Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Sirtuins (SIRTs) are NAD+-dependent enzymes implicated in cancer and other diseases, but the high conservation of their catalytic sites complicates the development of isoform-selective inhibitors. BZD9L1 is a benzimidazole-based sirtuin inhibitor with previously reported activity against SIRT1 and SIRT2. However, its potential interactions with other human sirtuin isoforms remain incompletely characterized. Here, we applied a comparative structure-based modelling framework integrating homology modelling, molecular docking, and targeted experimental assessment to investigate plausible binding modes of BZD9L1 across human SIRT1-7. Docking predicted that BZD9L1 could occupy the ADP-ribose cofactor-binding region of all seven isoforms, with broadly conserved orientations but differences in the predicted interaction networks. Hydrogen-bonding and π-mediated contacts predominated in the selected SIRT1-3 poses, whereas hydrophobic contacts were more apparent in several selected SIRT4-7 poses. The modest differences in docking scores were interpreted qualitatively and do not establish differential binding affinities or isoform selectivity. In colorectal cancer cells, BZD9L1 treatment altered acetyl-SOD2 levels, consistent with altered SIRT3-associated deacetylation in a cellular context. In a separate cell-free enzymatic assay, no measurable SIRT5 inhibition was detected under the conditions tested. These complementary assays provided distinct, independently interpreted readouts of SIRT3-associated cellular activity and SIRT5 enzymatic activity. Collectively, this study provides testable structural hypotheses regarding BZD9L1 recognition by human sirtuins and identifies interaction features that may guide subsequent biochemical and structure-based investigations.

HPV infection is a major global health concern, and recent evidence suggests that the gut microbiota may play a critical role in HPV progression and clearance. This study aimed to evaluate the modulatory effects of the probiotic strain Lactiplantibacillus plantarum Probio87 on the gut bacterial composition of HPV-positive women. A 12-week randomized, placebo-controlled trial was conducted in accordance with the Declaration of Helsinki, with ethical approval from the Medical Research and Ethics Committee, Ministry of Health Malaysia (NMRR-21-1819-61300), and registration at ClinicalTrials.gov (NCT05316064). Probiotic supplementation with L. plantarum Probio87 significantly modulated the gut microbiota. Specifically, reductions were observed in the relative abundance of potentially pathogenic bacteria, including Gardnerella vaginalis (p = 0.055), Fannyhessea vaginae (p = 0.039), and Bilophila species (p = 0.008). Conversely, levels of beneficial microbes such as L. plantarum (p = 0.001), Anaerotignum lactatifermentans (p = 0.039), Blautia faecis (p = 0.061), and Roseburia hominis A2-183 (p = 0.052) were elevated. These findings suggest that L. plantarum Probio87 promotes gut microbial balance by reducing dysbiosis-associated bacteria and enhancing beneficial populations. This modulation may contribute to improved vaginal and overall health in women with HPV infection.

Objectives:The current study investigated angiogenesis-arresting attributes of Mesua ferrea oleo-gum resin extract and its underlying molecular mechanisms. Methods:Series of in vitro, ex vivo and in vivo models were used to assess anti-angiogenic properties. Results:MTT cell viability experiments showed that oleo-gum resin extract induced moderate cytotoxicity towards EA.hy926 cells (IC50 = 42 µg/mL). Extract-treated cells showed significant reduction in invasion, migration, and tube formation potential. At the protein level, down-regulation in expression of angiopoietin-1 and -2, Tie-2, MMP-1 and -9, VEGF-A, and VEGFR2 pro-angiogenic proteins was observed in extract-treated EA.hy926 cells. Signalling array data indicated a marked down-regulation of transcription factors, i.e., HIF-1α and WNT (-3.68 ± 5.74 and -6.24 ± 6.50 fold-change). Furthermore, extract treatment diminished vessel-sprouting in in vitro 3D spheroids, ex vivo rat aorta ring, and in vivo chick embryo chorioallantoic membrane models. Treatment with extract significantly reduced intracellular ROS and caspases-8 and -9 levels. GC-MS and HPLC analyses of extract indicated the presence of (+)-α-longipinene, isoledene, cedrene and α-elemene. ADMET prediction of detected compounds revealed good intestinal absorption (> 90%) and skin permeability (log Kp < -2.5), making the extract a suitable candidate for the treatment of angiogenesis-associated intestinal and skin disorders. Conclusion:Overall, these findings suggest that Mesua ferrea extract exhibits anti-angiogenic properties by down-regulating the VEGF/angiopoietin axis, warranting further investigations in treating angiogenesis-associated diseases.

