International Journal of Molecular Sciences

11 pages, 651 KiB

Open AccessArticle

Prognostic Significance of Plasma Short-Chain Fatty Acid Levels in Assessing Mortality Risk in Patients with Chronic Heart Failure and Sarcopenia

by Anna V. Sokolova, Dmitrii O. Dragunov, Anastasiya V. Klimova, Yaroslav V. Golubev, Tatiana A. Shmigol, Vadim V. Negrebetsky and Gregory P. Arutyunov

Int. J. Mol. Sci. 2025, 26(13), 5984; https://doi.org/10.3390/ijms26135984 (registering DOI) - 22 Jun 2025

Abstract

Short-chain fatty acids (SCFAs) are microbial metabolites involved in immune regulation, energy metabolism, and intestinal barrier integrity. Among them, the role of hexanoic acid (C6), predominantly derived from dietary sources, remains poorly understood in chronic heart failure (CHF) and sarcopenia. A total of [...] Read more.

Short-chain fatty acids (SCFAs) are microbial metabolites involved in immune regulation, energy metabolism, and intestinal barrier integrity. Among them, the role of hexanoic acid (C6), predominantly derived from dietary sources, remains poorly understood in chronic heart failure (CHF) and sarcopenia. A total of 636 patients with confirmed CHF were screened between 2019 and 2021. Sarcopenia was diagnosed in 114 patients, with 74 meeting the inclusion criteria for analysis. Plasma levels of SCFAs—including butanoic, propanoic, isobutyric, 2- and 3-methylbutanoic, hexanoic, pentanoic, and 4-methylpentanoic acids—were measured using HPLC-MS/MS. Muscle strength, mass, and physical performance were assessed using handgrip dynamometry, bioelectrical impedance analysis, and SPPB, respectively. All patients showed elevated SCFA levels compared to reference values. Butanoic acid levels exceeded reference values by 32.8-fold, propanoic acid by 10.9-fold, and hexanoic acid by 1.09-fold. Patients with plasma hexanoic acid levels above the 50th percentile had a seven-fold increased mortality risk (OR = 7.10; 95% CI: 1.74–28.9; p < 0.01). Kaplan–Meier analysis confirmed significantly lower survival in this group (p = 0.00051). The mean left ventricular ejection fraction was 41.2 ± 7.5%, and the mean SPPB score was 6.1 ± 1.8, indicating impaired physical performance. Elevated plasma hexanoic acid is associated with poor prognosis in CHF patients with sarcopenia. These findings suggest that C6 may serve as a potential prognostic biomarker and therapeutic target in this population. Full article

(This article belongs to the Special Issue Musculoskeletal Disease: From Molecular Basis to Therapy)

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22 pages, 2257 KiB

Open AccessArticle

Rare Evolutionary Events Support the Phylogenetic Placement of Orthonectida Within Annelida

by Olga V. Nikolaeva, Kirill V. Mikhailov, Maria S. Muntyan, Oleg A. Zverkov, Sergey A. Spirin, Vassily A. Lyubetsky, Georgy S. Slyusarev and Vladimir V. Aleoshin

Int. J. Mol. Sci. 2025, 26(13), 5983; https://doi.org/10.3390/ijms26135983 (registering DOI) - 21 Jun 2025

Abstract

Orthonectids are a group of highly simplified worm-like parasites that are placed within Lophotrochozoa by multigene mitochondrial and nuclear phylogenies. However, their exact position within Lophotrochozoa is uncertain due to the high rate of molecular evolution and putative long branch attraction artifacts. To [...] Read more.

Orthonectids are a group of highly simplified worm-like parasites that are placed within Lophotrochozoa by multigene mitochondrial and nuclear phylogenies. However, their exact position within Lophotrochozoa is uncertain due to the high rate of molecular evolution and putative long branch attraction artifacts. To examine the phylogenetic placement of orthonectids, we applied an alternative approach that takes into account rare evolutionary events (gene order rearrangements in mitochondrial DNA and individual changes in mitochondrial proteins) with an assessment of their probabilities based on a reference sequence database (RefSeq, NCBI). This approach strongly supports the branching of orthonectids among annelids, but does not conclusively resolve their position among the annelid taxa. Full article

(This article belongs to the Special Issue Mitochondrial Genome of Aquatic Animals: Analysis of Structure, Evolution and Diversity)

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15 pages, 2442 KiB

Open AccessArticle

Hesperidin Is a Promising Nutraceutical Compound in Counteracting the Progression of NAFLD In Vitro

by Miriam Cofano, Ilenia Saponara, Valentina De Nunzio, Giuliano Pinto, Emanuela Aloisio Caruso, Matteo Centonze and Maria Notarnicola

Int. J. Mol. Sci. 2025, 26(13), 5982; https://doi.org/10.3390/ijms26135982 (registering DOI) - 21 Jun 2025

