Inulin Reduces Kidney Damage in Type 2 Diabetic Mice by Decreasing Inflammation and Serum Metabolomics.

This study is aimed at assessing the impact of soluble dietary fiber inulin on the treatment of diabetes-related chronic inflammation and kidney injury in mice with type 2 diabetes (T2DM). The T2DM model was created by feeding the Institute of Cancer Research (ICR) mice a high-fat diet and intraperitoneally injecting them with streptozotocin (50 mg/kg for 5 consecutive days). The thirty-six ICR mice were divided into three dietary groups: the normal control (NC) group, the T2DM (DM) group, and the DM + inulin diet (INU) group. The INU group mice were given inulin at the dose of 500 mg/kg gavage daily until the end of the 12th week. After 12 weeks, the administration of inulin resulted in decreased serum levels of fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), blood urea nitrogen (BUN), and creatinine (CRE). The administration of inulin not only ameliorated renal injury but also resulted in a reduction in the mRNA expressions of inflammatory factors in the spleen and serum oxidative stress levels, when compared to the DM group. Additionally, inulin treatment in mice with a T2DM model led to a significant increase in the concentrations of three primary short-chain fatty acids (SCFAs) (acetic acid, propionic acid, and butyric acid), while the concentration of advanced glycation end products (AGEs), a prominent inflammatory factor in diabetes, exhibited a significant decrease. The results of untargeted metabolomics indicate that inulin has the potential to alleviate inflammatory response and kidney damage in diabetic mice. This beneficial effect is attributed to its impact on various metabolic pathways, including glycerophospholipid metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, and tryptophan metabolism. Consequently, oral inulin emerges as a promising treatment option for diabetes and kidney injury.

Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues.

Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53R172H-Akaluc and p53-mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo. Using these reporters, we identified and traced rare precancerous clones in deep noncancerous tissues in various cancer models. In classic mutp53-driven thymic lymphoma models, we found that precancerous clones exhibit broad chromosome number variations, upregulate precancerous stage-specific genes such as Ybx3 and enhance amino acid transport and metabolism. Inhibiting amino acid transporters downstream of Ybx3 at the early but not late stage effectively suppresses tumorigenesis and prolongs survival. Together, these protein-level mutp53 reporters reveal undercharacterized features and vulnerabilities of precancerous cells during early tumorigenesis, paving the way for precision cancer prevention.

Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.

Glioblastoma (GBM) constitutes the most lethal primary brain tumor for which immunotherapy has provided limited benefit. The unique brain immune landscape is reflected in a complex tumor immune microenvironment (TIME) in GBM. Here, single-cell sequencing of the GBM TIME revealed that microglia were under severe oxidative stress, which induced nuclear receptor subfamily 4 group A member 2 (NR4A2)-dependent transcriptional activity in microglia. Heterozygous Nr4a2 (Nr4a2+/-) or CX3CR1+ myeloid cell-specific Nr4a2 (Nr4a2fl/flCx3cr1Cre) genetic targeting reshaped microglia plasticity in vivo by reducing alternatively activated microglia and enhancing antigen presentation capacity for CD8+ T cells in GBM. In microglia, NR4A2 activated squalene monooxygenase (SQLE) to dysregulate cholesterol homeostasis. Pharmacologic NR4A2 inhibition attenuated the protumorigenic TIME, and targeting the NR4A2 or SQLE enhanced the therapeutic efficacy of immune-checkpoint blockade in vivo. Collectively, oxidative stress promotes tumor growth through NR4A2-SQLE activity in microglia, informing novel immune therapy paradigms in brain cancer. SIGNIFICANCE: Metabolic reprogramming of microglia in GBM informs synergistic vulnerabilities for immune-checkpoint blockade therapy in this immunologically cold brain tumor. This article is highlighted in the In This Issue feature, p. 799.

Lactiplantibacillus plantarum NKK20 Increases Intestinal Butyrate Production and Inhibits Type 2 Diabetic Kidney Injury through PI3K/Akt Pathway.

