoxicity were evaluated by 3-[4, 5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Florescent images were taken using a confocal microscope. P-gp function and apoptosis assays were performed using flow cytometry. Caspase activity was measured with the Caspase-Glo™ Assay System. The phosphorylation and expression of relevant proteins were assessed by western blots. Molecular docking was performed and scored by AutoDock. Cellular thermal shift assay (CETSA) was applied for experimental valuation. RESULTS: Our data demonstrated that asiatic acid induced cell death in multiple ways, including reactive oxygen species production, adenosine triphosphate (ATP) content reduction, and adaptive immunity balance via intrinsic apoptosis, AMP-activated protein kinase (AMPK), programmed death-ligand 1 (PD-L1), and indirect nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional pathways, using experimental validation and in silico analysis. Moreover, asiatic acid also enhanced the sensitivity of doxorubicin-resistant MCF-7 cells to doxorubicin by improving P-glycoprotein (P-gp) function. CONCLUSIONS: This study provides evidence that asiatic acid has strong anticancer effects to reverse multidrug resistance and could be developed as a promising adjuvant drug for the treatment of chemoresistant cancer.

Tanshinol Alleviates Microcirculation Disturbance and Impaired Bone Formation by Attenuating TXNIP Signaling in GIO Rats.

Impaired bone formation is the main characteristics of glucocorticoid (GC)-induced osteoporosis (GIO), which can be ameliorated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. However, the underlying mechanism is still not entirely clear. In the present study, we determined the parameters related to microstructure and function of bone tissue, bone microcirculation, and TXNIP signaling to investigate the beneficial effects of tanshinol on skeleton and its molecular mechanism in GIO rats. Male Sprague-Dawley rats aged 4 months were administrated orally with distilled water (Con), tanshinol (Tan, 25 mg kg-1 d-1), prednisone (GC, 5 mg kg-1 d-1) and GC plus tanshinol (GC + Tan) for 14 weeks. The results demonstrated that tanshinol played a significant preventive role in bone loss, impaired microstructure, dysfunction of bone metabolism and poor bone quality, based on analysis of correlative parameters acquired from the measurement by using Micro-CT, histomorphometry, ELISA and biomechanical assay. Tanshinol also showed a significant protective effect in bone microcirculation according to the evidence of microvascular perfusion imaging of cancellous bone in GIO rats, as well as the migration ability of human endothelial cells (EA.hy926, EA cells). Moreover, tanshinol also attenuated GC-elicited the activation of TXNIP signaling pathway, and simultaneously reversed the down-regulation of Wnt and VEGF pathway as manifested by using Western-blot method in GIO rats, EA cells, and human osteoblast-like MG63 cells (MG cells). Collectively, our data highlighted that tanshinol ameliorated poor bone health mediated by activation of TXNIP signaling via inhibiting microcirculation disturbance and the following impaired bone formation in GIO rats.

Asiatic acid protects articular cartilage through promoting chondrogenesis and inhibiting inflammation and hypertrophy in osteoarthritis.

Natural small molecules have become attractive in osteoarthritis (OA) treatment. This study aims to investigate the effect of asiatic acid (AA) on OA development in vitro and in vivo. Chondrocytes were pretreated with AA at optimized concentrations and subsequently treated with interleukin-1 beta (IL-1ß). Inflammatory mediator nitric oxide (NO) was measured by Griess method. The mRNA expression level of inflammatory markers nitric oxide synthase (iNOS) and cyclooxygenase 2 (Cox2), as well as chondrogenic or hypertrophic markers including SRY-box transcription factor 9 (Sox9), Aggrecan, Collagen 2a1 (Col II), and Matrix metalloproteinase-13 (Mmp13) were measured by using real-time PCR analysis. The nuclear factor-kappa B (NF-κB) signaling activity was determined by dual luciferase assay and Western blot analysis. Surgery-induced OA animal model was constructed, and AA was administrated to study its effect on OA pathogenesis. AA induced a dose-dependent inhibitory effect up to -67.4% on NO production. AA could repress iNOS and Cox2 protein expression levels (-77.2% and -73.4%, respectively) in IL-1ß induced chondrocytes. AA increased the formation of cartilage extracellular matrix components including glycosaminoglycans (GAGs) and collagen type II. AA also mRNA expression of chondrogenesis marker including Aggrecan, Sox9, Col II and Fibronectin (402.87%, 151.04%, 314.15% and 187.76%, respectively) as well as hypertrophic marker Mmp13 (-67.8%). AA repressed the chondrocyte inflammation by directly inhibiting NF-κB signaling activity, which was revealed by the inhibition effect of AA on IκBα phosphorylation (-105.4%) and NF-κB/p65 translocation (-60.9%) induced by IL-1ß. Furthermore, In vivo OA study indicated the protective effect of AA on OA progression by preventing articular cartilage from degeneration and destruction. AA treatment could significantly reduce OA score (16.125 vs 5.25) and repress mRNA expression level of Mmp13 and Col X (23.5, vs 2.375 and 18.125 vs 94.5). Taken together, our findings suggest that AA could effectively rescue IL-1ß induced chondrocytes and protected cartilage in OA progression, which shed light on a potential novel therapeutic strategy of OA treatment.