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 ± 0.06 vs. 0.39 ± 0.03 at 100 µg/mL) and SCD1 (0.05 ± 0.001 vs. 0.03 ± 0.004 at 50 µg/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 ± 0.16 vs. 2.36 ± 0.10 at 50 µg/mL) and PGC1α (0.71 ± 0.03 vs. 0.89 ± 0.003 at 50 µg/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 ± 0.10 vs. 0.90 ± 0.11 at 100 µg/mL) and α-SMA (1.21 ± 0.16 vs. 0.76 ± 0.07 at 75 µg/mL) and upregulated MMP3 (0.64 ± 0.05 vs. 0.98 ± 0.07) and MMP9 (0.99 ± 0.005 vs. 2.61 ± 0.16 at 100 µg/mL). In conclusion, HE may offer a promising approach for NAFLD/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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27 pages, 3506 KiB

Open AccessArticle

The Involvement of LvSRSF2 in Circular RNA Biogenesis and Its Role in Immunity Against White Spot Syndrome Virus (WSSV) in Litopenaeus vannamei

by Wutthipat Potiyanadech, Cheeranan Sriphuttha, Tuangrak Seabkongseng, Neung Teaumroong, Panlada Tittabutr and Pakpoom Boonchuen

Int. J. Mol. Sci. 2025, 26(13), 5981; https://doi.org/10.3390/ijms26135981 (registering DOI) - 21 Jun 2025

Abstract

Serine/arginine splicing factors (SRSFs) are critical regulators of gene expression that influence alternative splicing through RNA binding via the RNA recognition motif (RRM). Circular RNAs (circRNAs) are a subset of non-coding RNAs that exhibit differential expression in WSSV-infected Litopenaeus vannamei. This study [...] Read more.

Serine/arginine splicing factors (SRSFs) are critical regulators of gene expression that influence alternative splicing through RNA binding via the RNA recognition motif (RRM). Circular RNAs (circRNAs) are a subset of non-coding RNAs that exhibit differential expression in WSSV-infected Litopenaeus vannamei. This study investigates the role of LvSRSF2 in regulating circRNA expression in response to WSSV infection. LvSRSF2 was highly expressed in hemocytes and upregulated during WSSV infection. Silencing LvSRSF2 using dsRNA significantly upregulated the expression of circRNAs (circ-Alpha2, circ-Anillin, circ-Hemocytin, circ-Nephrin, and circ-Toll) in both WSSV-infected and uninfected shrimps at 72 h post-injection with dsRNAs. Knockdown of LvSRSF2 also significantly reduced WSSV copy numbers at 24 h post-infection and extended shrimp survival, with knockdown shrimp surviving up to 9 d compared to the control group. In addition, circ-Hemocytin, an SRSF2-related circRNA, was predicted to interact with six miRNAs targeting immune-related genes such as Toll, STAT, NF-κB, and Vago4. Following WSSV infection, circ-Hemocytin expression increased at 24 and 48 hpi, and the immune genes STAT and Vago4 were also upregulated, suggesting a potential circRNA–miRNA–mRNA regulatory axis in shrimp antiviral defense. Furthermore, targeted suppression of circ-Hemocytin expression using siRNAs significantly reduced its expression without affecting the corresponding linear transcript and resulted in a notable decrease in WSSV load in shrimp gills, highlighting its potential role in antiviral defense. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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25 pages, 8721 KiB

Open AccessArticle

Synthesis, Antimicrobial Activities, and Model of Action of Novel Tetralone Derivatives Containing Aminoguanidinium Moiety

by Qing-Jie Zhang, Yu-Xi Li, Wen-Bo Ge, Li-Xia Bai, Xiao Xu, Ya-Jun Yang, Xi-Wang Liu and Jian-Yong Li

Int. J. Mol. Sci. 2025, 26(13), 5980; https://doi.org/10.3390/ijms26135980 (registering DOI) - 21 Jun 2025

Abstract

The objectives of this study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-tetralone derivatives. Thirty-four new compounds were effectively synthesized through nucleophilic substitution reaction and guanidinylation reaction. Chemical structures of all the desired compounds were identified [...] Read more.

The objectives of this study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-tetralone derivatives. Thirty-four new compounds were effectively synthesized through nucleophilic substitution reaction and guanidinylation reaction. Chemical structures of all the desired compounds were identified by NMR and HR-MS spectroscopy. Most of the synthesized compounds showed significant antibacterial activity against ESKAPE pathogens and clinically resistant Staphylococcus aureus (S. aureus) isolates. S. aureus is an important pathogen that has the capacity to cause a variety of diseases, including skin infections, pneumonia, and sepsis. The most active compound, 2D, showed rapid bactericidal activity against S. aureus ATCC 29213 and MRSA-2 with MIC/MBC values of 0.5/4 µg/mL and 1/4 µg/mL, respectively. The hemolytic activity and cytotoxicity of 2D was low, with HC₅₀ and IC_{50 (HEK 293-T)} values of 50.65 µg/mL and 13.09 µg/mL, respectively. Compound 2D induced the depolarization of the bacterial membrane and disrupted bacterial membrane integrity, ultimately leading to death. Molecular docking revealed that dihydrofolate reductase (DHFR) may be a potential target for 2D. In the mouse skin abscess model caused by MRSA-2, 2D reduced the abscess volume, decreased bacterial load, and alleviated tissue pathological damage at doses of 5 and 10 mg/kg. Therefore, compound 2D may be a promising drug candidate for antibacterial purposes against S. aureus. Full article

