Current Pharmaceutical Biotechnology - Online First

This study investigated the role and potential mechanisms of discoidin domain receptor 1 (DDR1) in colon fibrogenesis.

We employed the DSS-induced chronic colitis and fibrosis model to evaluate the therapeutic potential of DDR1 knockout on colonic fibrosis. In vitro experiments involved generating human normal colonic epithelial cells (HIEC line) with DDR1 overexpression by lentivirus transfection. Human colonic fibroblasts were exposed to conditioned medium (CM) from the stably transfected cells that had been treated with transforming growth factor-beta 1 (TGF-β1). The cells were collected for molecular and biochemical analyses.

Our proteomics analysis of DDR1 indicated significant enrichment of proteins involved in the extracellular matrix and fibrosis. In DSS-treated DDR1-KO mice, attenuation of colonic fibrosis and reduced activation of colonic fibroblasts were observed, contrasting significantly with their counterparts in DSS-treated WT mice. Colonic fibroblasts exhibited a marked increase in α-smooth muscle actin and type I collagen expression when exposed to CM from HIEC cells with DDR1 overexpression. Finally, overexpression of DDR1 markedly elevated the levels of p-PI3K, p-Akt, p-mTOR, p62, and LC3B in HIEC cells, resulting in enhanced secretion of TGF-β1.

DDR1 in HIEC cells attenuates autophagy primarily by activating the PI3K/AKT/ mTOR signaling axis and concurrently increasing the autophagic markers LC3B and p62, thereby inducing paracrine secretion of TGF-β1, which drives the activation and proliferation of colonic fibroblasts and elicits a robust profibrotic response.

Our study suggests that DDR1 may be a potential therapeutic target for colonic fibrosis.

Rabies Virus (RV or RABV) is a neurophilic pathogen predominantly transmitted to humans through bites, scratches, or wounds. Upon entering the central nervous system, the virus can cause severe symptoms, including acute encephalitis and paralysis, ultimately leading to death with an almost 100% mortality rate. Hence, it is essential to develop an effective oral rabies vaccine.

We designed and synthesized three modified 5'-cap mRNA vaccines (RV-01(CAP-01), RV-01(CAP-02) and RV-01(CAP-03)) encoding rabies virus glycoproteins in vitro and evaluated their immunogenicity and protective effect in mice.

The modified 5'-cap vaccine was successfully constructed and could be effectively expressed in HEK293 cells. The antibody detection results revealed the abundance of RABV-G in RV-01(CAP-01), RV-01(CAP-02) and RV-01(CAP-03). ELISPOT assays indicated that these variants promoted the production of immune-related cytokines. Furthermore, the modified 5'-cap vaccines could reduce the rabies viral load of mice and effectively prolong their survival.

The rabies mRNA vaccine had high efficacy and safety in preventing rabies, suggesting the great potential of mRNA as a promising candidate for RABV vaccines. However, the potential causes of the differences in the performance of the three modified 5'-cap rabies mRNA vaccines and the clinical application of 5’-Cap altered rabies mRNA vaccines need to be explored.

Hence, these results demonstrated that the modified 5’-cap mRNA vaccine was effective in inducing immune responses, which might be considered a promising prophylactic strategy for rabies.

Breast cancer is a global health challenge with a high mortality rate of 30% of total cases in a year. Breast cancer presents in 4 main types, namely, TNBC, HER2+, luminal A, and Luminal B. Current treatments, though not without side effects, incur substantial cost, and are rendered ineffective by rising drug resistance. Phytochemicals are being investigated for their beneficial effects on breast cancer. Systematically collecting, organizing, and analyzing this data from available literature could benefit the development of more potent chemopreventive and chemotherapeutic approaches with reduced side effects.

