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Background: Stattic offers a unique inhibitory effect on the STAT3 signaling pathway, a crucial mechanism in the progression of metastatic cancer. However, the development of Stattic has been impeded by its hydrophobicity and lack of specificity. To overcome these limitations, encapsulation of Stattic with polymeric micelles was previously attempted, which led to a significant increase in the potency of Stattic on breast cancer cell lines. The presence of albumin was believed to contribute to such enhancement, as the protein corona layer formation helps retain the micellar structure before eventual uptake by the cells. Moreover, a previous study had reported the unique affinity of Stattic towards albumin molecule. Objective: This study aimed to explore the integration of Stattic in albumin-based nanoparticles and to assess the in vitro effects. Methods: Albumin/Stattic nanoparticles were prepared by crosslinking with glutaraldehyde. Results: The yielded nanoparticles were 150.0 ± 6.6 nm in size, with 53% entrapment efficiency. The cumulative release of Stattic in a tumoric acidic environment (pH 5.3; 59%) was 2.6-fold more than neutral environment (pH 7.4; 23%). In blood plasma, 7% cumulative release was observed. The mathematical modeling of the release kinetics revealed that the albumin/Stattic nanoparticles in phosphate buffer saline and plasma followed Korsmeyer-Peppas and Higuchi models, respectively. Among the two cell lines tested, metastatic MDA-MB-231 cells were more sensitive to entrapment of Stattic with albumin nanoparticles, as the IC50 value decreased by 2.5-fold compared to free Stattic. Conclusion: This study reports the formation of low immunogenic and cost-efficient albumin nanoparticles to improve the delivery of Stattic.

Most cases of hepatocellular carcinoma (HCC) arise with the fibrotic microenvironment where hepatic stellate cells (HSCs) and carcinoma-associated fibroblasts (CAFs) are critical components in HCC progression. Therefore, CAF normalization could be a feasible therapy for HCC. Galectin-1 (Gal-1), a β-galactoside-binding lectin, is critical for HSC activation and liver fibrosis. However, few studies has evaluated the pathological role of Gal-1 in HCC stroma and its role in hepatic CAF is unclear. Here we showed that Gal-1 mainly expressed in HCC stroma, but not cancer cells. High expression of Gal-1 is correlated with CAF markers and poor prognoses of HCC patients. In co-culture systems, targeting Gal-1 in CAFs or HSCs, using small hairpin (sh)RNAs or an therapeutic inhibitor (LLS30), downregulated plasminogen activator inhibitor-2 (PAI-2) production which suppressed cancer stem-like cell properties and invasion ability of HCC in a paracrine manner. The Gal-1-targeting effect was mediated by increased a disintegrin and metalloprotease 17 (ADAM17)-dependent TNF-receptor 1 (TNFR1) shedding/cleavage which inhibited the TNF-α → JNK → c-Jun/ATF2 signaling axis of pro-inflammatory gene transcription. Silencing Gal-1 in CAFs inhibited CAF-augmented HCC progression and reprogrammed the CAF-mediated inflammatory responses in a co-injection xenograft model. Taken together, the findings uncover a crucial role of Gal-1 in CAFs that orchestrates an inflammatory CSC niche supporting HCC progression and demonstrate that targeting Gal-1 could be a potential therapy for fibrosis-related HCC.