Background/Objectives: This study evaluated the in vitro probiotic potential of Lactiplantibacillus plantarum Probio87 (Probio87), focusing on its physiological robustness, safety, antimicrobial properties, and anticancer activity, with relevance to vaginal and cervical health. Methods: Tests included acid and bile salt tolerance, mucin adhesion, and carbohydrate utilization. Prebiotic preferences were assessed using FOS, GOS, and inulin. Antibiotic susceptibility was evaluated per EFSA standards. Antimicrobial activity of the cell-free supernatant (CFS) was tested against Staphylococcus aureus, Escherichia coli, and Candida species. Effects on Lactobacillus iners and L. crispatus were analyzed. Anticancer properties were assessed in HeLa, CaSki (HPV-positive), and C-33A (HPV-negative) cervical cancer cell lines through proliferation, apoptosis, angiogenesis, and cell cycle assays. Results: Probio87 showed strong acid and bile tolerance, efficient mucin adhesion, and broad carbohydrate utilization, favoring short-chain prebiotics like FOS and GOS over inulin. It met EFSA antibiotic safety standards. The CFS exhibited potent antimicrobial activity, including complete inhibition of Candida albicans. Probio87 selectively inhibited L. iners without affecting L. crispatus, indicating positive modulation of vaginal microbiota. In cervical cancer cells, the CFS significantly reduced proliferation and angiogenesis markers (p < 0.05), and induced apoptosis and cell cycle arrest in HPV-positive cells, with minimal effects on HPV-negative C-33A cells. Conclusions: Probio87 demonstrates strong probiotic potential, with safe, selective antimicrobial and anticancer effects. Its ability to modulate key microbial and cancer-related pathways supports its application in functional foods or therapeutic strategies for vaginal and cervical health.

This study examined the effects of administering the probiotic Lactiplantibacillus plantarum Probio87 on the vaginal microbiota of HPV-positive women, highlighting alterations in bacterial and fungal communities and their potential influence on vaginal and overall health. In a double-blind, randomized, placebo-controlled study, participants consumed daily doses of Probio87 (1 × 109 CFU/sachet) or a placebo for 12 weeks. Vaginal swabs were collected, and DNA was extracted for 16S rRNA and the internal transcribed spacer (ITS) region amplification via PCR, followed by sequencing of bacterial and fungal microbiota. The probiotic group showed improved alpha and beta diversity, with an increase in beneficial Lactobacillus (p = 0.014) and Phascolarctobacterium faecium (p = 0.041), while decreasing the abundance of pathogens like Streptococcus and Candida (p = 0.011). Additionally, vaginal health questionnaires linked probiotic use to improved vaginal and mental health in HPV-positive women. L. plantarum Probio87 demonstrated clinical and psychological benefits in HPV-positive women by balancing the vaginal microbiome, reducing pathogenic species, and promoting the growth of beneficial microorganisms.

Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.

Human papillomavirus (HPV) is a sexually transmitted virus, whose persistent infection is the main reason for invasive cervical cancer (ICC), which is the fourth most common type of cancer in women, with more than 500 000 new cases every year. After infection, various alterations occur in the host, facilitating the virus's evasion of immune system clearance and promoting its proliferation. Oral probiotic consumption can influence the whole body's immunity, inflammatory reflection, neural, endocrine humoral, metabolic pathways and other organs by adjusting the components of gut microbiota (GM). Some evidence shows there is a tight connection between GM and vaginal microbiota (VM), which is referred to as the gut-vaginal axis. This review investigates the potential role of probiotics in clearing HPV via the gut-vagina axis, emphasizing the effectiveness of Lactobacillus in preventing vaginal diseases and suggesting its potential for HPV clearance. Understanding the role of probiotics in the gut-vagina axis could pave the way for new strategies to reduce and eliminate HPV and related diseases.

