Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.

Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.

Fatty acid binding protein type 7 deficiency preserves auditory function in noise-exposed mice.

Fatty acid-binding protein 7 (FABP7) is vital for uptake and trafficking of fatty acids in the nervous system. To investigate the involvement of FABP7 in noise-induced hearing loss (NIHL) pathogenesis, we used Fabp7 knockout (KO) mice generated via CRISPR/Cas9 in the C57BL/6 background. Initial auditory brainstem response (ABR) measurements were conducted at 9 weeks, followed by noise exposure at 10 weeks. Subsequent ABRs were performed 24 h later, with final measurements at 12 weeks. Inner ears were harvested 24 h after noise exposure for RNA sequencing and metabolic analyses. We found no significant differences in initial ABR measurements, but Fabp7 KO mice showed significantly lower thresholds in the final ABR measurements. Hair cell survival was also enhanced in Fabp7 KO mice. RNA sequencing revealed that genes associated with the electron transport chain were upregulated or less impaired in Fabp7 KO mice. Metabolomic analysis revealed various alterations, including decreased glutamate and aspartate in Fabp7 KO mice. In conclusion, FABP7 deficiency mitigates cochlear damage following noise exposure. This protective effect was supported by the changes in gene expression of the electron transport chain, and in several metabolites, including excitotoxic neurotransmitters. Our study highlights the potential therapeutic significance of targeting FABP7 in NIHL.

Curcumin analog GO-Y030 inhibits tumor metastasis and glycolysis.

Tumor metastasis is one of the worst prognostic features of cancer. Although metastasis is a major cause of cancer-related deaths, an effective treatment has not yet been established. Here, we explore the antitumor effects of GO-Y030, a curcumin analog, via various mechanisms using a mouse model. GO-Y030 treatment of B16-F10 melanoma cells inhibited TGF-ß expression and glycolysis. The invasion assay results showed almost complete invasion inhibition following GO-Y030 treatment. Mouse experiments demonstrated that GO-Y030 administration inhibited lung tumor metastasis without affecting vascular endothelial cells. Consistent with this result, GO-Y030 treatment led to the downregulation of MMP2 and VEGFα, inhibiting tumor invasion and metastasis. The silencing of eIF4B, a downstream molecule of S6, attenuated MMP2 expression. Our study demonstrates the novel efficacy of GO-Y030 in inhibiting tumor metastasis by regulating metastasis-associated gene expression via inhibiting dual access, glycolytic and TGF-ß pathways.

Effects of Ndufs4 Deletion on Hearing after Various Acoustic Exposures.

Mitochondrial dysfunction can cause cochlear dysfunction and accelerate noise-induced hearing loss (NIHL). NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and has a role in the assembly and stabilization of complex I. However, the involvement of Ndufs4 in the pathogenesis of NIHL has not been reported. The aim of this study was to evaluate whether Ndufs4 deletion causes vulnerability to noise exposures. The wild-type (WT) and Ndufs4 knockout (KO) mice with C57BL/6J genetic background were used. Cochlear histology and hearing thresholds were assessed after noise exposure at 100 or 86 dB sound pressure level (SPL). Immunostaining showed the widespread expression of Ndufs4 in the cochlea. After noise exposure at 100 dB SPL, auditory brainstem response (ABR) threshold shifts at 4 kHz in Ndufs4 KO mice were significantly higher than that in WT mice. After noise exposure at 86 dB SPL, ABR threshold shifts, wave 1 amplitudes, and the number of synapses in the inner hair cells were not significantly different. RNA sequencing revealed the decreased expression of energy generation-related genes inNdufs4 KO mice. Ndufs4 deficiency accelerates permanent low-frequency threshold shifts after moderate noise exposure.

Pyrolyzed deketene curcumin controls regulatory T cell generation and gastric cancer metabolism cooperate with 2-deoxy-d-glucose.

Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-ß). However, GO-Y022 showed less impact on Foxp3+ Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-ß. Therefore, naïve CD4+ T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. GO-Y022-induced tumor cell death was further enhanced by 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Combination treatment of GO-Y022 and 2DG results in reduced L-lactate production and Treg generation in gastric tumor cells. Overall, GO-Y022-treatment with restricted glucose metabolism inhibits gastric tumor cell survival and promotes anti-tumor immunity.

Integrin expression and extracellular matrix adhesion of septoclasts, pericytes, and endothelial cells at the chondro-osseous junction and the metaphysis of the proximal tibia in young mice.

