Current Issues in Molecular Biology

25 pages, 10724 KB

Open AccessArticle

Olive Leaf Extract Suppresses Sebogenesis and Inflammation via AKT/ERK and SREBP-1/PPAR-γ Signaling in Human Sebocytes

by Jeeyoung Kim, Ye-Won Jo, Weon Jeong Bang, Kwang Won Lee, Yung Hyup Joo, Sung Hyeon Lee and Chang-Seok Lee

Curr. Issues Mol. Biol. 2026, 48(6), 549; https://doi.org/10.3390/cimb48060549 (registering DOI) - 23 May 2026

Abstract

This study evaluated olive leaf extract (OLE) as a multifunctional dermocosmetic candidate for sebum-related and inflammatory responses relevant to oily and acne-prone skin using an axis-aligned in vitro panel: (i) sebocyte lipogenesis, (ii) inflammatory mediator production in keratinocytes, and (iii) fibroblast-mediated collagen gel [...] Read more.

This study evaluated olive leaf extract (OLE) as a multifunctional dermocosmetic candidate for sebum-related and inflammatory responses relevant to oily and acne-prone skin using an axis-aligned in vitro panel: (i) sebocyte lipogenesis, (ii) inflammatory mediator production in keratinocytes, and (iii) fibroblast-mediated collagen gel contraction. In addition, supportive mechanistic evidence for the sebum-related effects of OLE was obtained by examining signaling proteins associated with sebocyte lipogenesis, including PPAR-γ and SREBP-1. As a result, OLE significantly inhibited linoleic acid-induced lipid accumulation in SEB-1 sebocytes without cytotoxicity. In HaCaT keratinocytes, OLE significantly reduced the production of pro-inflammatory cytokines, including IL-8, TNF-α, and PGE₂, induced by Cutibacterium acnes or UVB. In dermal fibroblast-containing collagen gels, OLE enhanced fibroblast-mediated gel contraction. Additionally, analysis of the main mechanisms of lipid inhibition using SEB-1 sebocytes revealed that OLE exerts a dual regulatory role in lipid synthesis and inflammation by downregulating AKT and ERK phosphorylation and inhibiting PPAR-γ and SREBP-1 expression. Furthermore, among the tested extracts, the 70% ethanol extract (OLE70) exhibited the strongest antioxidant activity, the greatest gel contraction response, and the highest content of oleuropein, a major bioactive phenolic compound derived from olive. Like OLE, oleuropein also showed sebum-regulatory activity by reducing lipid accumulation in SEB-1 sebocytes, an inhibitory effect on IL-8 expression in HaCaT keratinocytes, and an inhibitory effect on the expression of PPAR-γ and SREBP-1, which are involved in sebum secretion. Taken together, these findings suggest that OLE and its major phenolic constituent, oleuropein, may modulate sebum-related, inflammatory, oxidative, and dermal remodeling-associated responses in skin cell models. These results should be interpreted as exploratory and provide a basis for further mechanistic and translational investigation. Full article

(This article belongs to the Special Issue Natural Products in Biomedicine and Pharmacotherapy, 2nd Edition)

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13 pages, 283 KB

Open AccessArticle

Association of Polymorphisms of Inflammatory-Relevant Genes with Cancer Risk

by Sara AlSrayea, Maryam H. Alrashid, Nasmah K. Bastaki and Jasem Al-Barrak

Curr. Issues Mol. Biol. 2026, 48(6), 548; https://doi.org/10.3390/cimb48060548 (registering DOI) - 23 May 2026

Abstract

Colorectal cancer (CRC) and non-Hodgkin lymphoma (NHL) are among the most prevalent cancer types globally by incidence and mortality. Both types are influenced differentially by chronic inflammation. Central to this inflammation are inflammatory genes that are meticulously regulated by nuclear factor kappa B [...] Read more.

