Research progress on the roles of dopamine and dopamine receptors in digestive system diseases.

Dopamine (DA) is a neurotransmitter synthesized in the human body that acts on multiple organs throughout the body, reaching them through the blood circulation. Neurotransmitters are special molecules that act as messengers by binding to receptors at chemical synapses between neurons. As ligands, they mainly bind to corresponding receptors on central or peripheral tissue cells. Signalling through chemical synapses is involved in regulating the activities of various body systems. Lack of DA or a decrease in DA levels in the brain can lead to serious diseases such as Parkinson's disease, schizophrenia, addiction and attention deficit disorder. It is widely recognized that DA is closely related to neurological diseases. As research on the roles of brain-gut peptides in human physiology and pathology has deepened in recent years, the regulatory role of neurotransmitters in digestive system diseases has gradually attracted researchers' attention, and research on DA has expanded to the field of digestive system diseases. This review mainly elaborates on the research progress on the roles of DA and DRs related to digestive system diseases. Starting from the biochemical and pharmacological properties of DA and DRs, it discusses the therapeutic value of DA- and DR-related drugs for digestive system diseases.

Early relapse within 18 months is a powerful dynamic predictor for prognosis and could revise static risk distribution in multiple myeloma.

BACKGROUND: The duration of response to treatment is a major prognostic factor, and early relapse (ER) strongly predicts inferior survival in multiple myeloma (MM). However, the definitions of ER in MM vary from study to study and how to dynamically integrate risk distribution is still unsolved. METHODS: This study evaluated these ER definitions and further investigated the underlying relationship with static risk distribution in 629 newly diagnosed MM (NDMM) patients from the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). RESULTS: These data indicated that early relapse within 18 months (ER18) after initial treatment was the best time point for identifying early progression and dynamic high-risk in MM. The ER18 population (114 of 587, 19.4%) presented with more aggressive biologic features and the inferior response to treatment compared to a reference cohort (p < .001), with a significantly short median overall survival (OS) of 28.9 months. Multivariate analyses confirmed the most significant prognostic value of ER18 on OS in the context of International Staging System stage, elevated lactate dehydrogenase, thrombocytopenia, cytogenetic abnormalities, and treatment (hazard ratio, 4.467; p < .001). The authors also described the specific transitions from static risk profile to dynamic risk distribution and then constructed a mixed-risk-pattern to identify four novel populations with distinct survival (p < .001). Additionally, the authors proposed a second-state model that predicts dynamic risk changes, enabling a complementary role to the Revised International Staging System model in facilitating individualized systematic treatment. CONCLUSIONS: Collectively, this study concludes that ER18 is a simple and dynamic prognostic predictor in MM. In addition to static risk assessment, dynamic risk plays an important role in survival prediction.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Development and validation of an individualized and weighted Myeloma Prognostic Score System (MPSS) in patients with newly diagnosed multiple myeloma.

Current standard predictive models of disease risk do not adequately account for the heterogeneity of survival outcomes in patients with new-diagnosed multiple myeloma (NDMM). In this retrospective, multicohort study, we collected clinical and genetic data from 1792 NDMM patients and identified the prognostic impact of all features. Using the top-ranked predictive features, a weighted Myeloma Prognostic Score System (MPSS) risk model was formulated and validated to predict overall survival (OS). In the training cohort, elevated lactate dehydrogenase level (LDH), International Staging System (ISS) Stage III, thrombocytopenia, and cumulative high-risk cytogenetic aberration (HRA) numbers were found to have independent prognostic significance. Each risk factor was defined as its weighted value respectively according to their hazard ratio for OS (thrombocytopenia 2, elevated LDH 1, ISS III 2, one HRA 1, and ≥2 HRA 2, points). Patients were further stratified into four risk groups: MPSS I (22.5%, 0 points), II (17.6%, 1 points), III (38.6%, 2-3 points), and IV (21.3%, 4-7 points). MPSS risk stratification showed optimal discrimination, as well as calibration, of four risk groups with median OS of 91.0, 69.8, 45.0, and 28.0 months, for patients in MPSS I to IV groups (p < .001), respectively. Importantly, the MPSS model retained its prognostic value in the internal validation cohort and an independent external validation cohort, and exhibited significant risk distribution compared with conventional prognostic models (R-ISS, R2-ISS, and MASS). Utilization of the MPSS model in clinical practice could improve risk estimation in NDMM patients, thus prompting individualized treatment strategies.