We previously reported that septoclasts, which are uncalcified growth plate (GP) cartilage matrix-resorbing cells, are derived from pericytes surrounding capillary endothelial cells. Resorption of the GP is assumed to be regulated synchronously by septoclasts, pericytes, and endothelial cells. To reveal the contribution of the extracellular matrix (ECM) to the regulatory mechanisms of septoclastic cartilage resorption, we investigated the spatial correlation between the cells and the ECM in the GP matrix and basement membrane (BM) and investigated the expression of integrins-ECM receptors-in the cells. Septoclasts attached to the transverse septa containing collagen-II/-X at the tip of their processes and to the longitudinal septa containing collagen-II/-X at the spine-like processes extending from their bodies and processes. Collagen-IV and laminin α4 in the BM were sparsely detected between septoclasts and capillary endothelial cells at the chondro-osseous junction (COJ) and were absent in the outer surface of pericytes at the metaphysis. Integrin α1/α2, integrin α1, and integrin α2/α6 were detected in the cell membranes of septoclasts, pericytes, and endothelial cells, respectively. These results suggest that the adhesion between septoclasts and the cartilage ECM forming the scaffolds for cartilage resorption and migration is provided by integrin α2-collagen-II/-X interaction and that the adhesions between the BM and pericytes or endothelial cells are mediated by integrin α1-collagen-IV and integrin α2/α6-laminin interaction, respectively.

Genetics of bipolar disorder: insights into its complex architecture and biology from common and rare variants.

Bipolar disorder (BD) is a common mental disorder characterized by recurrent mood episodes, which causes major socioeconomic burdens globally. Though its disease pathogenesis is largely unknown, the high heritability of BD indicates strong contributions from genetic factors. In this review, we summarize the recent achievements in the genetics of BD, particularly those from genome-wide association study (GWAS) of common variants and next-generation sequencing analysis of rare variants. These include the identification of dozens of robust disease-associated loci, deepening of our understanding of the biology of BD, objective description of correlations with other psychiatric disorders and behavioral traits, formulation of methods for predicting disease risk and drug response, and the discovery of a single gene associated with bipolar disorder and schizophrenia spectrum with a large effect size. On the other hand, the findings to date have not yet made a clear contribution to the improvement of clinical psychiatry of BD. We overview the remaining challenges as well as possible paths to resolve them, referring to studies of other major neuropsychiatric disorders.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.

Unpredictable chronic mild stress differentially impacts resting brain glucose metabolism in fatty acid-binding protein 7 deficient mice.

Fatty acid-binding proteins (FABPs) are intracellular chaperone proteins involved in the trafficking of n-3 polyunsaturated fatty acids and endocannabinoids. Inhibiting two of the main FABP subtypes found in the brain (FABP5 and FABP7) hinders endocannabinoid uptake and hydrolysis. Prior data indicates that cannabinoid receptor stimulation can ameliorate the consequences associated with chronic stress. To this end, FABP expression may play a similar role in response to stressful conditions. Male C57BL/6 J (WT) and FABP7 knockout (KO) mice were assigned to either a non-stress cohort or an unpredictable chronic mild stress (UCMS) cohort for a period of 4 weeks. Immediately after 4 weeks, mice were injected with [18F]2-fluoro-2-deoxy-d-glucose (FDG) and scanned using micro positron emission tomography (mPET) to examine brain glucose metabolism (BGluM). WT mice exposed to UCMS showed reduced BGluM in striatal, cortical, and hypothalamic regions and showed increased BGluM in the hippocampus, thalamus, periaqueductal gray, superior colliculi, inferior colliculi, and cerebellum. In contrast, there were limited effects of UCMS on BGluM in FABP7 KO mice, with a reduction in the thalamus, periaqueductal gray, and superior colliculi. These findings provide novel insight into FABP7 expression and indicate this gene to play an important role in response to aversive stimuli.

Environmental enrichment sex-dependently rescues memory impairment in FABP5 KO mice not mediated by brain-derived neurotrophic factor.