Breast cancer is the most commonly diagnosed cancer among women and one of the leading causes of cancer mortality worldwide, in which the most severe form happens when it metastasizes to other regions of the body. Metastasis is responsible for most treatment failures in advanced breast cancer. Epithelialmesenchymal transition (EMT) plays a significant role in promoting metastatic processes in breast cancer. MicroRNAs (miRNAs) are highly conserved endogenous short noncoding RNAs that play a role in regulating a broad range of biological processes, including cancer initiation and development, by functioning as tumor promoters or tumor suppressors. Expression of miR-548m has been found in various types of cancers, but the biological function and molecular mechanisms of miR-548m in cancers have not been fully studied. Here we demonstrated the role of miR-548m in modulating EMT in the breast cancer cell lines MDA-MB-231 and MCF-7. Expression data for primary breast cancer obtained from NCBI GEO data sets showed that miR-548m expression was downregulated in breast cancer patients compared with healthy group. We hypothesize that miR-548m acts as a tumor suppressor in breast cancer. Overexpression of miR-548m in both cell lines increased E-cadherin expression and decreased the EMT-associated transcription factors SNAI1, SNAI2, ZEB1, and ZEB2, as well as MMP9 expression. Consequently, migration and invasion capabilities of both MDA-MB-231 and MCF-7 cells were significantly inhibited in miR-548m-overexpressing cells. Analysis of 1,059 putative target genes of miR-548m revealed common pathways involving both tight junction and the mTOR signaling pathway, which has potential impacts on cell migration and invasion. Furthermore, this study identified aryl hydrocarbon receptor (AHR) as a direct target of miR-548m in breast cancer cells. Taken together, our findings suggest a novel function of miR-548m in reversing the EMT of breast cancer by reducing their migratory and invasive potentials, at least in part via targeting AHR expression.

Background: Liposomes are mostly known to be prepared from phospholipids and lipids and have a remarkable capacity to encapsulate both lipophobic and lipophilic molecules. However, there is little research on developing fatty acid liposomes for chemotherapy. Objective: We have successfully prepared mixed fatty acid liposomes from two monounsaturated fatty acids, namely oleic acid and erucic acid, which stabilised by DOPEPEG2000. The Critical Vesicular Concentration (CVC) of liposomes was found to be within 0.09 to 0.21 mmol dm-3, with an average particle size of 400 nm. Methods: Encapsulation of various anticancer drugs such as folinic acid, methotrexate, doxorubicin, or irinotecan resulted in Encapsulation Efficiency (%EE) of up to 90%. Using a 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the median Inhibitory Concentration (IC50) values of mixed oleic acid-erucic acid encapsulating hydrophilic drugs was remarkably reduced at the end of 24 hours of incubation with the human lung carcinoma cell line A549. Results: The results suggest that mixed oleic acid-erucic acid liposomes are a potential new approach to further develop as an alternative vehicle of various drugs for cancer treatment.

Background: Liposomes are mostly known to be prepared from phospholipids and lipids and have a remarkable capacity to encapsulate both lipophobic and lipophilic molecules. However, there is little research on developing fatty acid liposomes for chemotherapy. Objective: We have successfully prepared mixed fatty acid liposomes from two monounsaturated fatty acids, namely oleic acid and erucic acid, which stabilised by DOPEPEG2000. The Critical Vesicular Concentration (CVC) of liposomes was found to be within 0.09 to 0.21 mmol dm-3, with an average particle size of 400 nm. Methods: Encapsulation of various anticancer drugs such as folinic acid, methotrexate, doxorubicin, or irinotecan resulted in Encapsulation Efficiency (%EE) of up to 90%. Using a 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the median Inhibitory Concentration (IC50) values of mixed oleic acid-erucic acid encapsulating hydrophilic drugs was remarkably reduced at the end of 24 hours of incubation with the human lung carcinoma cell line A549. Results: The results suggest that mixed oleic acid-erucic acid liposomes are a potential new approach to further develop as an alternative vehicle of various drugs for cancer treatment.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, partly due to the lack of targeted therapy available. Cancer cells heavily reprogram their metabolism and acquire metabolic plasticity to satisfy the high-energy demand due to uncontrolled proliferation. Accumulating evidence shows that deregulated lipid metabolism affects cancer cell survival, and therefore we sought to understand the function of fatty acid binding protein 7 (FABP7), which is expressed predominantly in TNBC tissues. As FABP7 was not detected in the TNBC cell lines tested, Hs578T and MDA-MB-231 cells were transduced with lentiviral particles containing either FABP7 open reading frame or red fluorescent protein. During serum starvation, when lipids were significantly reduced, FABP7 decreased the viability of Hs578T, but not of MDA-MB-231, cells. FABP7-overexpressing Hs578T (Hs-FABP7) cells failed to efficiently utilize other available bioenergetic substrates such as glucose to sustain ATP production, which led to S/G2 phase arrest and cell death. We further showed that this metabolic phenotype was mediated by PPAR-α signaling, despite the lack of fatty acids in culture media, as Hs-FABP7 cells attempted to survive. This study provides imperative evidence of metabolic vulnerabilities driven by FABP7 via PPAR-α signaling.

