New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Май 18, 2023

Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When endoplasmic reticulum (ER) was stressed, translocated to cell surface, mitochondria, and nucleus complexed other proteins execute its functions. On HSPA5/BiP/GRP78 can play diverse functional roles in viability, proliferation, apoptosis, attachments, innate adaptive immunity regulations, which lead various diseases, including cancers coronavirus disease 2019 (COVID-19). COVID-19 caused severe acute respiratory syndrome 2 (SARS-CoV-2) infection, pandemic since first outbreak late December 2019. HSPA5, highly expressed malignant tumors, likely plays critical role SARS-CoV-2 invasion/attack cancer patients via tumor tissues. In current study, we review newest research progresses surface expressions, functions, mechanisms for invasion. The therapeutic prognostic significances prospects targeting are also discussed. Targeting expression natural products may imply significance clinical both anti-COVID-19 anti-cancers future.

Язык: Английский

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Editorial: Community series in adenosine pathways in cancer immunity and immunotherapy, volume II

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Янв. 29, 2025

1.Cancer Immunity and ImmunotherapyCancer immunity refers to the impressive ability of immune system recognize eliminate cancerous cells in body. This complex defense mechanism involves various types cells, including T natural killer cells. These work together identify abnormal that may lead tumor formation, thereby protecting body from cancer progression. By effectively distinguishing between healthy those could be harmful, plays a vital role maintaining overall health preventing spread (1). process is essential because can develop normal find ways evade response. Understanding enhancing crucial research treatment, as these efforts more effective therapies better patient outcomes.Immunotherapy gaining recognition significant approach treating cancer. method includes innovative techniques, such checkpoint inhibitors CAR T-cell therapies, which empower body's combat effectively. Nevertheless, key challenge optimizing treatments accommodate broader range patients (2). Researchers emphasize microenvironment—the area surrounding influence treatment efficacy. A component this environment adenosine signaling. Tumors manipulate pathway deceive system, it launching an attack. Consequently, targeting signaling promising improve (3; 4). Immune block proteins suppress responses, system's attack therapy modifies patient's express chimeric antigen receptors (CARs) target specific antigens, allowing destroy However, tumors often create hostile environments partly through signaling, inhibits activity. Ongoing aims understand interactions immunotherapy effectiveness by pathways like would ultimately enhance responses (5).2.Adenosine receptorsAdenosine, purine nucleoside, primarily produced under low oxygen conditions, found microenvironment. Elevated levels act potent immunosuppressive metabolite. compound influences innate adaptive systems binding on inhibiting their activation function. exploit response, promoting altered landscape supports growth metastasis. Tumor generate enzymatic activities ecto-nucleotide triphosphate diphosphohydrolase-1 ecto-5'-nucleotidase, convert ATP adenosine. leads promotes how affects our for developing diseases levels, hypoxic metabolite, function (NK) are fighting off (6). Adenosine summarized Figure 1. binds suppressing response cell proliferation, reducing cytokine production, regulatory differentiation. creates conditions allow detection, supporting metastasis while hindering Additionally, accumulation other (4). Therefore, help defenses against existing (https://www.frontiersin.org/journals/immunology/ articles/10.3389/fimmu.2024.1455469/full). In addition, some adenosinederivatives play roles targeted gene (7).Adenosine G protein-coupled mediate effects adenosine, nucleoside. There four main types: A1, A2A, A2B, A3, each with functions tissue distributions. Among them, A1 inhibitory predominantly located central nervous tissues throughout When activated, they initiate cascade typically decrease cellular also release neurotransmitters communication nerve Activating several physiological effects, reduction heart rate enhanced sleep promotion, making them players regulating cardiovascular patterns. A2A excitatory brain, vascular smooth muscle. They promote vasodilation regulate mainly linked tumors. inhibit support growth. Moreover, A2B present tissues, mediating inflammation allergic responses. permeability angiogenesis biology. Meanwhile, A3 involved anti-inflammatory apoptosis lungs, asthma (8).In cancer, manipulating enables environment, evading detection destruction system. Targeting receptors, especially being explored strategy The or antagonize reinvigorate activity clinical outcomes (4) 3.Targeting therapyCurrent strategies aim its production receptors. enhances potentially rejuvenating Combining receptor antagonists antitumor beyond single-agent highlighting need personalized plans considering tumor's unique presents immunotherapy. restore enzymes responsible blocking involve combining immunotherapeutic agents, inhibitors, achieve synergistic effects. Current initiatives increasingly directing attention toward Approaches adenosine-generating enzymes, CD26 CD39, have potential (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1434118/full). disrupting rejuvenate Tim3 A2a solid caution needed, single knockdown MSLN-CAR resulted decreased survival mice, emphasizing importance careful efficacy assessments (https://www.frontiersin.org/journals/ immunology/articles/10.3389/fimmu.2024.1362904/full). Besides, disintegrin metalloproteinase domain-10 (ADAM10) surface protein cleaved numerous proteins; inhibited expression ADAM10 modulated different malignant cancers articles/10.3389/fimmu.2024.1434027/full).3.1.Adenosine adenosine's action at counteracting compounds been extensively studied agents proliferation boost production. enhancement allows Istradefylline (KW-6002) selective antagonist has Parkinson's disease. ongoing investigates applications treatment. Another antagonist, talonapride, shown results preclinical studies. AB928 dual tested trials. DPI-287 another targets currently investigated therapy. specifically demonstrated beneficial across types. instrumental angiogenesis—processes utilize ZM241385 MRS1754 commonly employed investigate pharmacological receptor. TS-1 further therapeutic treatment.A1 infrequently elevated increase neurotransmitter release, whereas due properties. DPCPX (1,3-dipropyl-8-cyclopentylxanthine) used study receptors—additionally, caffeine non-selective neurotransmitters. Furthermore, MRS1191 IB-MECA contexts, cancer.Several investigation promise patients' outcomes, when combined mitigate created tumors, revitalizing cancer.3.2.Adenosine-generating enzymes' inhibitorsTargeting produce CD38, CD73, Inhibiting reduces significantly infections exciting avenue therapy.Daratumumab monoclonal antibody multiple myeloma. It CD38 myeloma marking inhibitor, isunakinra, undergoing trials cancers, selinexor although primary revolves around XPO1 protein. serves both CD39 CD73 enzymes. inhibition disrupts biochemical molecule contrast, Pz-039 small inhibitor altering metabolism microenvironment anti-tumor immunity. INO-1400 investigational product designed explore harness (9).CD73 include AB680, studies evaluated MPI-0479605, microenvironment, alongside therapies. eflornithine recognized impact contexts. ONO-1780 novel small-molecule presently evaluation assess malignancies (10).Researchers exploring decreasing within improving outcomes. 4.ConclusionA growing highlighted One noteworthy example combination inhibitors. powerful resulting compared using agent. findings underscore critical carefully strategies, context regimens. Such regimens consider characteristics tailoring approaches optimize care.To fully adenosine-targeted treatments, mechanisms behind marked interaction among components signals, requires deeper understanding generated confirm tumorigenesis identifying investigating new pathway. unraveling complexities development creating malignancies.