Ion channels and transporters regulate nutrient absorption in health and disease.

Ion channels and transporters are ubiquitously expressed on cell membrane, which involve in a plethora of physiological process such as contraction, neurotransmission, secretion and so on. Ion channels and transporters is of great importance to maintaining membrane potential homeostasis, which is essential to absorption of nutrients in gastrointestinal tract. Most of nutrients are electrogenic and require ion channels and transporters to absorb. This review summarizes the latest research on the role of ion channels and transporters in regulating nutrient uptake such as K+ channels, Ca2+ channels and ion exchangers. Revealing the mechanism of ion channels and transporters associated with nutrient uptake will be helpful to provide new methods to diagnosis and find potential targets for diseases like diabetes, inflammatory bowel diseases, etc. Even though some of study still remain ambiguous and in early stage, we believe that ion channels and transporters will be novel therapeutic targets in the future.

Research Progress on TRPA1 in Diseases.

For a long time, the physiological activity of TRP ion channels and the response to various stimuli have been the focus of attention, and the physiological functions mediated by ion channels have subtle links with the occurrence of various diseases. Our group has been engaged in the study of ion channels. In recent years, the report rate of TRPA1, the only member of the TRPA subfamily in the newly described TRP channel, has been very high. TRPA1 channels are not only abundantly expressed in peptidergic nociceptors but are also found in many nonneuronal cell types and tissues, and through the regulation of Ca2+ influx, various neuropeptides and signaling pathways are involved in the regulation of nerves, respiration, circulation, and various diseases and inflammation throughout the body. In this review, we mainly summarize the effects of TRPA1 on various systems in the body, which not only allows us to have a more systematic and comprehensive understanding of TRPA1 but also facilitates more in-depth research on it in the future.

The role of Chemerin in human diseases.

Chemerin is a protein encoded by the Rarres2 gene that acts through endocrine or paracrine regulation. Chemerin can bind to its receptor, regulate insulin sensitivity and adipocyte differentiation, and thus affect glucose and lipid metabolism. There is growing evidence that it also plays an important role in diseases such as inflammation and cancer. Chemerin has been shown to play a role in the pathogenesis of inflammatory and metabolic diseases caused by leukocyte chemoattractants in a variety of organs, but its biological function remains controversial. In conclusion, the exciting findings collected over the past few years clearly indicate that targeting Chemerin signaling as a biological target will be a major research goal in the future. This article reviews the pathophysiological roles of Chemerin in various systems and diseases,and expect to provide a rationale for its role as a clinical therapeutic target.

Impact of residual tumor cells in the stem cell collection on multiple myeloma patients receiving autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) is the standard therapy for patients with transplant-eligible multiple myeloma (TEMM). However, the ideal depth of response required before ASCT and the impact of residual tumor cells in the stem cell collection (SCC) on survival remains unclear. Here we collected data of 89 patients with TEMM undergoing ASCT and analyzed the minimal residual disease of SCC (cMRD) and bone marrow (BM) (mMRD) before transplantation. Before ASCT, 31.5% and 76.4% of patients achieved MRD negativity in BM and SCC, respectively. Tumor cells were less in SCC samples than that in BM samples. Neoplastic cells in SCC could be observed in patients with different responses after induction therapy, and there were no significant differences in the percentage and level of cMRD among these subgroups (P > 0.05). No correlation was found between the cMRD status and the response patients achieved after ASCT (P > 0.05). The median follow-up was 26.8 months. mMRD negativity before ASCT was associated with longer PFS (55.9 vs. 27.1 months; P = 0.009) but not OS (not reached vs. 58.9 months; P = 0.115). Patients with different cMRD statuses before ASCT experienced similar PFS (40.5 vs. 76.4 months for negativity vs. positivity; P = 0.685) and OS (not reached vs. 58.8 months for negativity vs. positivity; P = 0.889). These results suggested that detectable cMRD does not significantly predict the inferior post-ASCT response or shorter survival, and patients are eligible to undergo ASCT upon achieving partial response.

The role of Nod-like receptor protein 3 inflammasome activated by ion channels in multiple diseases.