(This article belongs to the Special Issue Advanced Research in Veterinary Drugs)

30 pages, 29722 KiB

Open AccessArticle

Modeling Possible G-Quadruplexes and i-Motifs at DNA–DNA Contact Sites: Strategy, Classification, and Examples

by Vladimir Borisovich Tsvetkov

Int. J. Mol. Sci. 2025, 26(13), 5979; https://doi.org/10.3390/ijms26135979 (registering DOI) - 21 Jun 2025

Abstract

Tetrahelical DNA structures, such as G-quadruplexes (G4s) or i-motifs (iMs), are adopted by sequences comprising several G/C tracts, exist in equilibria with respective duplexes, and may contribute to genomic instability upon helicase deficiency. To understand genomic rearrangements resulting from the juxtaposition of G/C-rich [...] Read more.

Tetrahelical DNA structures, such as G-quadruplexes (G4s) or i-motifs (iMs), are adopted by sequences comprising several G/C tracts, exist in equilibria with respective duplexes, and may contribute to genomic instability upon helicase deficiency. To understand genomic rearrangements resulting from the juxtaposition of G/C-rich DNA duplexes, models of possible intermediate structures are needed. In this study, a general strategy for creating and verifying in silico 3D models of tetrahelical DNA was proposed. This strategy was used to investigate contacts of two or more duplexes with n G₃/C₃ tracts (n = 2–6) separated by T/A nucleotides. The revealed viable structures of DNA–DNA contacts include stacks of right-handed and left-handed G-quadruplexes (G4s), Holliday structure-resembling assemblies with the G4 and iM opposite each other on the borders of the central “hole”, etc. Based on molecular dynamic simulations, the most probable variants were determined by estimating the contributions to the free energy. The results may be used to clarify the mechanisms of strand exchange and other rearrangements upon DNA breaks near prolonged G/C-rich sites in living systems. Additionally, they provide a balanced view on the polymorphic versus programmed DNA assemblies in artificial systems. Full article

(This article belongs to the Collection State-of-the-Art Macromolecules in Russia)

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27 pages, 10241 KiB

Open AccessArticle

Comparing Protein Stability in Modern and Ancient Sabkha Environments: Implications for Molecular Remnants on Ancient Mars

by Qitao Hu, Ting Huang, Aili Zhu, Angélica Anglés, Osman Abdelghany, Alaa Ahmed and David C. Fernández-Remolar

Int. J. Mol. Sci. 2025, 26(13), 5978; https://doi.org/10.3390/ijms26135978 (registering DOI) - 21 Jun 2025

Abstract

Understanding the mechanisms of protein preservation in extreme environments is essential for identifying potential molecular biosignatures on Mars. In this study, we investigated five sabkha sedimentary samples from the Abu Dhabi coast, spanning from the present day to ~11,000 years before present (BP), [...] Read more.

Understanding the mechanisms of protein preservation in extreme environments is essential for identifying potential molecular biosignatures on Mars. In this study, we investigated five sabkha sedimentary samples from the Abu Dhabi coast, spanning from the present day to ~11,000 years before present (BP), to assess how mineralogy and environmental conditions influence long-term protein stability. Using LC-MS/MS and direct Data-independent Acquisition (DIA) proteomic analysis, we identified 722 protein groups and 1300 peptides, revealing a strong correlation between preservation and matrix composition. Carbonate- and silica-rich samples favored the retention of DNA-binding and metal-coordinating proteins via mineral–protein interactions, while halite- and gypsum-dominated facies showed lower recovery due to extreme salinity and reduced biomass input. Functional profiling revealed a shift from metabolic dominance in modern samples to genome maintenance strategies in ancient ones, indicating microbial adaptation to prolonged environmental stress. Contrary to expectations, some ancient samples preserved large, multi-domain proteins, suggesting that early mineral encapsulation can stabilize structurally complex biomolecules over millennial timescales. Taxonomic reconstruction based on preserved proteins showed broad archaeal diversity, including Thaumarchaeota and thermophilic lineages, expanding our understanding of microbial ecology in hypersaline systems. These findings highlight sabkhas as valuable analogs for Martian evaporitic environments and suggest that carbonate–silica matrices on Mars may offer optimal conditions for preserving ancient molecular traces of life. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 972 KiB

Open AccessArticle

Tracking Drug Resistance in Plasmodium falciparum: Genetic Diversity of Key Resistance Markers in Brazilian Malaria Hotspots

by Rebecca de Abreu-Fernandes, Lucas Tavares de Queiroz, Natália Ketrin Almeida-de-Oliveira, Aline Rosa de Lavigne Mello, Jacqueline de Aguiar Barros, Lilian Rose Pratt-Riccio, Gisely Cardoso de Melo, Patrícia Brasil, Cláudio Tadeu Daniel-Ribeiro, Didier Menard and Maria de Fátima Ferreira-da-Cruz

Int. J. Mol. Sci. 2025, 26(13), 5977; https://doi.org/10.3390/ijms26135977 (registering DOI) - 21 Jun 2025

Abstract

Malaria remains a health problem, with Plasmodium falciparum accounting for 96% of cases in Africa and 15% in Brazil. The growing threat of drug resistance to artemisinin-based combination therapies (ACTs) jeopardizes progress toward elimination. This study examined P. falciparum samples collected from 141 [...] Read more.