To overcome the challenges posed by diverse naming practices, we adopted a sentiment (subjective) based text-mining approach to systematically extract and analyze data on anti-breast cancer phytochemicals from biomedical literature. This method is based on anchor and associated terms to capture authors’ sentiments regarding the therapeutic potential of these compounds. Subsequently, comprehensive and objective information was extracted and curated for each phytochemical, including target genes, pathways, study type, IC50 values, PMIDs, plant sources, and geographical availability.

PhytoCAT (PhytoChemical Affordable Therapeutics for Breast Cancer) is a comprehensive database of phytochemicals, plant extracts, and essential oils, enriched with links to phytogeographic data and chemical structures. PhytoCAT includes data on 28 essential oils, 470 plant extracts, and 1,649 phytochemical compounds. These compounds were classified into several chemical groups, including alkaloids (167), coumarins (43), flavonoids (290), lignans (47), quinones (43), saponins (27), sesquiterpenoid lactones (40), terpenoids (282), triterpenoid saponins (28), and xanthones (22) groups. Additionally, 505 phytochemicals belong to other subclasses such as esters, glucosides, phenanthrenes, and phenylpropanoids. Further, information on their mechanisms of action is also provided.

Phytochemicals have gained significant attention in recent years because of their potential health benefits, particularly in the prevention and treatment of various diseases, including cancer. Compounds such as curcumin, resveratrol, and epigallocatechin gallate (EGCG) are examples of phytochemicals that have shown promise in preclinical studies. PhytoCAT offers a centralized and searchable database enriched with biological, chemical, and pharmacological details. Its structured presentation allows researchers to identify promising compounds and study patterns in chemical class-specific activity.

PhytoCAT provides an evidence-based platform for researchers and clinicians to explore the potential of phytochemicals in breast cancer management. Although PhytoCAT has an advanced search engine, it lacks analytical tools, which we envisage integrating in the future. future. (https://phytocat.igib.res.in/)

Radiation targets cancer but risks causing infertility by damaging sensitive testes, especially spermatogonia. This study investigates IR-induced testicular damage and assesses PGZ's potential protective role as a ferroptosis inhibitor.

In this study, Seventy-two BALB/c mice were randomly divided into eight groups: a control, PGZ (10, 20, and 30 mg/kg), IR (8 Gy), and IR+ PGZ (in three doses). PGZ was administered for 10 consecutive days, and mice were exposed to IR on the 11^th day of the study. 24 h after RT, the mice's testis tissue was subjected to a series of evaluations to assess oxidative stress and antioxidant parameters, with histopathological analyses conducted one week after IR.

Biochemical analyses revealed that exposure to IR significantly increased ferroptosis markers, while concurrently decreasing intracellular antioxidants GSH. Histological examinations confirmed damage to spermatogenic cells, leading to detachment from the basement membrane and reduced sperm counts. Pre-treatment with PGZ at 30 mg/kg effectively reduced the levels of oxidative stress markers and improved antioxidant levels, demonstrating its potential protective effects against ferroptosis.

The results suggest PGZ can protect against radiation-induced testicular damage by inhibiting ferroptosis and promoting spermatogenesis recovery.

These results indicate that PGZ may act as a protective agent against radiation-induced testicular damage and support the recovery of spermatogenesis following IR exposure. Further research is warranted to explore the molecular mechanisms of PGZ's protective effects.

The research on traditional Chinese medicine (TCM) has experienced the transition from qualitative research to quantitative study. The application of mathematical modeling for data processing and analysis offers a more efficient and precise approach compared to conventional methods, enabling the timely acquisition of key efficacy indicators for preliminary evaluation. Therefore, the concept of mathematical modeling has been proposed to form a systematic theoretical system of TCM and diseases.

The article reviews the application of mathematical models in the research of traditional Chinese medicine in terms of compounding, extraction, optimization, quality evaluation, production, new drug development, pharmacokinetics, pharmacodynamics, and clinical symptom analysis. Relevant Chinese and English literature was obtained from PubMed, Cochrane Library, China Science and Technology Journal Database (VIP), Wanfang Data, CNKI and China Biomedical Literature Database (CBM).