Nephropathy injury is a prevalent complication observed in individuals with diabetes, serving as a prominent contributor to end-stage renal disease, and the advanced glycation products (AGEs) are important factors that induce kidney injury in patients with diabetes. Addressing this condition remains a challenging aspect in clinical practice. The aim of this study was to explore the effects of Lactiplantibacillus plantarum NKK20 strain (NKK20) which protects against diabetic kidney disease (DKD) based on animal and cell models. The results showed that the NKK20 can significantly reduce renal inflammatory response, serum oxidative stress response, and AGE concentration in diabetic mice. After treatment with NKK20, the kidney damage of diabetic mice was significantly improved, and more importantly, the concentration of butyrate, a specific anti-inflammatory metabolite of intestinal flora in the stool of diabetic mice, was significantly increased. In addition, nontargeted metabolomics analysis showed a significant difference between the metabolites in the mouse serum contents of the NKK20 administration group and those in the nephropathy injury group, in which a total of 24 different metabolites that were significantly affected by NKK20 were observed, and these metabolites were mainly involved in glycerophospholipid metabolism and arachidonic acid metabolism. Also, the administration of butyrate to human kidney- (HK-) 2 cells that were stimulated by AGEs resulted in a significant upregulation of ZO-1, Occludin, and E-cadherin gene expressions and downregulation of α-SMA gene expression. This means that butyrate can maintain the tight junction structure of HK-2 cells and inhibit fibrosis. Butyrate also significantly inhibited the activation of PI3K/Akt pathway. These results indicate that NKK20 can treat kidney injury in diabetic mice by reducing blood glucose and AGE concentration and increasing butyrate production in the intestine. By inhibiting PI3K pathway activation in HK-2 cells, butyrate maintains a tight junction structure of renal tubule epithelial cells and inhibits renal tissue fibrosis. These results suggest that NKK20 is helpful to prevent and treat the occurrence and aggravation of diabetic kidney injury.

Suppressing MDSC Infiltration in Tumor Microenvironment Serves as an Option for Treating Ovarian Cancer Metastasis.

It is still a big puzzle how ovarian cancer cells and the tumor microenvironment (TME) attract lymphocytes infiltration for facilitating metastasis, a leading cause of death from gynecological malignancies. Using genome-wide LncRNA microarray assay, here we report that a LncRNA associated with ovarian cancer metastasis (LncOVM) is highly correlated with poor prognosis and survival. LncOVM interacts with and stabilizes PPIP5K2 by suppressing ubiquitinated degradation to promote complement C5 secretion from ovarian cancer cells. The TME-enriched complement C5 attracts myeloid-derived suppressor cells (MDSCs) infiltration in TME to facilitate metastasis. Knockdown of LncOVM or PPIP5K2 inhibits tumor progression in xenograft models. Application of C5aR antibody or inhibitor (CCX168) inhibits MDSC recruitment and restores the suppression of tumorigenesis and metastasis in vivo. Our study reveals that suppression of ovarian cancer metastasis can be achieved by targeting MDSC infiltration in TME through disrupting LncOVM-PPIP5K2-complement axis, providing an option for treating ovarian cancer patients.

Plasma cells shape the mesenchymal identity of ovarian cancers through transfer of exosome-derived microRNAs.

Ovarian cancer represents a highly lethal disease that poses a substantial burden for females, with four main molecular subtypes carrying distinct clinical outcomes. Here, we demonstrated that plasma cells, a subset of antibody-producing B cells, were enriched in the mesenchymal subtype of high-grade serous ovarian cancers (HGSCs). Plasma cell abundance correlated with the density of mesenchymal cells in clinical specimens of HGSCs. Coculture of nonmesenchymal ovarian cancer cells and plasma cells induced a mesenchymal phenotype of tumor cells in vitro and in vivo. Phenotypic switch was mediated by the transfer of plasma cell-derived exosomes containing miR-330-3p into nonmesenchymal ovarian cancer cells. Exosome-derived miR-330-3p increased expression of junctional adhesion molecule B in a noncanonical fashion. Depletion of plasma cells by bortezomib reversed the mesenchymal characteristics of ovarian cancer and inhibited in vivo tumor growth. Collectively, our work suggests targeting plasma cells may be a novel approach for ovarian cancer therapy.