Colorectal cancer (CRC) and non-Hodgkin lymphoma (NHL) are among the most prevalent cancer types globally by incidence and mortality. Both types are influenced differentially by chronic inflammation. Central to this inflammation are inflammatory genes that are meticulously regulated by nuclear factor kappa B (NF-κB) and tumor necrosis factor-α (TNF-α). NF-κB is negatively regulated by IκBα (encoded by NFKBIA), while TNF-α’s actions can be modulated by ghrelin (encoded by GHRL). We investigated four single nucleotide polymorphisms (SNPs) in NFKB1 (rs4648068), NFKBIA (rs2233406), TNF-α (rs1800629), and GHRL (rs1629816) as biomarkers for CRC and NHL risk in a cohort of Kuwaiti individuals. DNA samples from patients and controls were collected and genotyped for all SNPs, and their association with CRC or NHL risk was assessed. While rs4648068 showed a modest association with increased CRC risk, it had no significant impact on NHL risk. Conversely, rs2233406 increased NHL risk without affecting CRC risk. Interestingly, while rs1800629 showed a protective effect against NHL, it showed an increased risk for CRC. Finally, rs1629816 was associated with greater NHL but not CRC risk. Our findings suggests that variations of these inflammatory genes may be useful indicators for predicting cancer risk but might have unpredictable effects on cancer susceptibility, depending on the cancer type. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers, 3rd Edition)

17 pages, 5467 KB

Open AccessArticle

Notch Overexpression Potentiates Interferon Signaling in Glioma Cells

by Marina Giannaki, Elena Parmigiani, Karin Burger, Verdon Taylor and Claudio Giachino

Curr. Issues Mol. Biol. 2026, 48(6), 547; https://doi.org/10.3390/cimb48060547 (registering DOI) - 23 May 2026

Abstract

Interferons (IFNs) play fundamental roles in cancer immunity. We have previously shown that conditional ablation of Notch pathway genes in a mouse model of glioma results in impaired IFNγ signaling and immunosuppressive tumors. However, it remained unclear whether the interaction between the Notch [...] Read more.

Interferons (IFNs) play fundamental roles in cancer immunity. We have previously shown that conditional ablation of Notch pathway genes in a mouse model of glioma results in impaired IFNγ signaling and immunosuppressive tumors. However, it remained unclear whether the interaction between the Notch and IFN signaling pathways could be leveraged to counteract immune evasion in glioma. Here, we investigated whether expression of the intrinsically active Notch intracellular domain (NICD) could enhance IFN responses in glioma cells. Using a doxycycline (Dox)-inducible system, we overexpressed (OE) NICD in U-251MG human glioma cells. NICD-OE dramatically potentiated STAT1 phosphorylation in response to stimulation with either IFNγ or IFNα. Moreover, NICD-OE induced the expression of the transcription factor IRF1, a regulator of IFN signaling responses. Notably, NICD-OE in U-251MG human glioma cells boosted the IFNγ-dependent transcription of the CXCL9 and CXCL10 genes, which encode cytokines that regulate T cell function. Accordingly, NICD-OE in vivo promoted cytotoxic T lymphocyte recruitment to the tumor and reduced tumor cell proliferation in a murine glioma model. Hence, we have identified a signaling network that could be exploited to enhance anti-tumor immunity in glioma subtypes. Full article

(This article belongs to the Special Issue The Molecular Basis of Immunotherapy in Cancer Treatment)

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20 pages, 1884 KB

Open AccessReview

Role of MAPK Pathways in the Pathogenesis of Vitiligo

by Yuexi Liu, Yukun Yuan, Xiaoyi Shi, Rongsi Sun and Xiaolan Ding

Curr. Issues Mol. Biol. 2026, 48(6), 546; https://doi.org/10.3390/cimb48060546 (registering DOI) - 23 May 2026

Abstract

Vitiligo is a chronic, acquired autoimmune disorder characterized by white skin patches resulting from the loss of epidermal melanocytes. Vitiligo may arise through multiple mechanisms, including genetic susceptibility, oxidative stress, autoimmune dysfunction, and environmental factors. Treatment strategies have focused on inhibiting melanocyte loss [...] Read more.