Fatty acid-binding proteins (FABPs) are intracellular carriers of bioactive lipids and play a role in the trafficking of endocannabinoids as well as polyunsaturated fatty acids. Mice lacking the FABP5 gene have memory impairments. Environmental enrichment is a potent manipulation known to rescue or improve memory performance. The extent to which the memory impairments in FABP5 knockout (KO) mice can be rescued or improved through environmental conditions remains to be understood. To address this, we raised wild type (WT) and FABP5 KO mice in either socially isolated or environmental enrichment conditions during adolescence. Once in adulthood, mice were tested for Novel Object Recognition (NOR), T-maze, and Morris Water Maze (MWM) to evaluate memory performance. Mice were then euthanized to assess hippocampal brain-derived neurotrophic factor (BDNF) concentrations. MWM results showed that male FABP5 KO mice performed worse compared to WT counterparts. Male and female mice raised in an enriched environment improved performance regardless of genotype. Results on the NOR test showed that male FABP5 KO mice displayed lower object recognition compared to WT counterparts across both environments. No differences of genotype or environment were seen in female mice. T-maze findings revealed impaired performance in socially isolated FABP5 KO mice. Adolescent environmental enrichment rescued this deficit in male, but not female, FABP5 KO mice. Lastly, environmental enrichment increased hippocampal BDNF levels in male WT mice only. Our results corroborate the previously observed role of the FABP5 gene on memory performance and identify an important interaction with the environment during adolescence.

Spatial and chronological localization of septoclasts in the mouse Meckel's cartilage.

Meckel's cartilage (MC) in the first branchial arch of mammals is a transient structure that disappears before birth, except for the most anterior and posterior portions. Recent studies reported that some congenital abnormalities in craniofacial regions are linked with the persistence or dysplasia of MC. However, the mechanisms underlying the resorption of MC have not been elucidated. Cartilage resorption in endochondral ossification is performed by multinuclear osteoclasts/chondroclasts as well as mononuclear septoclasts, which were newly added to the list of cartilage phagocytes. Septoclasts located exclusively at the chondro-osseous junction of the growth plate resorb the uncalcified cartilage matrix. We hypothesized that septoclasts participate in the resorption of MC and attempted to clarify the localization and roles of septoclasts in MC of mouse using a specific immunohistochemistry marker, epidermal type-fatty acid-binding protein (E-FABP/FABP5). E-FABP-immunopositive septoclasts were detected for the first time at the beginning of MC resorption and localized along the resorption surface. Septoclasts of MC in embryonic mice possessed several processes that elongated toward the uncalcified cartilage matrix, expressed cathepsin B, and exhibited characteristic pericapillary localization. Additionally, they localized between hypertrophied cartilage and osteoclasts/chondroclasts in the resorption surface. Confocal laser-scanning microscopy revealed a decrease in the numbers of septoclasts and their processes with the progression of MC disappearance before birth. The present study showed that E-FABP-immunopositive septoclasts participated in the disappearance of MC through the resorption of the uncalcified cartilage matrix and that they have different roles from osteoclasts/chondroclasts.

Usefulness of Thiel-Embalmed Cadavers for Training in Organ Procurement.

BACKGROUND: The number of brain-dead donors has been increasing; however, the opportunity for young surgeons to experience deceased donor surgeries is extremely limited, especially in many Asian countries including Japan. Deceased donor surgeries require unique surgical skills and knowledge; however, it is difficult to provide on-the-job guidance and education. Therefore, cadaver training is meaningful and suitable for the training of deceased donor surgeries. Thiel's embalming method (TEM) provides natural coloration, flexibility, and tissue plasticity, and is widely used for cadaver surgical training. In this study, we evaluated the usefulness of Thiel's embalmed cadaver training for organ procurement surgery. MATERIAL AND METHODS: Each trainee performed hepatectomy, pancreatectomy, and nephrectomy using conventional open techniques. Faculty experts of transplantation surgery and organ procurement took attendees through surgical steps. After the procedure, all participants were asked to complete a voluntary, anonymous survey, consisting of a 10-point satisfaction scale, to evaluate their perceptions of the training. RESULTS: A total of 33 gastrointestinal surgeons participated in the training program for procuring the liver, pancreas, and kidneys. In the questionnaire administered to the participants, the evaluation was generally satisfactory, with an average of 9.1 points on the 10-point scales. Some participants expressed that Thiel-embalmed cadavers are more suitable for training on organ procurement compared with animals used in wet-lab training. CONCLUSION: We conclude that organ procurement training in human cadavers preserved by TEM is useful and suitable for practicing deceased donor organ procurement, especially in countries where deceased donors are not common, as in Japan.

Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.

Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene (Fabp7) influence changes in stress-dependent sleep disturbances and associated anxiety behavior.

Septoclasts expressing epidermal fatty acid-binding protein (E-FABP, FABP5) in endochondral ossification.