Targeting Nuclear Receptors for Cancer Therapy: Premises, Promises, and Challenges.

Nuclear receptors are a family of transcription factors localized in cell nuclei, sensing specific ligands and fine-tuning a variety of cell physiological events. They have been intensively investigated in cancer biology. With their excellent properties of druggability and actionability, nuclear receptors have demonstrated much promise as novel therapeutic targets for different cancer types. Accumulating evidence has highlighted the essential roles of certain nuclear receptors in tumor immunology, suggesting the possibility for them to serve as cancer immunotherapeutic targets. Here, we summarize the roles of nuclear receptors in cancer biology and tumor immunology, and underscore the current advances of clinical trials for nuclear receptor-based cancer therapeutics.

Combined Detection of Exosome Concentration and Tumor Markers in Gastric Cancer.

It has been an established fact that exosomes act as a mediator in tumor microenvironment as well as participate actively in intercellular communication between cancer cells. Exosomes carry a variety of molecular cargoes that prevent cyclic degradation and represent the cells of their origin. In this study, the difference in expression levels of exosomes was measured for diagnosis of gastric cancer. We isolated exosomes from plasma by size-selective method. The morphology of the exosomes was characterized by transmission electron microscopy, and the particle size and concentration of the exosomes were detected by NanoSight's Nanoparticle Tracking Analysis. Results indicated that the expression level of exosomes in gastric cancer patients was higher than that in healthy individuals. The specificity and sensitivity were 65.2% and 73.1%, respectively. Currently, clinical tumor markers for gastric cancer detection mainly included Carbohydrate antigen 72-4 (CA72-4), Alpha-fetoprotein, Carbohydrate antigen 125, Carbohydrate antigen 19-9 (CA19-9), Carcinoembryonic Antigen, Carbohydrate antigen 242. When we combined positive rate for combined gastric cancer biomarkers, results showed that exosomes concentration +CA19-9 and exosomes concentration +CA72-4 in the two-combined test can provide enough positive rate. Therefore, it can be concluded that for gastric cancer, the concentration of exosomes may be regarded as a diagnostic indicator, eventually.

Immunoregulatory Functions of Nuclear Receptors: Mechanisms and Therapeutic Implications.

Members of the nuclear receptor superfamily serve as master regulators in signaling by either positively or negatively regulating gene expression. Accumulating evidence has suggested that nuclear receptors are actively involved in immune responses, with specific roles in different immune cell compartments that contribute to both normal function and to disease development. The druggable properties of nuclear receptors have made them ideal modulatory therapeutic targets. Here, we revisit nuclear receptor biology, summarize recent advances in our understanding of the immunological functions of nuclear receptors, describe cell-type-specific roles and specific nuclear receptors in disease pathogenesis, and explore their potential as novel therapeutic targets. These nuclear receptor-dependent alterations in the immune system are amenable to pharmacological manipulation and suggest novel therapeutic strategies.

Epigenetics in ovarian cancer: premise, properties, and perspectives.

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.

Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis.

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

The RNA binding protein SORBS2 suppresses metastatic colonization of ovarian cancer by stabilizing tumor-suppressive immunomodulatory transcripts.