Identification of SHMT2 as a Potential Prognostic Biomarker and Correlating with Immune Infiltrates in Lung Adenocarcinoma.

It has attracted growing attention that the role of serine hydroxy methyl transferase 2 (SHMT2) in various types of cancers. However, the prognostic role of SHMT2 in lung adenocarcinoma (LUAD) and its relationship with immune cell infiltration is not clear. In this study, the information of mRNA expression and clinic data in LUAD were, respectively, downloaded from the GEO and TCGA database. We conducted a biological analysis to select the signature gene SHMT2. Online databases including Oncomine, GEPIA, TISIDB, TIMER, and HPA were applied to analyze the characterization of SHMT2 expression, prognosis, and the correlation with immune infiltration in LUAD. The mRNA expression and protein expression of SHMT2 in LUAD tissues were higher than in normal tissue. A Kaplan-Meier analysis showed that patients with lower expression level of SHMT2 had a better overall survival rate. Multivariate analysis and the Cox proportional hazard regression model revealed that SHMT2 expression was an independent prognostic factor in patients with LUAD. Meanwhile, the gene SHMT2 was highly associated with tumor-infiltrating lymphocytes in LUAD. These results suggest that the SHMT2 gene is a promising candidate as a potential prognostic biomarker and highly associated with different types of immune cell infiltration in LUAD.

Exploration in the mechanism of fucosterol for the treatment of non-small cell lung cancer based on network pharmacology and molecular docking.

Fucosterol, a sterol isolated from brown algae, has been demonstrated to have anti-cancer properties. However, the effects and underlying molecular mechanism of fucosterol on non-small cell lung cancer remain to be elucidated. In this study, the corresponding targets of fucosterol were obtained from PharmMapper, and NSCLC related targets were gathered from the GeneCards database, and the candidate targets of fucosterol-treated NSCLC were predicted. The mechanism of fucosterol against NSCLC was identified in DAVID6.8 by enrichment analysis of GO and KEGG, and protein-protein interaction data were collected from STRING database. The hub gene GRB2 was further screened out and verified by molecular docking. Moreover, the relationship of GRB2 expression and immune infiltrates were analyzed by the TIMER database. The results of network pharmacology suggest that fucosterol acts against candidate targets, such as MAPK1, EGFR, GRB2, IGF2, MAPK8, and SRC, which regulate biological processes including negative regulation of the apoptotic process, peptidyl-tyrosine phosphorylation, positive regulation of cell proliferation. The Raf/MEK/ERK signaling pathway initiated by GRB2 showed to be significant in treating NSCLC. In conclusion, our study indicates that fucosterol may suppress NSCLC progression by targeting GRB2 activated the Raf/MEK/ERK signaling pathway, which laying a theoretical foundation for further research and providing scientific support for the development of new drugs.

Rejuvenated ageing mesenchymal stem cells by stepwise preconditioning ameliorates surgery-induced osteoarthritis in rabbits.

