Review Article
Junhua Liao; Tang Zhu; Jie Wu; Mingyu Huang; Xianxian Luo
Abstract
Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular ...
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Transforming growth factor-β (TGF-β) signaling plays a complex and dual role in regulating cellular senescence and tumor progression. In normal tissues, TGF-β acts as a tumor suppressor by regulating the cell cycle, inducing apoptosis, and maintaining the integrity of the extracellular matrix (ECM). These functions collectively restrict tumor initiation and support tissue homeostasis. However, in the tumor microenvironment, sustained TGF-β signaling frequently switches to a tumor-promoting role, driving tumor cell proliferation, metastatic dissemination, immune evasion, and therapy resistance. This review aims to clarify the dual role of TGF-β signaling in cellular senescence and tumor progression. It focuses on the molecular mechanisms that drive its transition between tumor suppression and tumor promotion in various biological contexts. We analyze the key determinants governing this functional switch, including tumor type, cellular environment, and signaling crosstalk. Furthermore, we critically evaluate the clinical challenges of therapeutic TGF-β targeting. We highlight emerging strategies to therapeutically modulate TGF-β signaling, focusing on precision medicine approaches that reconcile its tumor-suppressive and oncogenic functions. By providing a comprehensive understanding of TGF-β's dual role, this review offers new insights that may guide personalized cancer therapies and optimize treatment strategies for improved clinical outcomes.
Original Article
Jafar Mahmoudian; Roya Ghods; Mahmood Jeddi-Tehrani; Nassim Ghaffari-Tabrizi-Wizsy; Mohammad Reza Nejadmoghaddam; Ramin Ghahremanzadeh; Seyed Nasser Ostad; Amir-Hassan Zarnani
Abstract
Background: Placenta-specific 1 (PLAC1) is one of the oncoplacental genes ectopically expressed in various cancers. Antibody-drug conjugates (ADC) have the potential to substantially improve efficacy and reduce toxicity of treatment compared with cytotoxic small-molecule drugs. They have recently been ...
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Background: Placenta-specific 1 (PLAC1) is one of the oncoplacental genes ectopically expressed in various cancers. Antibody-drug conjugates (ADC) have the potential to substantially improve efficacy and reduce toxicity of treatment compared with cytotoxic small-molecule drugs. They have recently been employed to treat cancers.
Objective: To examine the efficacy of an SN38-conjugated monoclonal anti-PLAC1 antibody in breast cancer.
Methods: Anti-human PLAC1 monoclonal antibodies were produced and characterized. SN38 was conjugated to an anti-PLAC1 antibody (clone: 2H12C12) and conjugation efficacy was evaluated by UV spectrophotometry. Post-conjugation reactivity was then tested using ELISA and flow cytometry. In vitro, cytotoxicity profiling of 2H12C12-SN38 was examined on MDA-MB-231 breast cancer cells using a fluorimetric assay. The effect of 2H12C12-SN38 on MDA-MB-231 tumor growth and angiogenesis ex vivo was tested by chorioallantoic membrane (CAM) assay followed by immunohistochemical analysis of the tumor. Pharmacokinetics of 2H12C12-SN38 in mice was measured by successive venipuncture after ADC administration. Inhibitory effects of anti-PLAC1 ADC on tumor growth were assessed in a nude mice xenograft model of human breast cancer.
Results: Anti-PLAC1 ADC exerted a substantial cytotoxicity on MDA-MB-231 cells starting from a concentration of about 33 nM. ADC also significantly decreased the growth of MDA-MB-231 tumors on CAM assay but did not show a significant effect on tumor angiogenesis. Pharmacokinetics of anti-PLAC1 ADC in mice showed an average half-life (t1/2) of about 80 hours.
Conclusion: Treatment of nude mice with ADC resulted in a significant decrease in tumor size compared to isotype-matched antibody-SN38 conjugate, unconjugated anti-PLAC1 antibody, or free SN38.
Short Paper
Bo Dong; Wenqian Hu; Shuo Zhang; Xiaodong Zhang; Weijie Zou; Yina Guo; Weiming Lin
Abstract
Background: Currently, there is no effective vaccine against feline coronavirus infections. The coronavirus Spike (S) protein plays a critical role in viral binding to cell receptors and contains multiple neutralizing antibody epitopes that trigger the host's immune response to combat infection. Selecting ...