BACKGROUND: Ovarian cancer constitutes one of the most lethal gynecologic malignancies for females. Currently, early detection strategies and therapeutic options for ovarian cancer are far from satisfactory, leading to high diagnosis rates at late stages and disease relapses. New avenues of therapy are needed that target key processes in ovarian cancer progression. While a variety of non-coding RNAs have been proven to regulate ovarian cancer metastatic progression, the functional roles of RNA-binding proteins (RBPs) in this process are less well defined. RESULTS: In this study, we identify that the RBP sorbin and SH3 domain containing 2 (SORBS2) is a potent suppressor of ovarian cancer metastatic colonization. Mechanistic studies show that SORBS2 binds the 3' untranslated regions (UTRs) of WFDC1 (WAP four-disulfide core domain 1) and IL-17D (Interleukin-17D), two secreted molecules that are shown to act as metastasis suppressors. Enhanced expression of either WFDC1 or IL-17D potently represses SORBS2 depletion-mediated cancer metastasis promotion. By enhancing the stability of these gene transcripts, SORBS2 suppresses ovarian cancer invasiveness and affects monocyte to myeloid-derived suppressor cell and M2-like macrophage polarization, eliciting a tumor-suppressive immune microenvironment. CONCLUSIONS: Our data illustrate a novel post-transcriptional network that links cancer progression and immunomodulation within the tumor microenvironment through SORBS2-mediated transcript stabilization.

Continuous production of polymer nanoparticles using a membrane-based flow cell.

We demonstrate the surfactant-free production of polymer nanoparticles using a continuous membrane-based tangential flow cell. Co-current streams of water and polymethylmethacrylate (PMMA)/acetone/water solution were separated by a porous regenerated cellulose (RC) membrane. The water concentration in the PMMA solution was adjusted so that as additional water diffused through the RC membrane, the PMMA solution composition crossed the two phase boundary to precipitate PMMA nanoparticles. The size of these nanoparticles varied with the concentration of the PMMA feed and the amount of water diffusing across the membrane. The size distribution of PMMA particles produced in a continuous flow membrane cell was much narrower than those produced by drop-wise water addition or batch dialysis precipitation of PMMA particles. A continuous production of polymer nanoparticles of high purity and narrow polydispersity are important requirements for biomedical applications such as delivering therapeutics.

[Investigation on injury of liver and kidney among the workers exposed to terephthalic acid, ethylene glycol and(or) dowtherm A].

OBJECTIVE: To study injury of liver and kidney among the workers exposed to terephthalic acid(TPA), ethylene glycol(EG) and(or) dowtherm A(DOW), and research for early biological monitoring indexes. METHODS: By using the method of occupational epidemiology, an investigation of industrial hygiene in a chemical fibre corporation was carried out and the changes of the liver and kidney functions were analyzed among the workers who had been exposed to TPA, EG, DOW. RESULTS: The values of serum gamma-glutamyl traspetidase(GGT) and total bile acid(TBA) in TPA + EG + DOW group men were (35.45 +/- 16.09) U/L, (10.29 +/- 6.76) mumol/L respectively and the values of serum alanine transaminase(ALT) and TBA in TPA + EG + DOW group women were(30.68 +/- 8.58) U/L, (9.53 +/- 6.63) mumol/L respectively, significantly higher than those in TPA, DOW and control groups(P < 0.05, P < 0.01). Compared with TPA, DOW and control groups, the values of urine N-acetyl-beta-D-glucosaminidase(NAG) and beta 2-2-microglobulim (beta 2-MG) in TPA + EG + DOW group of both men and women increased significantly(P < 0.05, P < 0.01), with(5.68 +/- 4.01) U/mmol Cr and (23.49 +/- 13.44) mg/mol Cr, and(6.68 +/- 4.68) U/mmol Cr and (22.80 +/- 13.00) mg/mol Cr, respectively. Analysis of regression indicated that both liver and renal injuries of the workers were evidently correlated with their exposure to TPA, EG and DOW after adjustment for the confounding factors such as sex, smoking, drinking, etc(P < 0.001). CONCLUSION: Based on available knowledge, it is reasonable to assume that the joint actions should be considered on the injury of liver and kidney caused by TPA, EG and(or) DOW among the workers. Serum ALT, GGT, TBA, urine NAG and beta 2-MG should be suggested as biomarkers for liver and kidney damage.