Vitiligo is a chronic, acquired autoimmune disorder characterized by white skin patches resulting from the loss of epidermal melanocytes. Vitiligo may arise through multiple mechanisms, including genetic susceptibility, oxidative stress, autoimmune dysfunction, and environmental factors. Treatment strategies have focused on inhibiting melanocyte loss and stimulating repigmentation. Mitogen-activated protein kinase (MAPK) pathways regulate various cellular processes, including differentiation, survival, and inflammatory responses. The dysregulated MAPK pathways play distinct roles in the development of vitiligo through a complex interplay of melanogenesis, oxidative stress, and autoimmune responses within different cells, thereby leading to melanocyte damage. Thus, therapeutic targeting of MAPK pathways has the potential to mitigate oxidative stress-induced damage and inhibit the exaggerated autoimmunity, thereby controlling disease progression and supporting repigmentation. This review provides an overview of MAPK signaling across the multicellular network in vitiligo pathogenesis and summarizes agents that may provide new perspectives for therapeutic intervention. Full article

(This article belongs to the Section Molecular Medicine)

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10 pages, 3300 KB

Open AccessArticle

miR-30c-2-3p Regulates METTL14 Expression and Inhibits Cell Migration in Breast Cancer

by Zeliha Emrence, Seyma Punar, Vahideh Zarerajabi, Sena Uslu, Neslihan Abaci and Sema Sirma Ekmekci

Curr. Issues Mol. Biol. 2026, 48(6), 545; https://doi.org/10.3390/cimb48060545 (registering DOI) - 23 May 2026

Abstract

Breast cancer remains a leading cause of cancer-related mortality worldwide, with epigenetic mechanisms like N⁶ methyladenosine (m⁶A) modification playing a crucial role in tumorigenesis. The interaction between microRNAs and m⁶A regulators, such as the methyltransferase METTL14, is increasingly [...] Read more.

Breast cancer remains a leading cause of cancer-related mortality worldwide, with epigenetic mechanisms like N⁶ methyladenosine (m⁶A) modification playing a crucial role in tumorigenesis. The interaction between microRNAs and m⁶A regulators, such as the methyltransferase METTL14, is increasingly recognized as a key pathway in oncogenesis. This study investigated whether miR-30c-2-3p regulates METTL14 expression to influence global m⁶A levels and cell migration in breast epithelial (MCF12A) and breast cancer (MCF7) cell lines. Following transfection with miR-30c-2-3p mimics, successful overexpression was confirmed in both cell lines. Subsequent RT-qPCR and Western blotting analyses demonstrated that METTL14 mRNA and protein levels were significantly reduced at 24 and 48 h post-transfection (p < 0.05). Concurrently, global m⁶A RNA methylation levels decreased, with a more pronounced reduction observed in MCF12A cells (p < 0.001). Functionally, wound healing assays revealed that miR-30c-2-3p significantly inhibited migration, reducing wound closure by 30–44% in MCF7 cells and by 66–72% in MCF12A cells. These findings reveal a novel regulatory axis involving miR-30c-2-3p, METTL14, and m⁶A, suggesting that miR-30c-2-3p functions as a tumor suppressor and represents a promising biomarker and therapeutic target in breast cancer. Full article

(This article belongs to the Special Issue Epigenetic Changes in Cancer: Mechanisms, Biomarkers, and Therapeutic Strategies)

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4 pages, 180 KB

Open AccessEditorial

Editorial for Special Issue “Natural Compounds: An Adjuvant Strategy in Cancer Management”

by Monia Cecati and Arianna Vignini

Curr. Issues Mol. Biol. 2026, 48(6), 544; https://doi.org/10.3390/cimb48060544 - 22 May 2026

Abstract

Despite remarkable advances in cancer therapy, treatment resistance, tumor heterogeneity, and therapy-associated toxicity remain major obstacles in achieving durable clinical responses [...] Full article

(This article belongs to the Special Issue Natural Compounds: An Adjuvant Strategy in Cancer Management)

17 pages, 141239 KB

Open AccessArticle

SIRT2 Alleviates Chronic Cold Stress-Induced Lung Injury by Regulating Lung Macrophage M1 Polarization

by Bin Xu, Shizhen Lu, Rongge Xia, Qi Han, Zhiqi Zhu, Xinpeng Chen, Huiying Shi, Wencong Wu, Wanqun Xing and Jingjing Lu

Curr. Issues Mol. Biol. 2026, 48(6), 543; https://doi.org/10.3390/cimb48060543 - 22 May 2026

Abstract

SIRT2 (Sirtuin 2) is an NAD+-dependent deacetylase that exerts crucial regulatory effects on immune homeostasis and macrophage activation. While chronic cold exposure is a known predisposing factor for pulmonary dysfunction, the precise mechanisms by which SIRT2 potentially modulates lung macrophage polarization under cold [...] Read more.