Язык: Английский

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CTSL, a prognostic marker of breast cancer, that promotes proliferation, migration, and invasion in cells in triple-negative breast cancer

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Июнь 29, 2023

Introduction In the world, incidence of breast cancer has surpassed that lung cancer, and it become first malignant tumor among women. Triple-negative (TNBC) shows an extremely heterogeneous malignancy toward high recurrence, metastasis, mortality, but there is a lack effective targeted therapy. It urgent to develop novel molecular targets in occurrence therapeutics for TNBC, therapeutic strategies block recurrence metastasis TNBC. Methods this study, CTSL (cathepsin L) expression tissues adjacent TNBC patients was monitored by immunohistochemistry western blots. The correlations between expressions clinicopathological characteristics patient were analyzed. Cell proliferation, migration, invasion assay also performed when over-expressed or knocked-down CTSL. Results We found level significantly higher than matched tissues, associated with differentiated degree, TNM Stage, size, lymph node metastatic status patients. correlated short RFS (p<0.001), OS DMFS PPS (p= 0.0025) from online databases; while node-positive, (p<0.001) (p<0.001). Moreover, vitro experiments showed overexpression promotes abilities MCF-7 MDA-MB-231 cell lines, knocking-down decreases its lines. Conclusion might involve into regulation invasion, Thus, would be novel, potential therapeutic, prognostic target