AIMS: Ageing-related incompetence becomes a major hurdle for the clinical translation of adult stem cells in the treatment of osteoarthritis (OA). This study aims to investigate the effect of stepwise preconditioning on cellular behaviours in human mesenchymal stem cells (hMSCs) from ageing patients, and to verify their therapeutic effect in an OA animal model. METHODS: Mesenchymal stem cells (MSCs) were isolated from ageing patients and preconditioned with chondrogenic differentiation medium, followed by normal growth medium. Cellular assays including Bromodeoxyuridine / 5-bromo-2'-deoxyuridine (BrdU), quantitative polymerase chain reaction (q-PCR), ß-Gal, Rosette forming, and histological staining were compared in the manipulated human mesenchymal stem cells (hM-MSCs) and their controls. The anterior cruciate ligament transection (ACLT) rabbit models were locally injected with two millions, four millions, or eight millions of hM-MSCs or phosphate-buffered saline (PBS). Osteoarthritis Research Society International (OARSI) scoring was performed to measure the pathological changes in the affected joints after staining. Micro-CT analysis was conducted to determine the microstructural changes in subchondral bone. RESULTS: Stepwise preconditioning approach significantly enhanced the proliferation and chondrogenic potential of ageing hMSCs at early passage. Interestingly, remarkably lower immunogenicity and senescence was also found in hM-MSCs. Data from animal studies showed cartilage damage was retarded and subchondral bone remodelling was prevented by the treatment of preconditioned MSCs. The therapeutic effect depended on the number of cells applied to animals, with the best effect observed when treated with eight millions of hM-MSCs. CONCLUSION: This study demonstrated a reliable and feasible stepwise preconditioning strategy to improve the safety and efficacy of ageing MSCs for the prevention of OA development. Cite this article: Bone Joint Res 2021;10(1):10-21.

Fucoxanthin attenuates LPS-induced acute lung injury via inhibition of the TLR4/MyD88 signaling axis.

Acute lung injury (ALI) is a critical clinical condition with a high mortality rate. It is believed that the inflammatory storm is a critical contributor to the occurrence of ALI. Fucoxanthin is a natural extract from marine seaweed with remarkable biological properties, including antioxidant, anti-tumor, and anti-obesity. However, the anti-inflammatory activity of Fucoxanthin has not been extensively studied. The current study aimed to elucidate the effects and the molecular mechanism of Fucoxanthin on lipopolysaccharide-induced acute lung injury. In this study, Fucoxanthin efficiently reduced the mRNA expression of pro-inflammatory factors, including IL-10, IL-6, iNOS, and Cox-2, and down-regulated the NF-κB signaling pathway in Raw264.7 macrophages. Furthermore, based on the network pharmacological analysis, our results showed that anti-inflammation signaling pathways were screened as fundamental action mechanisms of Fucoxanthin on ALI. Fucoxanthin also significantly ameliorated the inflammatory responses in LPS-induced ALI mice. Interestingly, our results revealed that Fucoxanthin prevented the expression of TLR4/MyD88 in Raw264.7 macrophages. We further validated Fucoxanthin binds to the TLR4 pocket using molecular docking simulations. Altogether, these results suggest that Fucoxanthin suppresses the TLR4/MyD88 signaling axis by targeting TLR4, which inhibits LPS-induced ALI, and fucoxanthin inhibition may provide a novel strategy for controlling the initiation and progression of ALI.

Development of small molecule inhibitors/agonists targeting STING for disease.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) -stimulator of interferon genes (STING) signaling pathway is the primary immune response pathway in the cytoplasm. Pharmacological regulation of the STING pathway has good characteristics in both structure and function, which plays a significant role in the immunotherapy of autoimmune diseases, autoinflammatory diseases, and cancer. In this review, we summarized the activation of STING signaling pathway, the STING-related diseases, the development principle and the latest progress of inhibitors and agonists targeting STING. Our review demonstrates that STING signal pathway is a promising drug target, providing effective clues and correct guidance for the discovery of novel small molecule inhibitors/agonists that targeted STING for cancer, autoimmune, and inflammatory diseases.

Parthenolide inhibits the growth of non-small cell lung cancer by targeting epidermal growth factor receptor.