SIRT2 (Sirtuin 2) is an NAD+-dependent deacetylase that exerts crucial regulatory effects on immune homeostasis and macrophage activation. While chronic cold exposure is a known predisposing factor for pulmonary dysfunction, the precise mechanisms by which SIRT2 potentially modulates lung macrophage polarization under cold stress remains poorly understood. In this study, we evaluated the protective capacity of SIRT2 using both wild-type (WT) and Sirt2-knockout (Sirt2−/−) murine models subjected to chronic cold exposure (4 °C for 3 h daily over 21 days). Our results demonstrated that Sirt2 deficiency significantly exacerbated cold-induced pulmonary histopathological damage and increased the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) (p < 0.05). Furthermore, chronic cold stress triggered a macrophage-centered inflammatory response, a process wherein SIRT2 was found to curtail M1 pro-inflammatory polarization. To further investigate these mechanisms, in vitro experiments were conducted using the mouse alveolar macrophage cell line MH-S. While LPS was utilized as a canonical inflammatory stimulus to mimic the injury environment, SIRT2 overexpression was found to reverse the LPS-induced increase in M1 markers and attenuate inflammatory cytokine secretion. These findings suggest that SIRT2 maintains intracellular homeostasis by modulating macrophage plasticity and plays a protective role in the development of chronic cold stimulus-induced lung injury. Consequently, SIRT2 activation may represent a potential therapeutic pathway for the treatment of environment-related respiratory diseases. Full article

(This article belongs to the Section Molecular Medicine)

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18 pages, 11358 KB

Open AccessArticle

Perfluorooctanoic Acid (PFOA) Alters the Structure of the Gut Microbial Community and Colonoid Transcription

by LinShu Liu, Adrienne B. Narrowe, Jenni Firrman, Karley K. Mahalak, Venkateswari J. Chetty, Johanna M. S. Lemons, Aurélien Baudot and Pieter Van den Abbeele

Curr. Issues Mol. Biol. 2026, 48(6), 542; https://doi.org/10.3390/cimb48060542 - 22 May 2026

Abstract

Perfluorooctanoic acid (PFOA) is an environmentally persistent chemical that enters the gastrointestinal tract (GIT) via the food chain, posing a harmful, long-term threat to human health. In response to this challenge, research on the PFOA-GIT interaction is thriving. Currently, studies on the effect [...] Read more.

Perfluorooctanoic acid (PFOA) is an environmentally persistent chemical that enters the gastrointestinal tract (GIT) via the food chain, posing a harmful, long-term threat to human health. In response to this challenge, research on the PFOA-GIT interaction is thriving. Currently, studies on the effect of PFOA on the epithelial cells of the GIT and those on its influence on the microbial community are often implemented separately, and less attention has been paid to the combinational effects of the chemical, the gut microbiome and metabolome. In the present study, we co-cultured fecal samples from healthy adults aged 25–70 in the ex vivo SIFR^® simulator, adding PFOA at 10 mg/L to represent the accumulated effects of long-term exposure. The results obtained from bacterial cell counting by flow cytometry and shotgun metagenomic sequencing revealed that PFOA was broadly disruptive to the microbiome and that Pseudomonadota emerged as the dominant phylum by replacing Bacteriodota and Bacillota, including key members of short-chain fatty acid-producing groups. Bacterial culture media with and without PFOA were collected and used in human colonoid cell culture for TEER and transcription measurement. It was shown that the PFOA-impacted microbial culture had stronger effects on the cell’s protective functions, in terms of tissue junction tightening, mucin biosynthesis, and immune response, than either untreated bacterial culture or PFOA alone. The results point out the possibility that the combination of PFOA and PFOA-impacted bacterial metabolites more strongly induces a change in epithelial cells’ protective function than either one alone. Full article

(This article belongs to the Section Molecular Microbiology)

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16 pages, 4805 KB

Open AccessArticle

Genome-Wide Identification of GRAS Gene Family and Drought Response Analysis of DELLA Proteins in Populus deltoides

by Changgeng Shang, Hu Huang, Yu Chen, Renying Zhuo, Hongsuo Shu and Zhengquan He

Curr. Issues Mol. Biol. 2026, 48(6), 541; https://doi.org/10.3390/cimb48060541 - 22 May 2026

Abstract

The GRAS transcription factor family plays a pivotal role in plant stress adaptation, yet its systematic characterization and the underlying drought-responsive mechanisms remain poorly elucidated in Populus deltoides. Here, a genome-wide identification and analysis of GRAS genes in P. deltoides was performed, [...] Read more.