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Background: Currently, there is no effective vaccine against feline coronavirus infections. The coronavirus Spike (S) protein plays a critical role in viral binding to cell receptors and contains multiple neutralizing antibody epitopes that trigger the host's immune response to combat infection. Selecting an optimized adjuvant is essential to ensure robust vaccine-induced immunity against pathogenic infections.Objectives: To produce a recombinant S protein for the development of subunit vaccines and evaluate the immune responses elicited by different adjuvants.Methods: In this study, we developed three subunit vaccines incorporating distinct adjuvants: Alh, ISA201, and CFA FCoV-SP. BALB/c mice were immunized three times via subcutaneous injections with each vaccine formulation. Serum samples were then analyzed to evaluate S protein-specific IgG levels and cytokine concentrations using enzyme-linked immunosorbent assay (ELISA), assessing the magnitude and nature of the vaccine-induced immune responses.Results: The ISA201 FCoV-SP vaccine induced significantly higher total IgG levels than those in the Alh or CFA groups. All tested protein concentrations resulted in increased serum IgG antibody levels, with the optimal immune dose of recombinant S protein being 15 µg/dose. Additionally, the ISA201 FCoV-SP vaccine led to increased expression of interferon-γ, interleukin-8, and tumor necrosis factor-α.Conclusion: Collectively, our findings suggest that ISA201 serves as the most effective adjuvant for a recombinant S protein subunit vaccine against FCoV. Additionally, the subunit vaccine developed in this study exhibited acceptable immune responses in mice.
Original Article
Trefa Mohammed Abdullah
Abstract
Background: Antitumor-targeting drugs can stimulate dendritic cells (DCs) indirectly through the shedding of dying tumor cells as part of what is referred to as a “danger signal”. Although chemotherapeutic agents have been shown to kill dendritic cells (DCs), the effects of low, non-cytotoxic ...
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Background: Antitumor-targeting drugs can stimulate dendritic cells (DCs) indirectly through the shedding of dying tumor cells as part of what is referred to as a “danger signal”. Although chemotherapeutic agents have been shown to kill dendritic cells (DCs), the effects of low, non-cytotoxic doses on DC function have not been studied.Objective: To investigate the impact of various concentrations of mitomycin C at low, non-cytotoxic doses on the maturation of DCs.Material and Methods: THP-1 monocytes were differentiated into immature dendritic cells using IL-4 and GM-CSF. HCT116 colorectal cancer cells were treated with mitomycin C at concentrations ranging from 10 to 80 nM and co-cultured with undifferentiated dendritic cells. The expression of co-stimulatory molecules (CD11c, CD80, CD83, CD86, HLA-DR, CD14) and IL-12p70 secretion were measured.Results: Different dosages of Mitomycin C-treated HCT116 cells enhanced the maturation of dendritic cell markers (CD80, CD83, CD86, HLA-DR), but reduced CD14 levels (p< 0.01). While increasing the Mitomycin C dose to 80 nM further upregulated HLA-DR and CD86 expression, the release of IL-12 was highest a 50 nM concentration of mitomycin C (686.7 ± 125.7 pg/mL compared to 263.8 ± 4.8 pg/mL in controls; p < 0.05). IL-12 levels were not significantly increased even with 30 nM Mitomycin C.Conclusion: Low concentrations of Mitomycin C contributed to an increase in dendritic cellmaturation and an increase in the expression of co-stimulatory molecules (CD80, CD86, CD83, and HLA-DR), along with the secretion of cytokines such as IL-12p70, IL-2, and GM-CSF.
Original Article
Hassan Abolhassani; Nima Rezaei; Reza Yazdani; Somaye Aletaha; Saied Bokaie; Laleh Sharifi; Abbas Mirshafiey
Abstract
Background: Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by a defect in terminal B cell differentiation, resulting in hypogammaglobulinemia and impaired production of specific antibodies. Stimulation via Toll-like receptors (TLRs) has been shown to promote the ...
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Background: Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by a defect in terminal B cell differentiation, resulting in hypogammaglobulinemia and impaired production of specific antibodies. Stimulation via Toll-like receptors (TLRs) has been shown to promote the differentiation and functional maturation of late-stage B cells.
Objective: To assess aberrations in TLR2 signaling among patients with CVID and to explore their associations with clinical manifestations and immunological parameters.
Methods: Sixteen CVID patients and 16 healthy controls were recruited for this individual-matched case-control study. Genetic variants in patients had been previously identified through whole-exome sequencing. TLR2 and TLR4 downstream gene expression were analyzed using qRT-PCR, while cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Statistical associations between clinical features and laboratory parameters were analyzed using SPSS software.
Results: Downstream gene expression following TLR2 stimulation was significantly reduced in 25% of CVID patients, while the TLR4 signaling pathway remained largely unaffected. Patients exhibiting TLR2 overexpression demonstrated a later disease onset, presenting with autoimmunity, lymphoproliferation, and atopic manifestations. A consistent immunologic feature among patients with defective TLR2 signaling was the reduction in marginal zone and switched memory B cell populations. Furthermore, Levels of IL-6 and IL-1β following agonist stimulation were significantly lower in CVID patients compared to healthy controls.