Growing evidence has highlighted that mitochondrial dysfunction contributes to drug-induced toxicities and leads to drug attrition and post-market withdrawals. The acetylation or deacetylation of mitochondrial proteins can affect mitochondrial functions as the cells adapt to various cellular stresses and other metabolic challenges. SIRTs act as critical deacetylases in modulating mitochondrial function in response to drug toxicity, oxidative stress, reactive oxygen species (ROS), and energy metabolism. We previously showed that a recently characterised SIRT inhibitor (BZD9L1) is non-toxic in rodents in a short-term toxicity evaluation. However, the impact of BZD9L1 on mitochondrial function is unknown. This work aims to determine the effects of BZD9L1 on mitochondrial function in human normal liver and kidney-derived cell lines using the Agilent Seahorse Cell Mito Stress Test to complement our short-term toxicity evaluations in vivo. The Mito Stress assay revealed that BZD9L1 could potentially trigger oxidative stress by inducing ROS, which promotes proton leak and reduces coupling efficiency in liver-derived THLE cells. However, the same was not observed in human kidney-derived HEK293 cells. Interestingly, BZD9L1 had no impact on SIRT3 protein expression in both cell lines but affected SOD2 and its acetylated form at 72 h in THLE cells, indicating that BZD9L1 exerted its effect through SIRT3 activity rather than protein expression. In contrast, BZD9L1 reduced SIRT1 protein expression and impacted the p53 protein differently in both cell lines. Although BZD9L1 did not affect the spare respiratory capacity in vitro, these findings call for further validation of mitochondrial function through assessment of other mitochondrial parameters to evaluate the safety of BZD9L1.

One of the serious health problems of today's societies is cancer, which many efforts have been made to deal with. Despite the many studies conducted in the field of cancer treatment and the provision of various treatments in this field, cancer cells show resistance to the offered treatment strategies (even chemotherapy) and leave the offered treatments without results. Therefore, scientists have tried (especially in the last two decades) to use smart ways to successfully fight cancer. Among

PDF file - 473K, Blockade of Notch signaling in endothelial cells by DBZ in vitro. Western blotting showed that the protein levels of activated Notch intracellular domain (NICD) and Hes-1 were significantly reduced by DBZ in human umbilical vein endothelial cells (HUVEC). HUVEC were grown to confluence and treated with increasing concentrations of DBZ for 8 hours.

PDF 584K, Combination therapy by blockade of both Notch signaling and the VEGF pathway displayed a synergistic therapeutic efficacy in HT1080 xenografted tumors. Single therapy with either DBZ or bevacizumab did not affect tumor growth and animal survival but combined DBZ with bevacizuamb synergistically inhibited tumor growth and increased animal survival in HT1080 xenografted tumors. Mean SE, N=5. *P<0.05, **P<0.01.

PDF file - 4.04 MB, DLL4 downregulated the expression of VEGFR3 in human microvascular EC in vitro and in xenograft tumor in vivo. (A). The expression of VEGFR3 at a mRNA level was decreased in human micrcovascular EC (hMEC-1) cultured in vitro after the 24 hour stimulation by recombinant hDLL4 coated on plates, as revealed by qPCR. (B). The expression of mouse VEGFR3 at a protein level was decreased in tumor neovasculature of U87-DLL4 xenografts versus U87-EV xenografts. Mean SE, N=5. **P<0.01.

Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today. Drug insensitivity and resistance are critical hurdles in cancer treatment; therefore, the development of new entities targeting malignant cells is considered a high priority. Targeted therapy is the cornerstone of precision medicine. The synthesis of benzimidazole has garnered the attention of medicinal chemists and biologists due to its remarkable medicinal and pharmacological properties. Benzimidazole has a heterocyclic pharmacophore, which is an essential scaffold in drug and pharmaceutical development. Multiple studies have demonstrated the bioactivities of benzimidazole and its derivatives as potential anticancer therapeutics, either through targeting specific molecules or non-gene-specific strategies. This review provides an update on the mechanism of actions of various benzimidazole derivatives and the structure‒activity relationship from conventional anticancer to precision healthcare and from bench to clinics.