Язык: Английский

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A SARS-CoV-2 related signature that explores the tumor microenvironment and predicts immunotherapy response in esophageal squamous cell cancer

Aging, Год журнала: 2023, Номер 15(19), С. 10501 - 10523

Опубликована: Окт. 6, 2023

Background: The existing therapeutic approaches for combating tumors are insufficient in completely eradicating malignancy, as cancer facilitates tumor relapse and develops resistance to treatment interventions. potential mechanistic connection between SARS-CoV-2 ESCC has received limited attention. Therefore, our objective was investigate the characteristics of SARS-CoV-2-related-genes (SCRGs) esophageal squamous (ESCC). Methods: Raw data were obtained from TCGA GEO databases. Clustering SCRGs scRNA-seq conducted using Seurat R package. A risk signature then generated Lasso regression, incorporating prognostic genes related SCRGs. Subsequently, a nomogram model developed based on clinicopathological signature. Results: Eight clusters identified utilizing data, which three exhibited implications. made up with bulk RNA-seq, displayed substantial correlations immune infiltration. novel verified have excellent efficacy. Conclusion: utilization signatures can efficiently forecast prognosis ESCC. thorough characterization could facilitate interpretation ESCC's response immunotherapy offer innovative therapy.

Язык: Английский

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Changes in Adenosine Deaminase Activity and Endothelial Dysfunction after Mild Coronavirus Disease-2019

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(17), С. 13140 - 13140

Опубликована: Авг. 24, 2023

Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as biomarker of endothelial activation and inflammation, while ADA2 plays critical role in monocyte macrophage function. In this study, investigated the activities circulating ADA isoenzymes patients 8 weeks after mild COVID-19 related them to parameters inflammation microvascular/endothelial Post-COVID revealed microvascular dysfunction associated with changes inflammatory activation. Interestingly, serum total were diminished post-COVID patients, ADA1 remained unchanged comparison healthy controls without prior diagnosis While activity tended positively correspond sICAM-1 TNFα, correlated IL-10. Simultaneously, had lower levels ADA1-anchoring protein, CD26, an alternative receptor virus binding. This suggests infection CD26 is rather maintained cell-attached form, enabling complexing. study points possible cardiovascular complications COVID-19.

Язык: Английский

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Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM)

Life Sciences, Год журнала: 2023, Номер 336, С. 122292 - 122292

Опубликована: Ноя. 27, 2023

Dipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) identified the most important risk factor SARS-CoV-2, and gliptins (DPP4 inhibitors) are prescribed diabetic treatment, this study aims to unravel impact of DPP4 in intersection T2DM/COVID-19.We analyzed 189 serum human samples, divided into six clinical groups (controls, T2DM, T2DM + gliptins, COVID-19, COVID-19 gliptins), measuring protein concentration activity by Western blot, ELISA, commercial kits. The obtained results were verified Huh-7 models.Both decreased patients, compared controls. Despite these lower levels, ratio activity/concentration sera was highest (0.782 ± 0.289 μU/ng vs. 0.547 0.050 controls, p < 0.0001), suggesting compensating mechanism patients. Supernatants cells incubated with showed consistent significantly activity. Furthermore, patients higher than gliptin subjects (p 0.05), indicating from convalescents interfere gliptins.Either or some metabolites present COVID-19-convalescent interact soluble even themselves since inhibitory effect on is being prevented. interactions between DPP4, should be further elucidated reveal action interesting observations.