Malaria remains a health problem, with Plasmodium falciparum accounting for 96% of cases in Africa and 15% in Brazil. The growing threat of drug resistance to artemisinin-based combination therapies (ACTs) jeopardizes progress toward elimination. This study examined P. falciparum samples collected from 141 patients in Brazil (2013–2023) by PCR and DNA sequencing to identify single-nucleotide polymorphisms in the pfcrt, pfmdr1, and pfk13 genes. Half of the samples carried the SVMNTMCGI haplotype in pfcrt, and none of the samples showed C350R mutations. In pfmdr1, the NYCDY haplotype was dominant (70%), with low occurrences of N86Y (4%) and no Y184F polymorphisms. No mutations linked to artemisinin partial resistance were detected in pfk13. Only one Amazonas sample exhibited wild-type haplotypes across all genes. Genetic diversity was more pronounced in pfcrt than pfmdr1, reflecting selective drug pressure. Significant linkage disequilibrium (LD) was observed within pfcrt (C72S and K76T) and pfmdr1 (S1034C and N1042D), but not between the two genes. The absence of pfk13-resistant mutations and the low prevalence of key pfmdr1 markers support the efficacy of ACTs. The persistence of diverse haplotypes and intragenic LD reflects ongoing drug pressure, underscoring the need for continuous genetic surveillance to anticipate emerging resistance. Full article

(This article belongs to the Special Issue Interactions Between Microbes and Hosts: Physiology, Pathology and Treatment)

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22 pages, 8370 KiB

Open AccessArticle

Identification and Screening of Novel Antioxidant Peptides from Yak Skin and Their Protective Effect on H₂O₂-Induced HepG2 Cells Oxidation

by Yan Jin, Nan Zhang, Yurong Huang, Ziyao Zhang, Enhui Jin, Yu Kong, Wenjie Sui, Tao Wu and Min Zhang

Int. J. Mol. Sci. 2025, 26(13), 5976; https://doi.org/10.3390/ijms26135976 (registering DOI) - 21 Jun 2025

Abstract

To improve the bioavailability of yak by-products, novel antioxidant peptides were prepared and identified from yak skin hydrolysate. The results showed that the ultrafiltration fraction of a molecular weight of less than 1 kDa had the strongest free radical scavenging activity. A total [...] Read more.

To improve the bioavailability of yak by-products, novel antioxidant peptides were prepared and identified from yak skin hydrolysate. The results showed that the ultrafiltration fraction of a molecular weight of less than 1 kDa had the strongest free radical scavenging activity. A total of 219 novel peptides were identified by mass spectrometry and five antioxidant peptides were screened based on molecular docking with Keap1 (LMGPR, GFDGD, FGFDGDF, GHNGLDGL, and GPAGPQGPR). These peptides may bind with Keap1 competitively and exert antioxidant effects by activating the Nrf2/ARE pathway. After synthesis, FGFDGDF showed a better free radical scavenging ability and protective effect on H₂O₂-induced oxidative damage of HepG2 cells among these peptides. The pretreatment of peptides could enhance the activity of intracellular antioxidant enzymes and reduce the level of malondialdehyde and IL-8. This study provides a scientific basis for the application of yak skin peptide as a novel antioxidant in functional food. Full article

(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)

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18 pages, 13680 KiB

Open AccessArticle

Upregulated BAP31 Links to Poor Prognosis and Tumor Immune Microenvironment in Breast Cancer

by Zhenzhen Hao, Bo Zhao, Xiaoshuang Zhu, Wanting Zhang and Bing Wang

Int. J. Mol. Sci. 2025, 26(13), 5975; https://doi.org/10.3390/ijms26135975 (registering DOI) - 21 Jun 2025

Abstract

BAP31, a transmembrane protein in the endoplasmic reticulum, is known for its oncogenic properties, but its role in immunotherapy is not well understood. While BAP31’s involvement in liver, gastric, and cervical cancers has been documented, its role in pan-cancer immune regulation, particularly in [...] Read more.

BAP31, a transmembrane protein in the endoplasmic reticulum, is known for its oncogenic properties, but its role in immunotherapy is not well understood. While BAP31’s involvement in liver, gastric, and cervical cancers has been documented, its role in pan-cancer immune regulation, particularly in breast cancer, remains unexplored. Using TCGA data, analysis via the Xiantao academic and GEPIA2 database showed that BAP31 upregulation correlates with advanced clinical stages and a poor prognosis. ROC analysis demonstrated BAP31’s high accuracy in distinguishing cancerous tissue from normal tissues. Additionally, BAP31 expression is associated with CNV, methylation, TMB, and MSI. In breast cancer, TIMER database analysis revealed that BAP31 expression is inversely correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs), macrophages, T lymphocytes, B lymphocytes, and neutrophils. Additionally, we investigated the relationship between BAP31 and the expression of major histocompatibility complex (MHC) molecules and chemokine receptors utilizing the TISIDB database. LinkedOmics analysis demonstrated associations between BAP31 and various immune-inflammatory pathways, while also indicating a negative correlation between BAP31 expression and four critical pathways: extracellular matrix receptor interaction, focal adhesion, JAK-STAT signaling, and TGF-β signaling. Furthermore, loss-of-function experiments employing shRNA-mediated knockdown of BAP31 resulted in a marked reduction in cell proliferation and an increase in apoptosis in breast cancer cells, thereby confirming its role in tumor promotion. These findings suggest that BAP31 may serve as a promising prognostic biomarker and a potential target for immunotherapy in breast cancer. Full article