Conclusion: This study demonstrates that functional impairment of TLR2 signaling influences the clinical presentation, immunologic profile, and cytokine production in patients with CVID. These findings suggest a potential underlying etiology in a subset of patients with unidentified monogenic defects.
Original Article
Mohammadreza Rahmani; Shahram Nazarian; Hossein Samiei-Abianeh; Seyed Mojtaba Aghaie; Davoud Sadeghi
Abstract
Background: Stonefish (Synanceia spp.) are among the most venomous marine organisms. Their venom contains stonustoxin (SNTX), a heterodimeric toxin that induces severe hemolytic and myotoxic effects primarily mediated by its β-subunit.Objective: To produce a recombinant SNTX β-subunit ...
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Background: Stonefish (Synanceia spp.) are among the most venomous marine organisms. Their venom contains stonustoxin (SNTX), a heterodimeric toxin that induces severe hemolytic and myotoxic effects primarily mediated by its β-subunit.Objective: To produce a recombinant SNTX β-subunit and develop neutralizing polyclonal antibodies against SNTX.Methods: A DNA cassette encoding immunogenic regions of the β-sntx was designed using bioinformatics analysis, and codon-optimized for expression in E. coli. The construct was cloned into pET17b vector, and expressed in E. coli BL21 (DE3). The recombinant protein was purified via Ni-NTA affinity chromatography. For antibody production, rabbits were immunized subcutaneously with the recombinant protein emulsified in Freund's complete adjuvant, followed by booster doses at 2-week intervals. Antiserum was purified using protein G chromatography, and antibody titers were assessed by indirect Enzyme-Linked Immunosorbent Assay (ELISA).Results: Epitope mapping revealed key immunogenic regions within residues 124–654 of the β-SNTX subunit. Following codon optimization, the codon adaptation index (CAI) increased to 0.93. Recombinant protein production was confirmed by SDS-PAGE and Western blot demonstrating successful purification of a 73 kDa recombinant protein (including TRX/His-tags), with a yield of 40 mg/L. Immunization of rabbits elicited a strong polyclonal IgG response, with antibody titers reaching 1:25,600 following the third booster. Purified IgG (1.8 mg/mL) exhibited high sensitivity in ELISA, detecting the recombinant β-SNTX at concentrations as low as 31.25 ng.Conclusion: The recombinant β-SNTX subunit demonstrated strong immunogenicity, inducing high-affinity antibodies with specific binding activity against the native toxin. The resulting antiserum demonstrated significant neutralization potential, highlighting its promise for antivenom development.
Original Article
Zohre Labbani-Motlagh; Zohreh Nozarian; Mohammad Taghi Haghi Ashtiani; Sajjadeh Movahedinia; Mohammad Vasei; Negin Hosseini Rouzbahani
Abstract
Background: Coronavirus Disease 2019 (COVID-19) typically manifests with milder symptoms and lower mortality rates in children when compared to adults.Objective: To investigate potential mechanisms underlying this age-related protection, we examined whether serum levels of angiotensin-converting ...
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Background: Coronavirus Disease 2019 (COVID-19) typically manifests with milder symptoms and lower mortality rates in children when compared to adults.Objective: To investigate potential mechanisms underlying this age-related protection, we examined whether serum levels of angiotensin-converting enzyme 2 (ACE2) and IgG antibody titers against Measles, Mumps, and Rubella (MMR) vaccines are associated with susceptibility to SARS-CoV-2 infection in the pediatric population.Methods: In this case-control study, conducted before the introduction of mass COVID-19 vaccination, we enrolled children aged 1–15 years. The cases were hospitalized children with confirmed COVID-19, while the control group consisted of outpatients with non-infectious, non-immunodeficient conditions and no documented history of COVID-19. The COVID-19 status was confirmed using RT-PCR. Serum levels of ACE2 and anti-MMR IgG antibodies were assessed using ELISA.Results: Eighty-three patients including 39 cases with COVID-19 infection and 44 controls were enrolled in this study. The median serum ACE2 levels were 3.6 in COVID-19 cases and 3.8 ng/mL in control cases (P=0.440). Similarly, antibody levels against Mumps (P=0.788), Measles (P=0.281), and Rubella (P=0.083) did not differ significantly between the groups, although Rubella seropositivity was more frequent in COVID-19 cases than in controls (P=0.039).Conclusions: Our findings did not support a significant association between serum ACE2 levels or MMR antibody titers and protection against COVID-19 in children. The higher prevalence of Rubella seropositivity among infected cases may suggest possible cross-reactivity, but causal relationships could not be established in this study.