BACKGROUND: EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of EGFR mutated NSCLC. Parthenolide, a natural product of parthenolide, which belongs to the sesquiterpene lactone family and has a variety of biological and therapeutic activities, including anti-cancer effects. However, its effect on non-small cell lung cancer is little known. METHODS: The CCK8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell apoptosis. In silico molecular docking was used to evaluate the binding of parthenolide to EGFR. Network pharmacology analysis was was used to evaluate the key gene of parthenolide target NSCLC. Western blotting was used to evaluate the key proteins involved apoptosis and EGFR signalling. The effect of parthenolide treatment in vivo was determined by using a xenograft mouse model. RESULTS: In this study, parthenolide could induce apoptosis and growth inhibition in the EGFR mutated lung cancer cells. Parthenolide also reduces the phosphorylation of EGFR as well as its downstream signaling pathways MAPK/ERK and PI3K/Akt. Molecular docking analysis of EGFR binding site with parthenolide show that the anti-cancer effect of parthenolide against NSCLC is mediated by a strong binding to EGFR. Network pharmacology analysis show parthenolide suppresses NSCLC via inhibition of EGFR expression. In addition, parthenolide inhibits the growth of H1975 xenografts in nude mice, which is associated with the inhibition of the EGFR signaling pathway. CONCLUSIONS: Taken together, these results demonstrate effective inhibition of parthenolide in NSCLC cell growth by targeting EGFR through downregulation of ERK and AKT expression, which could be promisingly used for patients carrying the EGFR mutation.

TMPRSS2 Correlated With Immune Infiltration Serves as a Prognostic Biomarker in Prostatic Adenocarcinoma: Implication for the COVID-2019.

Type 2 transmembrane serine protease (TMPRSS2) is a new member of the serine proteases, and studies have shown that TMPRSS2 plays a role in the occurrence of prostate malignancies and is closely related to the occurrence of the coronavirus disease 2019 (COVID-19). However, the role of TMPRSS2 in prostatic adenocarcinoma (PRAD) remains largely unclear. To better explore its function in PRAD, we examined the expression level of TMPRSS2 in the GEO, tumor immune assessment resource (TIMER), as well as Oncomine databases and studied the association between TMPRSS2 and overall survival (OS) rates in the UALCAN and gene expression profiling interactive analysis (GEPIA) databases. In addition, we studied the correlation of the level of immune infiltration and markers of immune cell type in the TIMER database, analyzed the prognosis based on the expression level of TMPRSS2 in the related immune cell subsets, and determined the methylation profile of TMPRSS2 promoter by UALCAN database. Subsequently, we conducted a survival analysis and gene ontology (GO) pathway analysis in the TISID database and detected the expression of TMPRSS2 in the Human Protein Atlas (HPA) database. We also studied the protein-protein interaction (PPI) network of TMPRSS2 in the GENEMANIA database. Additionally, we used the microarray GSE56677 and GSE52920 to illustrate changes in TMPRSS2 expression in vivo and in vitro after severe acute respiratory syndrome-coronavirus (SARS-COV) infection, finding that expression of TMPRSS2 decreased after SARS-COV infection in vitro. The function of TMPRSS2 in the dataset was further verified by gene set enrichment analysis (GSEA). In conclusion, the expression of TMPRSS2 is significantly increased in PRAD, elevated TMPRSS2 is associated with immune infiltration, and prognosis is positively correlated. In addition, tumor tissue from COVID-19 patients with PRAD may be more susceptible to infection with SARS-COV-2, which may render the prognosis gets worse.

Peptide-Decorated Supramolecules for Subcellular Targeted Cancer Therapy: Recent Advances.

Binding small molecules through non-covalent molecular forces affords supramolecules, such as hydrogen bonds, with electrostatic, π-π interactions, van der Waals forces, and hydrophobic effects. Due to their good biocompatibility, low immunogenicity, and biodegradability, supramolecules have been intensely studied as multifunctional drug delivery platforms in targeted cancer therapy. In consideration of the defective therapeutic efficacy induced by simply transporting the therapeutic agents into tumor tissues or cancer cells instead of subcellular organelles, research is progressing toward the development of subcellular targeted cancer therapy (STCT) strategies. STCT is one of the most recent developments in the field of cancer nanomedicine. It is defined as the specific transportation of therapeutic agents to the target organelles for cancer treatment, which makes therapeutic agents accumulate in the target organelles at higher concentrations than other subcellular compartments. Compared with tumor-targeted and cancer-cell-targeted therapies, STCT exhibits dramatically improved specificity and precision, diminished adverse effects, and enhanced capacity to reverse multidrug resistance (MDR). Over the past few decades, peptides have played increasingly essential roles in multi-types of tumor-targeted drug delivery systems. Moreover, peptide-mediated STCT is becoming an emerging approach for precision cancer therapy and has been used in various cancer treatments, such as photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy, gene therapy, and non-drug-loaded nanoassemblies. In this review, we will focus on recent innovations in the variety of peptides used in designing peptide-decorated supramolecules for cell-membrane-, mitochondria-, and nucleus-localized STCT.