The inflammasome is a multimeric protein complex located in the cytoplasm that is activated by many factors and subsequently promotes the release of proinflammatory factors such as interleukin (IL)-1ß and IL-18, resulting in a series of inflammatory responses that ultimately lead to the occurrence of various diseases. The Nod-like receptor protein 3 (NLRP3) inflammasome is the most characteristic type and the most widely studied among many inflammasomes. Activation of the NLRP3 inflammasome is closely related to the occurrence of many diseases, such as Alzheimer's disease. At present, a large number of studies have focused on the mechanisms underlying the activation of the NLRP3 inflammasome. Plenty of articles have reported the activation of the NLRP3 inflammasome by various ions, such as K+ and Na+ reflux and Ca2+ influx. However, few articles have reviewed the effects of various ion channels on the activation of the NLRP3 inflammasome and the relationship between the diseases caused by these proteins. This article mainly summarizes the relationship between intracellular and extracellular ion activities and ion channels and the activation of the NLRP3 inflammasome. We also provide a general summary of the diseases of each system caused by NLRP3 activation. We hope that more research will provide options for the treatment of diseases driven by the NLRP3 inflammasome.

Characterization of translocon proteins in the type III secretion system of Lawsonia intracellularis.

Lawsonia intracellularis, the etiologic agent of proliferative enteropathy (PE), is an obligate intracellular Gram-negative bacterium possessing a type III secretion system (T3SS), which enables the pathogen to translocate effector proteins into targeted host cells to modulate their functions. T3SS is a syringe-like apparatus consisting of a base, an extracellular needle, a tip, and a translocon. The translocon proteins assembled by two hydrophobic membrane proteins can form pores in the host-cell membrane, and therefore play an essential role in the function of T3SS. To date, little is known about the T3SS and translocon proteins of L. intracellularis. In this study, we first analyzed the conservation of the T3S apparatus between L. intracellularis and Yersinia, and characterized the putative T3S hydrophobic major translocon protein LI1158 and minor translocon protein LI1159 in the L. intracellularis genome. Then, by using Yersinia pseudotuberculosis as a surrogate system, we found that the full-length LI1158 and LI1159 proteins, but not the putative class II chaperone LI1157, were secreted in a - Ca2+ and T3SS-dependent manner and the secretion signal was located at the N terminus (aa 1-40). Furthermore, yeast-two hybrid experiments revealed that LI1158 and LI1159 could self-interact, and LI1159 could interact with LI1157. However, unlike CPn0809 and YopB, which are the major hydrophobic translocon proteins of the T3SS of C. pneumoniae and Yersinia, respectively, full-length LI1158 was non-toxic to both yeast and Escherichia coli cells, but full-length LI1159 showed certain toxicity to E. coli cells. Taken together, despite some differences from the findings in other bacteria, our results demonstrate that LI1158 and LI1159 may be the translocon proteins of L. intracellularis T3SS, and probably play important roles in the translocation of effector proteins at the early pathogen infection stage.

KIAA0101 promotes cisplatin resistance through regulating cell apoptosis in lung cancer cells.

Lung cancer is one of the most server mortality in the world and remains a huge threat to human health. Recently, cisplatin-based chemotherapy represented a common therapeutic strategy, however, cisplatin resistance greatly limits the therapy efficacy. We investigated whether KIAA0101 plays a role in cisplatin resistance of lung cancer cells and its mechanisms of action. The expression of KIAA0101 was evaluated based on comprehensive bioinformatic analysis. KIAA0101 knockdown and overexpression A549 cells were constructed to investigate its effects on cell proliferation and apoptosis induced by cisplatin treatment. Western blot analysis was performed to measure the levels of p53-related apoptosis proteins. We found that KIAA0101 was greatly increased in lung cancer tissues and cells. Knockdown of KIAA0101 suppressed cell proliferation and increased cisplatin-induced apoptosis. Knockdown of KIAA0101 also augmented the cisplatin-induced cell apoptosis signaling pathway. Then p53 was found to account for the role of KIAA0101 in cisplatin resistance. In conclusion, our findings provide a novel factor of KIAA0101 in lung cancer resistance, which suggests as a novel target for lung cancer therapy.

Beneficial effects of dietary capsaicin in gastrointestinal health and disease.