Many Gram-negative pathogens employ type three secretion systems to translocate specialised bacterial effector proteins into the host cell. Endogenous levels of arginine-GlcNAcylation by two Salmonellaeffectors, SseK1 and SseK3, were determined by quantitative MS-based proteomics. The effectors modified different host death domain containing signaling proteins required for inflammatory and cell death signaling. The study developed new tools to study host-effector interactions and established the importance of native levels of effector expression in distinguishing between authentic and misleading interactions and activities.

ABSTRACTThis study aims to assess COVID-19 vaccine acceptance among Muslims in Malaysia. A cross-sectional internet-based survey was to determine acceptance of COVID-19 vaccine. Other influential factors, namely socio-demographics, COVID-19 experience, self-perceived level of religiosity, support in immunization, COVID-19 immunization attitudes, and health fatalistic beliefs (measured using the Helpless Inevitability Subscale of the Religious Health Fatalism Questionnaire, RHFQ-HI) were investigated. The majority reported a definite intent to receive the COVID-19 vaccine (57.3%; 95% CI 55.0–59.6) followed by a probable intent (42.7%; 95% CI 40.4–45.0%). COVID-19 immunization attitudes measured by attitudinal barriers to vaccination scores were found to be the strongest influence of COVID-19 vaccination intent, whereby participants who have lower attitudinal barrier scores reported higher COVID-19 vaccination intent (OR = 6.75 ; 95% 5.20–8.75). Although religious health fatalism was not significantly associated with vaccination intent, a significantly higher proportion of participants with score 4–9 (61.9%) in the RHFQ-HI reported intent to receive COVID-19 vaccine than those with a score of 10–20 (53.5%), p < .001. Intervention for people with skeptical attitudes toward COVID-19 vaccination is warranted.

Stattic is a signaling pathway inhibitor that could potentially impede the progression of tumor metastasis. However, the pharmaceutical applications of Stattic are hampered by its poor water solubility. In this study, we explored the integration of Stattic within amphiphilic pendant-dendron copolymeric (P71D3) micelles to improve its water solubility and delivery towards tumor cells. The P71D3/Stattic micelles with a 1:1.2 (P71D3:Stattic) ratio optimized for subsequent studies were 164 nm in diameter with a drug loading percentage of 52% w/w. These P71D3/Stattic micelles demonstrated a higher drug release (32%) in acidic tumor conditions compared to neutral physiological conditions (14%). However, rapid and high Stattic release was observed when dialyzed against a simulated plasma solution containing 4% albumin. Interestingly, when the same Stattic-loaded micelles and 4% albumin solution were in direct contact, the albumin molecules bound to the surface of the micelles, forming a protein corona. P71D3/Stattic micelles were found to be 30- to 90-fold more potent and to decrease the effective antimotility concentration by 3- to 6-fold compared to free Stattic in metastatic human and murine mammary cancer cells. The P71D3/Stattic micelles effectively enhanced the potency of the drug as determined from the in vitrostudies, suggesting the use of P71D3/Stattic micelles as a promising antimetastatic agent worthy of further study.

For intracellular pathogens to thrive in host cells, an environment that supports survival and replication needs to be established. L. pneumophilaaccomplishes this through the activity of the ∼330 effector proteins that are injected into host cells during infection. Effector functions range from hijacking host trafficking pathways to altering host cell machinery, resulting in altered cell biology and innate immunity. One such pathway is the host protein synthesis pathway. Five L. pneumophilaeffectors have been identified that alter host cell translation, and 2 effectors have been identified that indirectly affect host cell transcription. No pathogenic effectors have been described that directly interfere with host cell transcription. Here we show a direct interaction of the AnkH effector with a host cell transcription complex involved in transcriptional elongation. We identify a novel process by which AnkH interferes with host transcriptional elongation through interference with formation of a functional complex and show that this interference is required for pathogen proliferation.