BACKGROUND: Long-chain fatty acids (LCFAs) and retinoic acid (RA) are abundant in the growth plates (GPs) of long bones; however, their roles have not been elucidated. We observed that epidermal fatty acid-binding protein (E-FABP/FABP5) with a high affinity for both LCFAs and RA is exclusively expressed in the septoclasts located at the chondro-osseous junction (COJ) of the GP. HIGHLIGHTS: E-FABP expressed in septoclasts is involved in both LCFA metabolism and RA signaling as an intracellular transporter of both LCFAs and RA. Septoclasts with shortened cytoplasmic processes are associated with cartilage resorptive activity downregulation because of E-FABP deficiency or excess or deficiency of RA. In ontogeny, the septoclasts are differentiated from the pericytes and involved in the resorption of the uncalcified matrix of the cartilage templates in endochondral ossification. CONCLUSION: Septoclasts originate from pericytes and express E-FABP to play crucial roles in uncalcified matrix resorption by LCFA metabolism and RA signaling during endochondral ossification.

Nuclear FABP7 regulates cell proliferation of wild-type IDH1 glioma through caveolae formation.

Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild-type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular-targeted therapies is of paramount importance. Fatty acid-binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild-type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin-1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin-1 promoter through controlling the nuclear acetyl-CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7. Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin-1 expression, increased levels of histone acetylation, and increased levels of acetyl-CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin-1, and this mechanism is critically important for IDH1wt tumor biology.

Fatty acid-binding protein 5 limits the generation of Foxp3+ regulatory T cells through regulating plasmacytoid dendritic cell function in the tumor microenvironment.

Plasmacytoid dendritic cells (pDCs) promote viral elimination by producing large amounts of Type I interferon. Recent studies have shown that pDCs regulate the pathogenesis of diverse inflammatory diseases, such as cancer. Fatty acid-binding protein 5 (FABP5) is a cellular chaperone of long-chain fatty acids that induce biological responses. Although the effects of FABP-mediated lipid metabolism are well studied in various immune cells, its role in pDCs remains unclear. This study, which compares wild-type and Fabp5-/- mice, provides the first evidence that FABP5-mediated lipid metabolism regulates the commitment of pDCs to inflammatory vs tolerogenic gene expression patterns in the tumor microenvironment and in response to toll-like receptor stimulation. Additionally, we demonstrated that FABP5 deficiency in pDCs affects the surrounding cellular environment, and that FABP5 expression in pDCs supports the appropriate generation of regulatory T cells (Tregs). Collectively, our findings reveal that pDC FABP5 acts as an important regulator of tumor immunity by controlling lipid metabolism.

Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis.

BACKGROUND: The Toll-like receptor signaling pathway contributes to the regulation of intestinal homeostasis through interactions with commensal bacteria. Although the transcriptional regulator IκB-ζ can be induced by Toll-like receptor signaling, its role in intestinal homeostasis is still unclear. AIMS: To investigate the role of IκB-ζ in gut homeostasis. METHODS: DSS-administration induced colitis in control and IκB-ζ-deficient mice. The level of immunoglobulins in feces was detected by ELISA. The immunological population in lamina propria (LP) was analyzed by FACS. RESULTS: IκB-ζ-deficient mice showed severe inflammatory diseases with DSS administration in the gut. The level of IgM in the feces after DSS administration was less in IκB-ζ-deficient mice compared to control mice. Upon administration of DSS, IκB-ζ-deficient mice showed exaggerated intestinal inflammation (more IFN-g-producing CD4+ T cells in LP), and antibiotic treatment canceled this inflammatory phenotype. CONCLUSION: IκB-ζ plays a crucial role in maintaining homeostasis in the gut.

SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

Curcumin analog GO-Y030 boosts the efficacy of anti-PD-1 cancer immunotherapy.

Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD-1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti-PD-1 antibody, is known to promote the proliferation of the Treg population in tumor-infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO-Y030, an antitumor chemical. GO-Y030 inhibited the immune-suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO-Y030 inhibited the mTOR-S6 axis in Tregs, which plays a pivotal role in their immune-suppressive ability. GO-Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF-ß + IL-6; however, it did not prevent Th17 differentiation. Notably, GO-Y030 significantly inhibited IL-10 production from Th17 cells. In the tumor microenvironment, L-lactate produced by tumors is known to support the suppressive ability of Tregs, and GO-Y030 treatment inhibited L-lactate production via metabolic changes. In addition, experiments in the B16-F10 melanoma mouse model revealed that GO-Y030 helped inhibit the anti-PD-1 immune checkpoint and reduce the Treg population in tumor-infiltrating lymphocytes. Thus, GO-Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti-immune checkpoint inhibitors.