Язык: Английский

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A disintegrin and metalloproteinase domain 10 expression inhibition by the small molecules adenosine, cordycepin and N6, N6-dimethyladenosine and immune regulation in malignant cancers

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Авг. 15, 2024

A disintegrin and metalloproteinase domain 10 (ADAM10), a member of the ADAM family, is cellular surface protein with potential adhesion protease/convertase functions. The expression regulations in cancers by natural products [adenosine (AD) its analogs, cordycepin (CD), N6, N6-dimethyladenosine (m 6 2 A)], immune regulation are unclear. As results, AD, CD, m inhibited ADAM10 various cancer cell lines, indicating their roles anti-cancer agents. Further molecular docking found binding energies all groups were &lt;-7 kcal/mol for small-molecules (AD, CD A), suggesting very good activities. In addition, analysis immunomodulatory showed that was negatively correlated genes such as CCL27, CCL14, CCL25, CXCR5, HLA-B, HLA-DOB1, LAG3, TNFRSF18, TNFRSF4 bladder urothelial carcinoma, thymoma, breast invasive TGCT, kidney renal papillary SKCM thyroid immune-promoting ADAM10. LAG3 mRNA levels reduced both AD vivo . also associated tumor immunosuppression interrelated infiltration tumors. Overall, present study determined A, or CD/ADAM10/LAG3 signaling cancers, suggested method immunotherapy targeting using small molecules A.

Язык: Английский

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Linking COVID-19 and cancer: Underlying mechanism

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2024, Номер 1871(1), С. 167563 - 167563

Опубликована: Ноя. 5, 2024

Язык: Английский

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Comprehensive analysis, immune, and cordycepin regulation for SOX9 expression in pan-cancers and the matched healthy tissues

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Март 20, 2023

SRY-box transcription factor 9 (SOX9) (OMIM 608160) is a factor. The expression of SOX9 in pan-cancers and the regulation by small molecules cancer cell lines are unclear. In current study, we comprehensively analyzed normal tissues, tumor tissues their matched healthy pan-cancers. study examined correlation between immunomodulators immune infiltrations tissues. Cordycepin (CD), an adenosine analog for regulation, was also conducted on cells. results found that protein expressed variety organs, including high 13 organs no only two organs; 44 there 31 medium four low other seven with 33 types, significantly increased fifteen cancers, CESC, COAD, ESCA, GBM, KIRP, LGG, LIHC, LUSC, OV, PAAD, READ, STAD, THYM, UCES, UCS, but decreased cancers (SKCM TGCT) compared It suggests upregulated most types (15/33) as proto-oncogene. fact decrease SKCM increase melanoma inhibit tumorigenicity both mouse human ex vivo models demonstrates could be suppressor. Further analyzing prognostic values individuals revealed OS long ACC short suggesting positively correlated worst which used maker. addition, CD inhibited mRNA expressions dose-dependent manner 22RV1, PC3, H1975 cells, indicating CD's anticancer roles likely via inhibition. Moreover, might play important role genesis development participating infiltration. Altogether, biomarker diagnostics prognostics emerging target drugs.

Язык: Английский

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Is it possible to identify COVID-19 infection-related biomarkers during pregnancy?: A prospective study in Turkish population

Medicine, Год журнала: 2024, Номер 103(19), С. e38062 - e38062

Опубликована: Май 10, 2024

The coronavirus disease 2019 (COVID-19) has raised concerns about the potential complications it may cause in pregnant women. Therefore, biomarkers that can predict course of COVID-19 women be great benefit as they would provide valuable insights into prognosis and, thus, management disease. In this context, objective study is to identify progression women, focusing on composite hemogram parameters and systemic inflammatory spike markers. population single-center prospective case–control consisted all consecutive with single healthy fetuses who tested positive for were admitted Bakirköy Dr Sadi Konuk Training Research Hospital Istanbul, Turkey, a referral hospital, between April 2020 March 2021, an obstetric indication, during their second or third trimester. control group fetus same hospital within date range, had demographic characteristics matching patient group, but negative COVID-19. groups compared terms platelet-to-lymphocyte ratio (PLR), platelet-to-neutrophil (PNR), neutrophil-to-lymphocyte (NLR), markers, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), cluster differentiation 26 (CD26), B7 homolog 4 (B7H4). There 45 (51.1%) 43 (48.8%) groups, respectively. was no significant difference ( P > .05). PNR, PLR, CRP values significantly higher than < On other hand, there IL-6, IL-10, CD26, B7H4 levels findings our showed specific such CRP, potentially However, more comprehensive, well-controlled studies are needed corroborate study’s investigate

Язык: Английский

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