Chili pepper and its major active compound capsaicin have long been used not only a daily food additive but also medication worldwide. Like in other human organs and systems, capsaicin has multiple actions in gastrointestinal (GI) physiology and pathology. Numerous studies have revealed that capsaicin acts on GI tract in TRPV1-dependent and -independent manners, mostly depending on its consumption concentrations. In this review, we will focus on the beneficial role of capsaicin in GI tract, a less highlighted aspect, in particular how dietary capsaicin affects GI health, the mechanisms of actions and its preventive/therapeutic potentials to several GI diseases. Dietary capsaicin affects GI tract not only via TRPV1-derpendent and independent manners, but also via acute and chronic effects. Although high dose intake of dietary capsaicin is harmful to human health sometimes, current literatures suggest that appropriate dose intake is likely beneficial to GI health and is preventive/therapeutic to GI disease in most cases as well. With extensive and intensive studies on its GI actions, capsaicin, as a daily consumed food additive, has potential to become a safe drug for the treatment of several GI diseases.

Evolutionary Analysis of Respiratory Burst Oxidase Homolog (RBOH) Genes in Plants and Characterization of ZmRBOHs.

The respiratory burst oxidase homolog (RBOH), as the key producer of reactive oxygen species (ROS), plays an essential role in plant development. In this study, a bioinformatic analysis was performed on 22 plant species, and 181 RBOH homologues were identified. A typical RBOH family was identified only in terrestrial plants, and the number of RBOHs increased from non-angiosperms to angiosperms. Whole genome duplication (WGD)/segmental duplication played a key role in RBOH gene family expansion. Amino acid numbers of 181 RBOHs ranged from 98 to 1461, and the encoded proteins had molecular weights from 11.1 to 163.6 kDa, respectively. All plant RBOHs contained a conserved NADPH_Ox domain, while some of them lacked the FAD_binding_8 domain. Plant RBOHs were classified into five main subgroups by phylogenetic analysis. Most RBOH members in the same subgroup showed conservation in both motif distribution and gene structure composition. Fifteen ZmRBOHs were identified in maize genome and were positioned in eight maize chromosomes. A total of three pairs of orthologous genes were found in maize, including ZmRBOH6/ZmRBOH8, ZmRBOH4/ZmRBOH10 and ZmRBOH15/ZmRBOH2. A Ka/Ks calculation confirmed that purifying selection was the main driving force in their evolution. ZmRBOHs had typical conserved domains and similar protein structures. cis-element analyses together with the expression profiles of the ZmRBOH genes in various tissues and stages of development suggested that ZmRBOH was involved in distinct biological processes and stress responses. Based on the RNA-Seq data and qRT-PCR analysis, the transcriptional response of ZmRBOH genes was examined under various abiotic stresses, and most of ZmRBOH genes were up-regulated by cold stress. These findings provide valuable information for further revealing the biological roles of ZmRBOH genes in plant development and abiotic stress responses.

Bioglass promotes wound healing by inhibiting endothelial cell pyroptosis through regulation of the connexin 43/reactive oxygen species (ROS) signaling pathway.

Bioactive glass (BG) has recently shown great promise in soft tissue repair, especially in wound healing; however, the underlying mechanism remains unclear. Pyroptosis is a novel type of programmed cell death that is involved in various traumatic injury diseases. Here, we hypothesized that BG may promote wound healing through suppression of pyroptosis. To test this scenario, we investigated the possible effect of BG on pyroptosis in wound healing both in vivo and in vitro. This study showed that BG can accelerate wound closure, granulation formation, collagen deposition, and angiogenesis. Moreover, western blot analysis and immunofluorescence staining revealed that BG inhibited the expression of pyroptosis-related proteins in vivo and in vitro. In addition, while BG regulated the expression of connexin43 (Cx43), it inhibited reactive oxygen species (ROS) production. Cx43 activation and inhibition experiments further indicate that BG inhibited pyroptosis in endothelial cells by decreasing Cx43 expression and ROS levels. Taken together, these studies suggest that BG promotes wound healing by inhibiting pyroptosis via Cx43/ROS signaling pathway.

Metformin promotes microglial cells to facilitate myelin debris clearance and accelerate nerve repairment after spinal cord injury.