We have found that integrating the concept of mathematical modeling with TCM theory has shortened the cycle of extracting active ingredients in traditional Chinese medicine and the development of new drugs, while also accelerating the realization of maximum clinical efficacy.

However, the comprehensiveness and precision of existing databases remain areas for improvement. In the future, further integration of multi-disciplinary technologies will be essential to advance the convergence of traditional medicine and modern science.

This review explores the application of mathematical models in the study of traditional Chinese medicine. It is evident that mathematical modeling has played a pivotal role in promoting fundamental research and the modernization of TCM.

This study aims to examine the impact of Rukangyin (RKY) and its components, LSQR and QTSS, on various cellular processes and signaling mechanisms in MDA-MB-231 triple-negative breast cancer (TNBC) cells.

Twenty-five Sprague-Dawley (SD) rats were randomly assigned to five groups according to the administered drugs, including the RKY group, LSQR group, QTSS group, fluorouracil group, and blank control group (n=5 in each group). The serum samples from each group were then used as a medicated medium for the culture of the TNBC cell line MDA-MB-231. Cell viability tests, apoptosis detection tests, and migration and invasion tests were used to evaluate the cytotoxicity of treated serum. YAP, TAZ, MST1, and LATS1 protein expression and phosphorylation were examined using conventional western blotting methods.

RKY and its QTSS and LSQR components significantly inhibited cell growth and promoted apoptosis in MDA-MB-231 cells. RKY also significantly blocked cell motility with a comparable effect to that of fluorouracil. All serum groups suppressed YAP and TAZ expressions while increasing p-YAP, p-TAZ, MST1, and LATS1 levels, with RKY showing superior efficacy.

In TNBC cells, RKY appears to enhance the tumor-suppressing signals of the Hippo signaling pathway via MST1, LATS1 activation, while restricting its pro-oncogenic action via YAP and TAZ blockade. However, in vivo and animal model experiments are required to confirm these findings.

RKY-medicated serum effectively inhibits growth, induces apoptosis, and reduces motility in the MDA-MB-231 cell line of breast cancer. This therapeutic potential of RKY on TNBC cells draws attention to the need for more investigations.

Cardiovascular diseases (CVDs) are the leading cause of death globally, often complicated by thromboembolic events. Plasmin, a key enzyme in fibrinolysis, is crucial for managing these conditions. Elevated or reduced plasmin levels can indicate thrombotic risks, making it a valuable diagnostic marker. Recent biotechnological advances have developed diagnostic kits to measure plasmin activity, aiding early detection and intervention. Fungal proteases, particularly from micromycetes, are emerging as promising agents in anticoagulant therapy. This study investigates three Aspergillus species — A. caespitosus, A. jensenii and A. neotritici for their potential to produce novel biomedical components.

The fungi were cultured, and their proteolytic profiles were analyzed. Key findings include the identification of specific proteases with plasmin-like and protein C-activating activities. These enzymes were purified using isoelectric focusing and characterized through SDS-PAGE and zymography.

The study confirmed that A. jensenii, and A. neotritici produce proteases with plasmin-like activity, with A. neotritici showing a single 35 kDa non-specific protease, and A. jensenii exhibiting two proteases (33 kDa and 100 kDa) in the acidic zone and one (110 kDa) in the neutral zone, the latter exhibiting specific chymotrypsin and plasmin-like activity.

Among the studied strains, A. neotritici exhibited the fastest secretion of proteases with plasmin-like activity, making it a promising source of enzymes with potential clinical applications. In contrast, A. caespitosus and A. jensenii displayed more complex protease compositions, featuring multiple active enzymes. Notably, one of the A. jensenii proteases showed pronounced specificity toward chymotrypsin and fibrinolytic substrates, indicating its suitability for the development of targeted therapeutic agents.

These findings suggest the potential of these fungal proteases for developing novel anticoagulant therapies and diagnostic tools.