Genetic Engineering Bacillus thuringiensis Enable Melanin Biosynthesis for Anti-Tumor and Anti-Inflammation.

Collaboration between cancer treatment and inflammation management has emerged as an integral facet of comprehensive cancer care. Nevertheless, the development of interventions concurrently targeting both inflammation and cancer has encountered significant challenges stemming from various external factors. Herein, a bioactive agent synthesized by genetically engineering melanin-producing Bacillus thuringiensis (B. thuringiensis) bacteria, simultaneously achieves eco-friendly photothermal agent and efficient reactive oxygen/nitrogen species (RONS) scavenger benefits, perfectly tackling present toughies from inflammation to cancer therapies. The biologically derived melanin exhibits exceptional photothermal-conversion performance, facilitating potent photonic hyperthermia that effectively eradicates tumor cells and tissues, thereby impeding tumor growth. Additionally, the RONS-scavenging properties of melanin produced by B. thuringiensis bacteria contribute to inflammation reduction, augmenting the efficacy of photothermal tumor repression. This study presents a representative paradigm of genetic engineering in B. thuringiensis bacteria to produce functional agents tailored for diverse biomedical applications, encompassing inflammation and cancer therapy.

Sonosynthetic Cyanobacteria Oxygenation for Self-Enhanced Tumor-Specific Treatment.

Photosynthesis, essential for life on earth, sustains diverse processes by providing nutrition in plants and microorganisms. Especially, photosynthesis is increasingly applied in disease treatments, but its efficacy is substantially limited by the well-known low penetration depth of external light. Here, ultrasound-mediated photosynthesis is reported for enhanced sonodynamic tumor therapy using organic sonoafterglow (ultrasound-induced afterglow) nanoparticles combined with cyanobacteria, demonstrating the proof-of-concept sonosynthesis (sonoafterglow-induced photosynthesis) in cancer therapy. Chlorin e6, a typical small-molecule chlorine, is formulated into nanoparticles to stimulate cyanobacteria for sonosynthesis, which serves three roles, i.e., overcoming the tissue-penetration limitations of external light sources, reducing hypoxia, and acting as a sonosensitizer for in vivo tumor suppression. Furthermore, sonosynthetic oxygenation suppresses the expression of hypoxia-inducible factor 1α, leading to reduced stability of downstream SLC7A11 mRNA, which results in glutathione depletion and inactivation of glutathione peroxidase 4, thereby inducing ferroptosis of cancer cells. This study not only broadens the scope of microbial nanomedicine but also offers a distinct direction for sonosynthesis.

Role of social organization engagement in high-risk groups intervention against HIV/AIDS: a case study from 176 cities of China.

BACKGROUND: A high-risk prevention strategy is an effective way to fight against human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). The China AIDS Fund for Non-Governmental Organizations (CAFNGO) was established in 2015 to help social organizations intervene to protect high-risk populations in 176 cities. This study aimed to evaluate the role of social organizations in high-risk population interventions against HIV/AIDS. METHODS: This study was based on the CAFNGO program from 2016 to 2020. The collected data included the number and types of social organizations participating in high-risk group interventions and the amount of funds obtained by these organizations each year. We explored the factors influencing the number of newly diagnosed AIDS cases using a spatial econometric model. Furthermore, we evaluated the effectiveness of intervention activities by comparing the percentages of the individuals who initially tested positive, and the individuals who took the confirmatory test, as well as those who retested positive and underwent the treatment. RESULTS: Overall, from 2016 to 2020, the number of social organizations involved in interventions to protect HIV/AIDS high-risk populations increased from 441 to 532, and the invested fund increased from $3.98 to $10.58 million. The number of newly diagnosed cases decreased from 9128 to 8546 during the same period. Although the number of cities with overall spatial correlations decreased, the spatial agglomeration effect persisted in the large cities. City-wise, the number of social organizations (direct effect 19.13), the permanent resident population (direct effect 0.12), GDP per capita (direct effect 17.58; indirect effect - 15.38), and passenger turnover volume (direct effect 5.50; indirect effect - 8.64) were the major factors influencing new positive cases confirmed through the testing interventions performed by the social organizations. The initial positive test rates among high-risk populations were below 5.5%, the retesting rates among those who initially tested positive were above 60%, and the treatment rates among diagnosed cases were above 70%. CONCLUSIONS: The spatial effect of social organizations participating in interventions targeting high-risk populations funded by CAFNGO is statistically significant. Nevertheless, despite the achievements of these social organizations in tracking new cases and encouraging treatment, a series of measures should be taken to further optimize the use of CAFNGO. Working data should be updated from social organizations to CAFNGO more frequently by establishing a data monitoring system to help better track newly diagnosed AIDS cases. Multichannel financing should be expanded as well.

Quercetin improves pancreatic cancer chemo-sensitivity by regulating oxidative-inflammatory networks.