The GRAS transcription factor family plays a pivotal role in plant stress adaptation, yet its systematic characterization and the underlying drought-responsive mechanisms remain poorly elucidated in Populus deltoides. Here, a genome-wide identification and analysis of GRAS genes in P. deltoides was performed, and a total of 92 family members were identified and classified into 12 distinct subfamilies through phylogenetic analysis. Evolutionary analysis revealed a high degree of conservation between the GRAS proteins of P. deltoides and those of Arabidopsis thaliana, Oryza sativa, and Solanum lycopersicum. Genomic duplication events, including 90 segmental and 11 tandem duplications, were identified as the primary drivers of GRAS family expansion. Promoter cis-element analysis uncovered an enrichment of stress-responsive elements (MBS, ABRE) and phytohormone-related motifs (e.g., TATC-box). Transcriptomic profiling further revealed distinct drought-inducible expression patterns of GRAS genes: PdeGRAS49 exhibited rapid upregulation at the early stage of drought exposure (1–3 h), whereas DELLA subfamily members PdeGRAS51 and PdeGRAS59 reached their expression peaks at 6–9 h, and PdeGRAS34 and PdeGRAS77 maintained sustained activation throughout 12–24 h. Moreover, the drought-inducible expression patterns of five DELLA genes were confirmed by qRT-PCR validation. Collectively, this study provides crucial genomic insights into the GRAS family and valuable candidate gene resources, which lay a foundation for molecular breeding of drought-tolerant P. deltoides cultivars via manipulating GRAS-mediated regulatory mechanisms. Full article

(This article belongs to the Section Molecular Plant Sciences)

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10 pages, 1679 KB

Open AccessArticle

Necroptosis in SJS/TEN: RIPK1 and RIPK3 Expression and Implications for Disease Pathogenesis

by Chandana Sooranahalli, Charles Bouchard and Omer Iqbal

Curr. Issues Mol. Biol. 2026, 48(5), 540; https://doi.org/10.3390/cimb48050540 - 21 May 2026

Abstract

Necroptosis has been implicated in the pathogenesis of Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), with prior studies demonstrating tissue-level involvement of receptor-interacting protein kinases RIPK1 and RIPK3. However, their systemic expression in the circulatory compartment remains incompletely characterized. The objective of this [...] Read more.

Necroptosis has been implicated in the pathogenesis of Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), with prior studies demonstrating tissue-level involvement of receptor-interacting protein kinases RIPK1 and RIPK3. However, their systemic expression in the circulatory compartment remains incompletely characterized. The objective of this study is to evaluate circulating levels of RIPK1 and RIPK3 in patients with SJS/TEN and explore their potential association with diseases. Serum samples from patients with SJS/TEN and control groups were analyzed for RIPK1 and RIPK3 levels using ELISA. Group differences were assessed using non-parametric statistical methods. Circulating levels of RIPK1 and RIPK3 were elevated in patients with SJS/TEN compared with controls. These findings were consistent across analyses; however, variability within groups and overlap between cohorts were observed. These results suggest an association between increased circulating RIPK1 and RIPK3 levels and SJS/TEN. Given the limited sample size, heterogeneous control populations, and lack of functional or phosphorylation-specific assays, these findings should be considered exploratory. Further studies incorporating larger cohorts and mechanistic validation are needed to clarify the role of necroptosis-related pathways in the systemic manifestations of SJS/TEN. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis and Treatment of Skin and Sexually Transmitted Diseases)

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3 pages, 156 KB

Open AccessEditorial

Editorial for the Special Issue “The Role of Bioactives in Inflammation, 2nd Edition”

by Chan-Yen Kuo

Curr. Issues Mol. Biol. 2026, 48(5), 539; https://doi.org/10.3390/cimb48050539 - 21 May 2026