(This article belongs to the Section Molecular Oncology)

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24 pages, 3770 KiB

Open AccessArticle

Effects of Polypropylene and Polyethylene Terephthalate Microplastics on Trypsin Structure and Function

by Tamara Lujic, Nikola Gligorijevic, Dragana Stanic-Vucinic, Maja Krstic Ristivojevic, Tamara Mutic, Lukas Wimmer, Lea Ann Dailey and Tanja Cirkovic Velickovic

Int. J. Mol. Sci. 2025, 26(13), 5974; https://doi.org/10.3390/ijms26135974 (registering DOI) - 21 Jun 2025

Abstract

Ingestion is one of the main exposure routes of humans and animals to microplastics (MPs). During digestion, MPs can interact with both gastrointestinal enzymes and food proteins. This study investigated the adsorption of trypsin onto polypropylene (PP) and polyethylene terephthalate (PET) MPs, the [...] Read more.

Ingestion is one of the main exposure routes of humans and animals to microplastics (MPs). During digestion, MPs can interact with both gastrointestinal enzymes and food proteins. This study investigated the adsorption of trypsin onto polypropylene (PP) and polyethylene terephthalate (PET) MPs, the influence of MPs on trypsin structure and activity, and the in vitro trypsin digestibility of bovine meat extract (BME) sarcoplasmic proteins and BME α-Gal-carrying allergens (α-GalA) in the presence of PP and PET MPs. Trypsin, BME and α-GalA proteins interact with MPs, resulting in the formation of a soft (SC) and hard (HC) corona. This interaction is dynamic, leading to the adsorption and desorption of protein through time. Trypsin adsorption onto MPs results in slight structural changes in the SC and bulk solution, while a trypsin fraction residing in the HC loses most of its specific activity. The presence of MPs slightly slows down the digestibility of proteins with a mass of 38 kDa, while it does not affect the digestion of α-GalA. According to our results, it is unlikely that realistic concentrations of MPs in the intestine would have significant effects on meat extract proteins’ and allergens’ digestibility by trypsin. We confirmed that during trypsin digestion, the corona on PP and PET MP is composed of BME sarcoplasmic proteins and allergenic α-Gal-carrying proteins. Full article

(This article belongs to the Section Biochemistry)

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28 pages, 1200 KiB

Open AccessReview

Tumor-Associated Macrophage in Breast Tumor Microenvironment

by Lingyao Ma, Yuexinzi Jin, Jian Xu and Jiexin Zhang

Int. J. Mol. Sci. 2025, 26(13), 5973; https://doi.org/10.3390/ijms26135973 (registering DOI) - 21 Jun 2025

Abstract

Breast cancer (BC) is the most common cancer in women worldwide. It is one of the main causes of cancer-related mortality. The breast tumor microenvironment (Br-TME) has emerged as an important factor related to BC development and prognosis. Tumor-associated macrophages (TAMs) are the [...] Read more.

Breast cancer (BC) is the most common cancer in women worldwide. It is one of the main causes of cancer-related mortality. The breast tumor microenvironment (Br-TME) has emerged as an important factor related to BC development and prognosis. Tumor-associated macrophages (TAMs) are the main effector cells in the Br-TME; they play key roles in regulating angiogenesis, immunosuppression, metastasis, and chemoresistance in BC patients. In this review, we introduce the macrophage niche in the Br-TME, particularly emphasizing the origin of TAMs. Next, we summarize the typical pathways and molecular mechanisms of the interactions between TAMs and various other components in the Br-TME. Finally, we provide an overview of drugs that target TAMs and discuss the prevailing technologies for drug delivery in the context of BC treatment. Identification of the dynamic variations in tumor-promoting TAMs will help reveal the key links that drive BC progression. This review provides a theoretical basis for upcoming clinical trials that may substantially benefit patients. Full article

(This article belongs to the Section Molecular Oncology)

19 pages, 4340 KiB

Open AccessArticle

PANDORA-Seq Unveils the Hidden Small Non-Coding RNA Landscape in Hypopharyngeal Carcinoma

by Miaoyan Pu, Luyu Shi, Haiyu Ma, Chuntao Tao, Ying Zhang, Youquan Bu and Junhong Ye

Int. J. Mol. Sci. 2025, 26(13), 5972; https://doi.org/10.3390/ijms26135972 (registering DOI) - 21 Jun 2025

Abstract

Hypopharyngeal carcinoma is a highly aggressive malignancy in the head and neck region with poor prognosis due to challenges in early diagnosis, high invasiveness, recurrence rate, and metastatic potential. Small non-coding RNAs (sncRNAs) play crucial roles in tumorigenesis and progression and hold potential [...] Read more.