Chemotherapy is the main method for controlling pancreatic cancer metastasis but the prevalent chemotherapy resistance limits its utilization. The response of oxidation and inflammation often promotes pancreatic cancer progression and chemo-resistance. It is critical to explore the potential natural products with few side effects to control inflammatory responses and understand the related mechanisms. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti-inflammatory properties, which may be associated with improvement of chemotherapy sensitivity during pancreatic cancer treatment. Quercetin may sensitize pancreatic cancer cells to the chemotherapeutic agents, including bromodomain and extraterminal domain inhibitors (BETI), daunorubicin, gemcitabine, sulforaphane, doxorubicin, and tumor necrosis factor-related signaling apoptosis-inducing ligand (TRAIL). Meanwhile, during the chemo-resistance therapy, many signaling molecules are involved with toll-like receptor 4 (TLR4)-mediated oxidative and inflammatory pathway. The effects of quercetin on other oxidative and inflammatory pathways were also explored. Quercetin may exert antitumor activity during the prevention of pancreatic cancer progression by regulating oxidative and inflammatory networks, which can promote immune escape of cancer cells by inducing immunosuppressive cytokines. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo-sensitivity. PRACTICAL APPLICATIONS: Chemotherapy is the major way for treating pancreatic cancer metastasis but the prevalent chemotherapy resistance caused by oxidative and inflammatory responses limits its utilization. It is necessary to explore the potential natural products with few side effects to prevent the oxidative and inflammatory responses. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti-inflammatory properties, which may be associated with improvement of chemotherapy sensitivity of pancreatic cancer treatment by sensitizing pancreatic cancer cells to various chemotherapeutic agents via the regulation of oxidative and inflammatory networks. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo-sensitivity.

[Professor GAO Wei-bin's clinical experience of electroacupuncture with dense wave at periotic points for neurotic tinnitus].

Professor GAO Wei-bin's clinical experience of electroacupuncture (EA) with dense wave at periotic points for neurotic tinnitus is introduced. Based on the basic theory of TCM and the perspective of neuroanatomy, EA with dense wave at new periotic points (four points at mastoid process) and Ermen (TE 21), Tinggong (SI 19) could have the effects of qi reaching affected area, and play the treatment role of "where the acupoint is, where the efficacy is".

The Ras-ERK signaling pathway regulates acetylated activating transcription factor 2 via p300 in pancreatic cancer cells.

BACKGROUND: Activating transcription factor 2 (ATF2) regulates the expression of downstream target genes and is phosphorylated by the Ras-extracellular-signal-regulated kinase (ERK) pathway. Acetylation of ATF2 is necessary for this type of regulation. However, the molecular mechanism by which the Ras-ERK pathway mediates the regulation of acetylated ATF2 is unknown. This study investigates the mechanism of Ras-ERK pathway-mediated regulation of acetylated ATF2 in maintaining the characteristic phenotype of pancreatic cancer cells. METHODS: This study was carried out using ASPC-1 and BXPC-3 pancreatic cancer cell lines transfected with the double mutant RasG12V/T35S. The levels of phosphorylated ERK1/2 were measured to establish the activated Ras-ERK pathway. The regulation of acetylated ATF2 was examined by detecting the protein level using western blotting, and the effects on cancer cell phenotype were measured using cell viability, proliferation, migration, and apoptosis assays. Also, chromatin immunoprecipitation (ChIP) assays were used to measure the effect on respective downstream target genes. RESULTS: The results showed that RasG12V/T35S reduced the level of acetylated ATF2 in ASPC-1 and BXPC-3 cells. Compared to wild-type ATF2, the mutant ATF2K357Q (which mimics the irreversible acetylated form of ATF2) reduced the cancer cell phenotype and showed decreased enrichment on target genes upon transfection with Ras. Moreover, the level of acetylated ATF2 was regulated by the degradation of p300 through E3 ubiquitin ligase mouse double minute 2 homolog (MDM2). CONCLUSIONS: Activation of the Ras-ERK pathway regulates acetylated ATF2 through degradation of p300 via a proteasome-dependent pathway, which alters the transcription of downstream target genes responsible for the cancer cell phenotype.

The Ras-ERK1/2 signaling pathway regulates H3K9ac through PCAF to promote the development of pancreatic cancer.

AIMS: The regulation of the Ras-ERK pathway is the crucial point in pancreatic carcinogenesis, and the Ras kinase is an essential regulatory upstream signal molecule of the ERK1/2 pathway. H3K9ac is a vital histone modification, but its specific role in pancreatic cancer remains unclear. This research aims to study whether the modification level of H3K9ac can regulate the characteristic phenotype of the pancreatic cancer cells by affecting the downstream expression, proliferation, migration, and other related genes. MAIN METHODS: The RasG12V/T35S were used to transfect pancreatic cancer cells, and the levels of phosphorylated ERK1/2 and H3K9ac were detected by western blotting. The colony formation assay, transwell assay, and chromatin immunoprecipitation assay were used to study cell viability, migration, and the downstream genes of the ERK1/2 pathway. KEY FINDINGS: The results showed that Ras ERK1/2 reduced H3K9ac expression in ASPC-1 cells, and H3K9ac significantly repressed the viability of cells, colony formation, and ASPC-1 cell movement induced by Ras ERK1/2. Besides, HDAC1 silencing increased H3K9ac expression, and changed the effect of Ras ERK1/2 on ASPC-1 cells proliferation, its movement, and mRNAs of ERK1/2 downstream genes. Moreover, Ras ERK1/2 inhibited H3K9ac expression by the degradation of PCAF via MDM2. SIGNIFICANCE: Ras ERK1/2 promotes pancreatic carcinogenesis cell movement, through down-regulating H3K9ac via MDM2 mediated PCAF degradation.