Abstract

Inflammation is increasingly recognized as a dynamic and interconnected regulatory network rather than a linear signaling cascade, in which immune signaling, oxidative stress, metabolic adaptation, and tissue-specific microenvironmental factors collectively shape inflammatory responses [...] Full article

(This article belongs to the Special Issue The Role of Bioactives in Inflammation, 2nd Edition)

15 pages, 2337 KB

Open AccessArticle

Hesperetin-7-O-Glucuronide Improves Endothelial Cell Function Through Improving NO/ET-1 Balance and Reducing Oxidative Stress via miRNAs

by Lu Li, Kexin Ji, Fengqi Du, Nini Jin, He Li and Xinqi Liu

Curr. Issues Mol. Biol. 2026, 48(5), 538; https://doi.org/10.3390/cimb48050538 - 21 May 2026

Abstract

Citrus flavonoid intake is associated with beneficial effects on endothelial function. Our previous randomized control trial demonstrated that the concentration of Hesperetin-7-O-glucuronide (H7G) was positively correlated with the improvement in endothelial function in overweight and obese participants following blood orange juice consumption. To [...] Read more.

Citrus flavonoid intake is associated with beneficial effects on endothelial function. Our previous randomized control trial demonstrated that the concentration of Hesperetin-7-O-glucuronide (H7G) was positively correlated with the improvement in endothelial function in overweight and obese participants following blood orange juice consumption. To explore the underlying mechanism by which H7G improves endothelial function, we investigated the regulation of H7G on endothelial function in a permanent human endothelial cell line (EA. hy926 cells) under normal and oxidative conditions treated with high-oxidation low-density lipoprotein. The results indicated that H7G improved the expression of nitric oxide synthase 3 (NOS3), heme oxygenase 1 (HMOX1) ad glutamate cysteine ligase catalytic (GCLC), and inhibited the expression of endothelin-1 (EDN1), through the upregulation of miR-660-5p and inhibition of miR-21-5p. In summary, H7G improves endothelial cell function via the upregulation of miR-660-5p and the inhibition of miR-21-5p. Full article

(This article belongs to the Special Issue Biologically Active Compounds: Sources, Mechanisms of Action, and Applications)

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3 pages, 168 KB

Open AccessEditorial

Editorial for Special Issue “Osteoclastogenesis and Osteogenesis: Physiological and Molecular Responses to Xenobiotics and Biomaterials”

by Maria Giovanna Rizzo

Curr. Issues Mol. Biol. 2026, 48(5), 537; https://doi.org/10.3390/cimb48050537 - 21 May 2026

Abstract

We are pleased to present this Special Issue of Current Issues in Molecular Biology, entitled “Osteoclastogenesis and Osteogenesis: Physiological and Molecular Responses to Xenobiotics and Biomaterials” [...] Full article

(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis: Physiological and Molecular Responses to Xenobiotics and Biomaterials)

17 pages, 2354 KB

Open AccessArticle

An Iron–Complement Network Model of Thromboinflammation and Humoral Immune Remodeling in Severe COVID-19

by Zhen Chen, Shanshan Wang and Yuzong Chen

Curr. Issues Mol. Biol. 2026, 48(5), 536; https://doi.org/10.3390/cimb48050536 - 21 May 2026

Abstract

Severe COVID-19 is characterized by profound thromboinflammatory and immune disturbances, but the network-level relationships among complement–coagulation dysregulation, humoral immune remodeling, and iron-associated immune regulation remain incompletely understood. Here, we performed integrative proteomic and transcriptomic analyses across peripheral blood and lung microenvironments using weighted [...] Read more.