Hypopharyngeal carcinoma is a highly aggressive malignancy in the head and neck region with poor prognosis due to challenges in early diagnosis, high invasiveness, recurrence rate, and metastatic potential. Small non-coding RNAs (sncRNAs) play crucial roles in tumorigenesis and progression and hold potential as clinical diagnostic biomarkers and therapeutic targets. However, the ability of traditional RNA-sequencing technologies to detect modified sncRNAs is limited, potentially leading to the failure to accurately identify some functionally relevant sncRNAs. In this study, we employed PANDORA-seq technology for the first time to systematically profile sncRNA expression in cancerous and adjacent normal tissues from five patients with hypopharyngeal carcinoma. Our results revealed dynamic changes in sncRNA expression in hypopharyngeal carcinoma tissues and found 4798 significantly differentially expressed sncRNAs. Among these, differentially expressed miRNAs and tsRNAs were primarily involved in key signaling pathways, including MAPK, FoxO, and TGF-β. Additionally, we validated the differential expression of eight sncRNAs in hypopharyngeal carcinoma tissues, which may represent potential diagnostic biomarkers and therapeutic targets. This study lays the foundation for the application of PANDORA-seq technology in human cancers and offers new directions for exploring the underlying molecular mechanisms of hypopharyngeal carcinoma and potential targets for its clinical diagnosis and treatment. Full article

(This article belongs to the Special Issue Molecular Research of Multi-omics in Cancer)

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21 pages, 2424 KiB

Open AccessReview

The Role of Biomarkers in Temporomandibular Disorders: A Systematic Review

by Joana Maria Soares, Bruno Daniel Carneiro and Daniel Humberto Pozza

Int. J. Mol. Sci. 2025, 26(13), 5971; https://doi.org/10.3390/ijms26135971 (registering DOI) - 21 Jun 2025

Abstract

Temporomandibular disorders (TMDs) impact quality of life and present diagnostic and treatment challenges. Biomarkers may serve as an additional tool to support diagnosis and monitor disease progression, offering supplementary information for treatment strategies in specific and selected patients. This systematic review aimed to [...] Read more.

Temporomandibular disorders (TMDs) impact quality of life and present diagnostic and treatment challenges. Biomarkers may serve as an additional tool to support diagnosis and monitor disease progression, offering supplementary information for treatment strategies in specific and selected patients. This systematic review aimed to assess the role of biomarkers in diagnosing TMD and guiding personalized treatment. It also examined key biomarkers linked to chronic temporomandibular joint (TMJ) pain and how therapies affect biomarker levels and clinical outcomes. A comprehensive search was conducted in PubMed, Scopus, and Web of Science to identify observational and interventional studies assessing the role of biomarkers in synovial fluid/tissue, saliva, and blood. The research was registered in PROSPERO, adhered to PRISMA guidelines, and employed Cochrane Risk of Bias tools. To assess the effect, only studies examining biomarker levels were considered. A total of forty-six studies met the inclusion criteria: three randomized controlled trials were rated as having some concerns, as were most of the observational studies. Elevated levels of interleukins (1ß and 6), tumour necrosis factor alpha, and prostaglandin E2 in synovial fluid were correlated with temporomandibular joint (TMJ) inflammation. Increased matrix metalloproteinases (2, 7, and 9) indicated cartilage deterioration, while oxidative stress markers such as malondialdehyde were higher in TMD patients. Treatments including hyaluronic acid, platelet-rich plasma, and low-level laser therapy effectively reduced inflammatory biomarkers and improved symptoms. Biomarkers show potential to contribute to the understanding of pathophysiological mechanisms in TMD and may support future diagnostic and therapeutic strategies for selected patients. After high-quality studies confirm these findings, this approach will enable personalized medicine by tailoring treatments to individual patient profiles, ultimately leading to improved outcomes and quality of life. Full article

(This article belongs to the Special Issue Pain in Human Health and Disease)

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19 pages, 4140 KiB

Open AccessArticle

Exploring the Therapeutic Potential of ¹⁷⁷Lu-PSMA-617 in a Mouse Model of Prostate Cancer Bone Metastases

by Cheng-Liang Peng, Chun-Tang Chen and I-Chung Tang

Int. J. Mol. Sci. 2025, 26(13), 5970; https://doi.org/10.3390/ijms26135970 (registering DOI) - 21 Jun 2025

Abstract

Prostate cancer is the second leading cause of cancer-related death in men, with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases representing a critical clinical challenge. Although radium-223 (Ra-223) is approved for treating mCRPC with bone metastases, its efficacy remains limited, necessitating the [...] Read more.