The SP1-Induced Long Noncoding RNA, LINC00339, Promotes Tumorigenesis in Colorectal Cancer via the miR-378a-3p/MED19 Axis.

INTRODUCTION: Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) are pivotal regulators involved in the pathogenesis of cancer; however, the molecular mechanism of LINC00339 in colorectal cancer (CRC) remains unclear. METHODS: The quantitative real-time polymerase chain reaction for the expression of LINC00339 and miR-378a-3p and Western blots for MED19 were performed. A dual-luciferase assay was used to investigate the interaction between LIN00339 and miR-378a-3p, as well as between miR-378a-3p and MED19. Cell proliferation was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) assay. The cell cycle was analyzed by propidium iodide staining followed by flow cytometry analysis. The wound-healing and transwell invasion assays were used to evaluate cell migration and invasion. RESULTS: The expression of LINC00339 was significantly upregulated in CRC cells and tissues, and high LINC00339 expression indicated an advanced tumor stage. Further experiments demonstrated that SP1 activated LINC00339 expression by binding to its promoter region. Luciferase activity and RNA pull-down assays demonstrated a direct interaction between LINC00339 and miR-378a-3p. miR-378a-3p expression was decreased in CRC samples and negatively correlated with LINC00339 expression in tumors. Gain- and loss-of-function assays indicated that LINC00339 contributed to cell proliferation, cell cycle progression, migration, and invasion, while miR-378a-3p reversed these effects. Furthermore, cotransfection of wild-type MED19 3'-UTR reporters and miR-378a-3p significantly reduced luciferase activity. MED19 mRNA and protein expression was inhibited and enhanced by miR-378a-3p and LINC00339, respectively. MED19 overexpression reversed the effect of miR-378a-3p on cellular processes. Moreover, LINC00339 promoted tumor growth in vivo and induced epithelial-mesenchymal transition (EMT) and activated the Wnt/ß-catenin signaling pathway in cells. CONCLUSION: Our findings demonstrate the regulatory role of the SP1/LINC00339/miR-378a-3p/MED19 axis in CRC tumorigenesis and provide novel insight into the molecular mechanism underlying CRC.

Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully.

Tumor-infiltrating lymphocytes (TILs) are infiltrating lymphocytes in tumor tissues. After isolation, screening and amplification in vitro, they will be implanted into patients and play a specific killing effect on tumors. Since TILs have not been genetically modified and come from the body of patients, there will be relatively few adverse reactions. This is also the advantage of TIL treatment. In recent years, its curative effect on solid tumors began to show its sharpness. However, due to the limitations of the immune microenvironment and the mutation of antigens, TIL's development was slowed down. This article reviews the research progress, biological characteristics, preparation and methods of enhancing the therapeutic effect of tumor-infiltrating lymphocytes, their roles in different tumors and prognosis, and emphasizes the important value of tumor-infiltrating lymphocytes in anti-tumor.

Cancer neoantigen: Boosting immunotherapy.

Tumor neoantigen has a high degree of immunogenicity. As one of the emerging methods of tumor immunotherapy, the vaccine developed against it has served to clinical trials of various solid tumors, especially in the treatment of melanoma. Currently, a variety of immunotherapy methods have been applied to the treatment of the tumor. However, other therapeutic methods have the disadvantages of low specificity and prominent side effects. Treatments require tumor antigen with higher immunogenicity as the target of immune attack. This review will recommend the identification of neoantigen, the influencing factors of neoantigen, and the application of personalized vaccines for neoantigen in metastatic tumors such as malignant melanoma.