Severe COVID-19 is characterized by profound thromboinflammatory and immune disturbances, but the network-level relationships among complement–coagulation dysregulation, humoral immune remodeling, and iron-associated immune regulation remain incompletely understood. Here, we performed integrative proteomic and transcriptomic analyses across peripheral blood and lung microenvironments using weighted gene co-expression network analysis (WGCNA), differential network analysis (DiNA), and immune deconvolution. Proteomic network analysis identified a disease-associated module enriched in complement activation, coagulation cascades, platelet degranulation, and acute inflammatory responses. Hub proteins, including C9, LBP, vWF, and F11, were prioritized based on module association and intramodular connectivity. Notably, C9 and LBP were repeatedly identified across WGCNA, DiNA, and differential expression analyses, underscoring their robust association with severe COVID-19-associated molecular network remodeling. Transcriptomic and CIBERSORTx-based immune deconvolution analyses showed altered immune-cell composition in blood and lung tissues, including B-cell and plasma-cell-associated changes. Notably, TFRC displayed cell-type-associated expression changes in naïve B cells and plasma cells, suggesting a potential link between iron-associated immune regulation and humoral immune remodeling. Collectively, these computational findings highlight coordinated complement–coagulation dysregulation, humoral immune remodeling, and TFRC-associated iron-related immune alterations in severe COVID-19, and prioritize TFRC, C9, and LBP as candidate molecular indicators requiring further experimental and clinical validation. Full article

(This article belongs to the Special Issue Molecular and Real-World Evidence Research of Respiratory Diseases and Infections, 2nd Edition)

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20 pages, 769 KB

Open AccessReview

Triple-Negative Breast Cancer: Molecular Subtypes; Immune Escape; Limitations of Current Immunotherapy; and the BTLA/HVEM/CD160 Axis as an Emerging Target

by Bernardo L. Rapoport, Ronald Anderson, Daniel van Tonder, Teresa Smit, Theresa M. Rossouw, Carol-Ann Benn and Helen C. Steel

Curr. Issues Mol. Biol. 2026, 48(5), 535; https://doi.org/10.3390/cimb48050535 - 20 May 2026

Abstract

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread [...] Read more.

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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21 pages, 1076 KB

Open AccessReview

Alpha-Fetoprotein as a Biomarker in Pregnancy: From Genetic Disorders to Obstetric Complications

by Shaqraa Musawi

Curr. Issues Mol. Biol. 2026, 48(5), 534; https://doi.org/10.3390/cimb48050534 - 20 May 2026

Abstract

Alpha-fetoprotein (AFP) is a glycoprotein primarily produced by the fetal liver and yolk sac during development. It is a multifaceted biomarker with significant applications in the prenatal screening of congenital abnormalities, cancer, and other disorders. The level of AFP in maternal blood may [...] Read more.

Alpha-fetoprotein (AFP) is a glycoprotein primarily produced by the fetal liver and yolk sac during development. It is a multifaceted biomarker with significant applications in the prenatal screening of congenital abnormalities, cancer, and other disorders. The level of AFP in maternal blood may indicate several obstetric concerns and complications during pregnancy. Atypical AFP levels are commonly utilized as a biomarker for detecting fetal anomalies, placental complications, and other pregnancy-related issues. These findings raise concerns regarding the effectiveness of screening maternal serum alpha-fetoprotein (MS-AFP) as a primary indicator of pregnancy problems and underscore the need for further investigation into the functional role of AFP throughout pregnancy. The measurement of MS-AFP has been utilized for the past four decades. It is anticipated that MS-AFP measurement will continue to be utilized as a component of integrated or sequential tests for chromosomal abnormalities and may serve as a prognostic indicator for adverse obstetric outcomes. Critically, whether AFP functions solely as a passive marker or plays active biological roles in pregnancy physiology and pathology remains unresolved, necessitating additional mechanistic investigation and discourse. This review consolidates critical data from numerous studies on AFP, focusing specifically on its diagnostic and prognostic applications for congenital abnormalities and problems during pregnancy. This review also identifies key research gaps regarding the functional biology of AFP, particularly whether AFP functions as a passive biomarker or an active participant in the pathophysiology of adverse pregnancy outcomes. Full article

(This article belongs to the Special Issue Targeted Therapies and Biomarker Discovery in Health and Disease)

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4 pages, 181 KB

Open AccessEditorial

Editorial for Special Issue “Molecular Research in Vaccinology and Vaccine Development”

by Attila Farsang

Curr. Issues Mol. Biol. 2026, 48(5), 533; https://doi.org/10.3390/cimb48050533 - 20 May 2026

Abstract

Infectious diseases have always posed a significant threat to both humankind and our livestock [...] Full article