Prostate cancer is the second leading cause of cancer-related death in men, with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases representing a critical clinical challenge. Although radium-223 (Ra-223) is approved for treating mCRPC with bone metastases, its efficacy remains limited, necessitating the development of more effective therapies. This study investigates the therapeutic potential of ¹⁷⁷Lu-PSMA-617, a PSMA-targeted radiopharmaceutical, in a murine model of prostate cancer bone metastases. To our knowledge, this is the first study to systematically evaluate ¹⁷⁷Lu-PSMA-617 in an orthotopic bone metastatic prostate cancer model, providing a clinically relevant preclinical platform to assess both imaging and therapeutic performance. We conducted comprehensive preclinical evaluations, including synthesis, stability analysis, cell binding assays, nuclear imaging, in vivo biodistribution, pharmacokinetics, and antitumor efficacy. The synthesis of ¹⁷⁷Lu-PSMA-617 demonstrated high radiochemical yield (99.2%), molar activity (25.5 GBq/μmol), and purity (>98%), indicating high product quality. Stability studies confirmed minimal release of free Lutetium-177, maintaining the compound’s integrity under physiological conditions. In vitro assays showed selective binding and internalization in PSMA-positive LNCaP prostate cancer cells, with negligible uptake in PSMA-negative PC-3 cells. In vivo biodistribution studies demonstrated efficient tumor targeting, with peak uptake in LNCaP tumors (23.31 ± 0.94 %IA/g) at 4 h post-injection. The radiopharmaceutical exhibited favorable pharmacokinetics, with high tumor-to-background ratios (tumor-to-blood, 434.4; tumor-to-muscle, 857.4). Therapeutic efficacy was confirmed by significant survival extension in treated mice (30.7% for 37 MBq and 53.8% for 111 MBq), with median survival times of 34 and 40 days, respectively, compared to 26 days in the control group. Radiation dosimetry analysis indicated a favorable safety profile with a calculated effective dose of 0.127 mSv/MBq. These findings highlight the novelty and translational relevance of using ¹⁷⁷Lu-PSMA-617 in a clinically relevant bone metastasis model, reinforcing its potential as a dual-purpose agent for both targeted therapy and molecular imaging in advanced prostate cancer. Full article

(This article belongs to the Section Molecular Pharmacology)

18 pages, 965 KiB

Open AccessReview

Refining Criteria for Choosing the First-Line Treatment for Real-World Patients with Advanced ALK-Rearranged NSCLC

by Edyta Maria Urbanska, Peter Rindom Koffeldt, Morten Grauslund, Linea Cecilie Melchior, Jens Benn Sørensen and Eric Santoni-Rugiu

Int. J. Mol. Sci. 2025, 26(13), 5969; https://doi.org/10.3390/ijms26135969 (registering DOI) - 21 Jun 2025

Abstract

Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in [...] Read more.

Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in evaluating their efficacy and safety, which patients benefit from a specific ALK-TKI may still be questioned. The methodological inconsistencies in these trials, which led to the inclusion of different patient populations, appear to have been inadequately addressed. ALK-rearranged NSCLC is a heterogeneous disease, and co-existing molecular alterations may affect the outcome. The questions explored in these trials appear insufficient to support a personalized approach to the first-line treatment, while defining long-term responders and early progressors would be clinically useful. This narrative review presents several considerations from oncologists’ and pathologists’ perspectives. We propose defining favorable and unfavorable features, such as histology, type of ALK fusion, co-existing molecular alterations, plasma circulating tumor DNA (ctDNA, performance status, and brain metastases, to help identify patients with lower and higher risk of progression. Consequently, the most potent ALK-TKI to date, Lorlatinib, may be considered as the first-line treatment for high-risk patients with unfavorable features, while sequencing of ALK-TKIs may be appropriate for low-risk patients with favorable features. Although ALK signal inhibition is critical in this disease, it may not be sufficient for clinical control due to de novo co-alterations. A more personalized approach to first-line therapy requires consideration of risk factors for each patient. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 2719 KiB

Open AccessArticle

Combinatorial Effects of CPP-Modified Antimicrobial Peptides: Synergistic and Additive Interactions Against Pathogenic Bacteria

by Oxana V. Galzitskaya, Sergey V. Kravchenko, Sergei Y. Grishin, Alena P. Zakhareva, Leila G. Mustaeva, Elena Y. Gorbunova, Alexey K. Surin and Viacheslav N. Azev

Int. J. Mol. Sci. 2025, 26(13), 5968; https://doi.org/10.3390/ijms26135968 (registering DOI) - 21 Jun 2025

Abstract

The development of novel antimicrobial peptides (AMPs) with broad-spectrum activity represents a promising strategy to overcome multidrug resistance in pathogenic bacteria. In this study, we investigated the antimicrobial activity of three designed peptides—R44K^S*, V31K^S*, and R23F^S*—engineered to [...] Read more.