PDF 712K, In vivo expression of mHey1, a downstream target of Notch signaling in the mouse stroma/ECs of U87 tumors. The relative expression of mHey1 in tumor tissues was analyzed by qPCR against mRNA extracted from xenograft tumors using mouse specific primers. Mean SE, N=5. *P<0.05; **P<0.01.

We previously reported that breast milk from women with (W) or without (WO) vaginal yeast infection during pregnancy differs in its immunological and antimicrobial properties, especially against pathogenic vaginal Candida sp.. Here, we investigated the differences in microbiota profiles of breast milk from these groups. Seventy-two breast milk samples were collected from lactating mothers (W, n=37; WO, n=35). The DNA of bacteria was extracted from each breast milk sample for microbiota profiling by 16S rRNA gene sequencing. Breast milk from the W-group exhibited higher alpha diversity than that from the WO-group across different taxonomic levels of class (P=0.015), order (P=0.011), family (P=0.020), and genus (P=0.030). Compositional differences between groups as determined via beta diversity showed marginal differences at taxonomic levels of phylum (P=0.087), family (P=0.064), and genus (P=0.067). The W-group showed higher abundances of families Moraxellaceae (P=0.010) and Xanthomonadaceae (P=0.008), and their genera Acinetobacter (P=0.015), Enhydrobacter (P=0.015), and Stenotrophomonas (P=0.007). Meanwhile, the WO-group showed higher abundances of genus Staphylococcus (P=0.046) and species Streptococcus infantis (P=0.025). This study shows that, although breast milk composition is affected by vaginal infection during pregnancy, this may not pose a threat to infant growth and development.

PDF file - 740K, Neither anti-EphrinB2 nor sEphB4 affected the growth of U87-EV tumors in vivo. Compared to the control, neutralizing anti-EphrinB2 antibody (B2) alone (blue arrowhead) did not affect the tumor growth. Also, combined anti-EphrinB2 antibody (blue arrowhead) with bevacizumab (purple arrowhead) did not increase the therapeutic efficacy of bevacizumab. Similar results were obtained for sEphB4. Mean SE, N=5. **P<0.01.

Background and aim: Gemcitabine remains the cornerstone of pancreatic cancer treatment, despite exhibiting a modest effect on patient survival due to the development of drug resistance. NuvastaticTM polymolecular botanical drug Orthosiphon stamineus (O. stamineus) is a folklore Asian herbal medicine that is used for the treatment of a variety of ailments. However, little is known about the mechanism of actions of the NuvastaticTM polymolecular botanical drug of O. stamineus as a complementary therapy in resistant pancreatic cancer. It is postulated that the proprietary O. stamineus extract formulation (ID: C5EOSEW5050ESA) in NuvastaticTM may sensitise resistant pancreatic cancer cells to gemcitabine. This study was conducted to assess the cytotoxic activity and synergistic effects of C5EOSEW5050ESA in gemcitabine-resistant pancreatic cancer cells.Experimental procedure: The effects of C5EOSEW5050ESA treatment on cell viability, multidrug-resistant genes, epithelial-mesenchymal transition, cellular senescence, cell death, and Notch signalling pathway were evaluated in gemcitabine-resistant Panc-1 cells.Results and conclusion: C5EOSEW5050ESA sensitised gemcitabine resistant cells towards C5EOSEW5050ESA-gemcitabine combination treatment by reducing the expression of multidrug-resistant genes and epithelial-mesenchymal transition markers in gemcitabine-resistant cells compared to the control group, possibly through the inhibition of Notch signalling. This study provides valuable insight into using C5EOSEW5050ESA as a potential complementary treatment for resistant pancreatic cancer.(c) 2022 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/).