(This article belongs to the Special Issue Molecular Research in Vaccinology and Vaccine Development)

29 pages, 2518 KB

Open AccessReview

AI and Machine Learning for Proteomics-Driven Drug Discovery: Methods, Tools, and Best Practices

by Suman Basak

Curr. Issues Mol. Biol. 2026, 48(5), 532; https://doi.org/10.3390/cimb48050532 - 20 May 2026

Abstract

Proteomics has become central to pharmacological research by providing quantitative readouts of protein abundance, post-translational modifications, interactions, and spatial context. However, proteomic datasets are high-dimensional, heterogeneous, and frequently affected by missingness, batch effects, and limited cohort size. Artificial intelligence (AI) and machine learning [...] Read more.

Proteomics has become central to pharmacological research by providing quantitative readouts of protein abundance, post-translational modifications, interactions, and spatial context. However, proteomic datasets are high-dimensional, heterogeneous, and frequently affected by missingness, batch effects, and limited cohort size. Artificial intelligence (AI) and machine learning (ML) can help convert these complex data into decision-relevant outputs for target identification, biomarker discovery, pharmacodynamic monitoring, and drug repurposing. This review critically compares supervised learning, ensemble methods, dimensionality reduction, clustering, deep learning, graph learning, survival modeling, causal inference, and calibration approaches in proteomics-driven drug discovery. We also summarize major software ecosystems for mass-spectrometry processing, targeted assays, spectrum prediction, phosphoproteomics, structure modeling, and reproducible workflows. Emphasis is placed on model selection, benchmarking, missing-data handling, batch correction, interpretability, uncertainty, experimental validation, and translational readiness. Finally, we highlight emerging directions, including contrastive learning, diffusion models, graph-based integration, and federated analytics. Full article

(This article belongs to the Special Issue Multi-Omics Integration for Precision Medicine: From Pathogenesis, Diagnosis to Treatment)

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17 pages, 1587 KB

Open AccessArticle

Screening the Combination of Gemcitabine, Clomipramine, and Resveratrol in HL-60 Leukemia Cells

by Burcu Biltekin, Yusuf Elgormus and Ayhan Bilir

Curr. Issues Mol. Biol. 2026, 48(5), 531; https://doi.org/10.3390/cimb48050531 - 19 May 2026

Abstract

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in [...] Read more.

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in this in vitro screening study. Materials and Methods: HL-60 cells were treated with gemcitabine, clomipramine, resveratrol, or their combinations at concentrations ranging from 1 to 200 µM. Cell viability was assessed at 24, 48, and 72 h using the trypan blue exclusion method, and results are expressed as a percentage of time-matched untreated controls. Cell proliferation was further evaluated by bromodeoxyuridine (BrdU) immunohistochemical labeling. All experiments were performed in triplicate, and statistical analyses were conducted using one-way analysis of variance (ANOVA) with post hoc comparisons. Results: Gemcitabine markedly reduced HL-60 cell viability at all concentrations and time points (p < 0.001), indicating strong time-dependent cytotoxicity, with a significant drop in BrdU proliferation index at 48 h (p < 0.001). Clomipramine exhibited a biphasic response: high concentrations decreased viability (p < 0.05), while low concentrations allowed partial recovery by 72 h. Resveratrol showed concentration-dependent cytotoxicity, with reduced viability at high concentration and near-control levels at low concentration by 72 h; BrdU indices remained significantly lower than control (p < 0.001). Combination treatments with gemcitabine showed no additive cytotoxic or antiproliferative effects (p > 0.05). A transient enhanced effect was observed in the clomipramine + resveratrol group at 24 h (p < 0.01 vs. clomipramine; p < 0.05 vs. gemcitabine). Conclusions: Gemcitabine, clomipramine, and resveratrol all exhibited inhibitory effects on cell proliferation in HL-60 cell cultures. However, the combination treatments did not show additional cytotoxicity or additive effects. These findings suggest that while each of these compounds individually has the potential to inhibit cell growth, their combined application does not enhance the cytotoxic effects beyond those observed with single treatments. These findings highlight the necessity of a rational approach when considering novel drug combinations. Full article

(This article belongs to the Special Issue Novel Drugs and Natural Products Discovery—2nd Edition)

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