Spinal cord injury (SCI) is one kind of severe trauma for central nervous system. Myelin debris clearance and axon regeneration are essential for nerve regeneration after SCI. Metformin, a glucose-lowering drug, has been demonstrated to promote the locomotor functional recovery after SCI. In this study, we investigated the role and molecular mechanism of metformin on myelin preservation in a rat SCI model. SCI was induced in rats by compression at T9 level using a vascular clip. We showed that administration of metformin (50 mg·kg-1·d-1, ip) for 28 days significantly improved locomotor function in SCI rats. Metformin also ameliorated SCI-induced neuronal apoptosis and promoted axon regeneration in the spinal cord. Using co-immunofluorescence of IBa-1 and MBP, and luxol fasting blue (LFB) staining, we demonstrated that metformin promoted the transformation of M1 to M2 phenotype polarization of microglial cells, then greatly facilitated myelin debris clearance and protected the myelin in SCI rats. Furthermore, metformin ameliorated SCI-induced blockade of autophagic flux in the spinal cord, and enhanced the fusion of autophagosome and lysosome by inhibiting the AMPK-mTOR signaling pathway. Moreover, metformin significantly attenuated inflammatory responses in the spinal cord. In LPS-treated BV2 cells, pretreatment with metformin (2 mM) significantly enhanced autophagy level, suppressed inflammation and cell apoptosis. The protective effects were blocked in the presence of an autophagy inhibitor 3-methyladenine (3-MA, 5 mM), suggesting that the effect of metformin on autophagy in microglial cells is essential for the myelin preservation during nerve recovery. This study reveals a novel therapeutic effect of metformin in SCI recovery by regulating the activation of microglial cells and enhancing its autophagy level.

Genome-wide identification and expression analysis of phospholipase D gene in leaves of sorghum in response to abiotic stresses.

Abiotic stress caused by unsuitable environmental changes brings serious impacts on the growth and development of sorghum, resulting in significant loss in yield and quality every year. Phospholipase D is one of the key enzymes that catalyze the hydrolysis of phospholipids, and participates in plants response to abiotic stresses and phytohormones, whereas as the main producers of Phosphatidic acid (PA) signal, the detailed information about Phospholipase D associated (SbPLD) family in sorghum has been rarely reported. This study was performed to identify the PLD family gene in sorghum based on the latest genome annotation and to determine the expression of PLDs under abiotic stresses by qRT-PCR analysis. In this study, 13 PLD genes were identified in sorghum genome and further divided into 7 groups according to the phylogenetic analysis. All sorghum PLD family members harbored two conserved domains (HDK1&2) with catalytic activity, and most members contained a C2 domain. In ζ subfamily, C2 domain was replaced by PX and PH domain. The exon-intron structure of SbPLD genes within the same subfamily was highly conservative. The tissue specific expression analysis revealed different expression of SbPLD genes in various developmental stages. High level expression of SbPLDα3 was observed in almost all tissues, whereas SbPLDα4 was mainly expressed in roots. Under abiotic stress conditions, SbPLD genes responded actively to NaCl, ABA, drought (PEG) and cold (4 °C) treatment at the transcriptional level. The expression of SbPLDß1 was significantly up-regulated, while the transcription of SbPLDζ was suppressed under various stress conditions. In addition, SbPLDß1 and SbPLDδ2 were predicted to be the target genes of sbi-miR159 and sbi-miR167, respectively. This study will help to decipher the roles of PLDs in sorghum growth and abiotic stress responses. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01200-9.

RAGE: A potential therapeutic target during FGF1 treatment of diabetes-mediated liver injury.

As a serious metabolic disease, diabetes causes series of complications that seriously endanger human health. The liver is a key organ for metabolizing glucose and lipids, which substantially contributes to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Exogenous fibroblast growth factor 1 (FGF1) has a great potential for the treatment of diabetes. Receptor of advanced glycation end products (RAGE) is a receptor for advanced glycation end products that involved in the development of diabetes-triggered complications. Previous study has demonstrated that FGF1 significantly ameliorates diabetes-mediated liver damage (DMLD). However, whether RAGE is involved in this process is still unknown. In this study, we intraperitoneally injected db/db mice with 0.5 mg/kg FGF1. We confirmed that FGF1 treatment not only significantly ameliorates diabetes-induced elevated apoptosis in the liver, but also attenuates diabetes-induced inflammation, then contributes to ameliorate liver dysfunction. Moreover, we found that diabetes triggers the elevated RAGE in hepatocytes, and FGF1 treatment blocks it, suggesting that RAGE may be a key target during FGF1 treatment of diabetes-induced liver injury. Thus, we further confirmed the role of RAGE in FGF1 treatment of AML12 cells under high glucose condition. We found that D-ribose, a RAGE agonist, reverses the protective role of FGF1 in AML12 cells. These findings suggest that FGF1 ameliorates diabetes-induced hepatocyte apoptosis and elevated inflammation via suppressing RAGE pathway. These results suggest that RAGE may be a potential therapeutic target for the treatment of DMLD.

DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress.

DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg-1· d-1) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.