The development of novel antimicrobial peptides (AMPs) with broad-spectrum activity represents a promising strategy to overcome multidrug resistance in pathogenic bacteria. In this study, we investigated the antimicrobial activity of three designed peptides—R44K^S*, V31K^S*, and R23F^S*—engineered to incorporate an amyloidogenic fragment from the S1 protein of Staphylococcus aureus and one or two cell-penetrating peptide (CPP) fragments to enhance cellular uptake. The antimicrobial efficacy of these peptides and their combinations was assessed against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Bacillus cereus. The results demonstrated that all three peptides exhibited significant antibacterial activity in a concentration-dependent manner, with R44K^S* being the most potent. Peptide combinations, particularly V31K^S*/R23F^S* and R44K^S*/V31K^S*, showed enhanced inhibitory effects and reduced minimum inhibitory concentrations (MICs), suggesting synergistic or additive interactions. Fractional inhibitory concentration index (FICI) analysis confirmed that most combinations exhibited synergy or additive effects. These findings highlight the potential of CPP-modified peptides as antimicrobial agents and underscore the importance of optimizing peptide combinations for therapeutic applications. Full article

(This article belongs to the Section Molecular Microbiology)

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18 pages, 1827 KiB

Open AccessArticle

Exploring the Impact of Extraplatelet Content on Fibrin-Based Scaffold Performance for Regenerative Therapies

by Daniel Marijuán-Pinel, Jon Mercader-Ruiz, Maider Beitia, Pello Sánchez, Leonor López de Dicastillo, Sergio Gonzalez, João Espregueira-Mendes, Beatriz Aizpurua, Jaime Oraá, Diego Delgado and Mikel Sánchez

Int. J. Mol. Sci. 2025, 26(13), 5967; https://doi.org/10.3390/ijms26135967 (registering DOI) - 21 Jun 2025

Abstract

This study investigated the impact of increased extraplatelet content on the tissue regenerative capacity of platelet-rich plasma (PRP)-derived fibrin scaffolds. Comparative analyses were performed between a “balanced protein-concentrate plasma” (BPCP) and a standard PRP (sPRP), focusing on platelet and fibrinogen content, scaffold microstructure, [...] Read more.

This study investigated the impact of increased extraplatelet content on the tissue regenerative capacity of platelet-rich plasma (PRP)-derived fibrin scaffolds. Comparative analyses were performed between a “balanced protein-concentrate plasma” (BPCP) and a standard PRP (sPRP), focusing on platelet and fibrinogen content, scaffold microstructure, and functional performance. Growth factor (GF) release kinetics from the scaffolds were quantified via ELISA over 10 days, while scaffold biomechanics were evaluated through rheological testing, indentation, energy dissipation, adhesion, and assessments of coagulation dynamics, biodegradation, swelling, and retraction. Microstructural analysis was conducted using scanning electron microscopy (SEM), with fiber diameter and porosity measurements. The results demonstrated that BPCP scaffolds released significantly higher amounts of GFs and total protein, especially beyond 24 h (* p < 0.05). Despite a delayed coagulation process (** p < 0.01), BPCP scaffolds exhibited superior structural integrity and cushioning behavior (* p < 0.05). SEM revealed thicker fibers in BPCP scaffolds (**** p < 0.0001), while adhesion and biodegradation remained unaffected. Notably, BPCP scaffolds showed reduced retraction after 24 h and maintained their shape stability over two weeks without significant swelling. These findings indicate that enhancing the extraplatelet content in PRP formulations can optimize fibrin scaffold performance. Further preclinical and clinical studies are warranted to evaluate the therapeutic efficacy of BPCP-derived scaffolds in regenerative medicine. Full article

(This article belongs to the Special Issue Recent Progress in Regenerative Therapy Using Blood-Derived Biomaterials)

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11 pages, 773 KiB

Open AccessReview

Inhaled Allergy Diagnostics and Treatment in a Polluted Environment

by Marcel Mazur and Ewa Czarnobilska

Int. J. Mol. Sci. 2025, 26(13), 5966; https://doi.org/10.3390/ijms26135966 (registering DOI) - 21 Jun 2025

Abstract

Allergic diseases have been increasing in prevalence over the last years. In a polluted environment, this problem can worsen and become more complex. Long-term exposure to air pollution can lead to the aggravation of allergic rhinitis (AR) and even to the development of [...] Read more.

Allergic diseases have been increasing in prevalence over the last years. In a polluted environment, this problem can worsen and become more complex. Long-term exposure to air pollution can lead to the aggravation of allergic rhinitis (AR) and even to the development of seasonal asthma. Climate changes can accelerate and extend the pollination season. Research indicates that air pollution may modify the properties of pollen, making it more aggressive. Asymptomatic allergic people disclose their allergies in a polluted environment. A polluted environment complicates the diagnosis of seasonal allergies. The treatment might be more challenging as standard allergy medications may not be enough to control symptoms. The causal treatment of allergic rhinitis is specific allergen immunotherapy (AIT), which may prove less effective in people living in a polluted environment. The problem may lie in the proper evaluation for AIT as well as the assessment of its effectiveness. To date, the best way to confirm an allergy and qualify a patient for AIT seems to be molecular diagnostics. The question arises whether patients exposed to air pollution, which could potentially reduce the effectiveness of AIT, are still eligible for AIT. It is also debatable whether molecular diagnostics remain effective in such cases. Advancing precision medicine alongside environmental management represents a critical pathway toward reducing the growing global burden of allergic diseases. Full article

(This article belongs to the Special Issue Molecular Therapeutic Strategies in Allergic Diseases)

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