The environmental effects of microplastics and microplastic derived dissolved organic matter in aquatic environments: A review.

Currently, microplastics (MPs) have ubiquitously distributed in different aquatic environments. Due to the unique physicochemical properties, MPs exhibit a variety of environmental effects with the coexisted contaminants. MPs can not only alter the migration of contaminants via vector effect, but also affect the transformation process and fate of contaminants via environmental persistent free radicals (EPFRs). The aging processes may enhance the interaction between MPs and co-existed contaminants. Thus, it is of great significance to review the aging mechanism of MPs and the influence of coexisted substances, the formation mechanism of EPFRs, environmental effects of MPs and relevant mechanism. Moreover, microplastic-derived dissolved organic matter (MP-DOM) may also influence the elemental biogeochemical cycles and the relevant environmental processes. However, the environmental implications of MP-DOM are rarely outlined. Finally, the knowledge gaps on environmental effects of MPs were proposed.

Inhibitory Effects of Soluble Dietary Fiber from Foxtail Millet on Colorectal Cancer by the Restoration of Gut Microbiota.

Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.

Expression and Purification of Recombinant Bowman-Birk Trypsin Inhibitor from Foxtail Millet Bran and Its Anticolorectal Cancer Effect In Vitro and In Vivo.

Trypsin inhibitors derived from plants have various pharmacological activities and promising clinical applications. In our previous study, a Bowman-Birk-type major trypsin inhibitor from foxtail millet bran (FMB-BBTI) was extracted with antiatherosclerotic activity. Currently, we found that FMB-BBTI possesses a prominent anticolorectal cancer (anti-CRC) activity. Further, a recombinant FMB-BBTI (rFMB-BBTI) was successfully expressed in a soluble manner in host strain Escherichia coli. BL21 (DE3) was induced by isopropyl-ß-d-thiogalactoside (0.1 mM) at 37 °C for 3.5 h by the pET28a vector system. Fortunately, a purity greater than 93% of rFMB-BBTI with anti-CRC activity was purified by nickel-nitrilotriacetic acid affinity chromatography. Subsequently, we found that rFMB-BBTI displays a strikingly anti-CRC effect, characterized by the inhibition of cell proliferation and clone formation ability, cell cycle arrest at the G2/M phase, and induction of cell apoptosis. It is interesting that the rFMB-BBTI treatment had no obvious effect on normal colorectal cells in the same concentration range. Importantly, the anti-CRC activity of rFMB-BBTI was further confirmed in the xenografted nude mice model. Taken together, our study highlights the anti-CRC activity of rFMB-BBTI in vitro and in vivo, uncovering the clinical potential of rFMB-BBTI as a targeted agent for CRC in the future.

The potential effects of N-Acyl homoserine lactones on aerobic sludge granulation during phenolic wastewater treatment.

The formation of aerobic granular sludge (AGS) is relatively difficult during the treatment of refractory wastewater, which generally shows small granular sizes and poor stability. The formation of AGS is regulated by N-Acyl homoserine lactones (AHLs)-mediated quorum sensing (QS). However, the potential role of AHLs in AGS formation under the toxic stress of refractory pollutants and the heterogeneity in the distribution and function of AHLs across different aggregates are not well understood. This study investigated the potential effects of AHLs on the formation of AGS during phenolic wastewater treatment. The distribution and succession of AHLs across varying granular sizes and development stages of AGS were investigated. Results showed that AGS was successfully formed in 13 days with an average granular size of 335 ± 39 µm and phenol removal efficiency of >99%. The levels of AHLs initially increased and then decreased. C4-HSL and 3-oxo-C10-HSL were enriched in large granules, suggesting they may play a pivotal role in regulating the concentration and composition of extracellular polymeric substances (EPS). The content of EPS constantly increased to 149.4 mg/gVSS, and protein (PN) was enriched in small and large granules. Luteococcus was the dominant genus constituting up to 62% after the granulation process, and exhibited a strong association with C4-HSL. AHLs might also regulate the bacterial community responsible for EPS production, and pollutant removal, and facilitate the proliferation of slow-growing microorganisms, thereby enhancing the formation of AGS. The synthesis and dynamics of AHLs were mainly governed by AHLs-producing bacterial strains of Rhodobacter and Pseudomonas, and AHLs-quenching strains of Flavobacterium and Comamonas. C4-HSL and 3-oxo-C10-HSL might be the major contributors to promoting sludge granulation under phenol stress and play critical roles in large granules. These findings enhance our understanding of the roles that AHLs play in sludge granulation under toxic conditions.

Advancements of the CRISPR/Cas9 System in the Treatment of Liver Cancer.

In recent years, the CRISPR/Cas9 system has become a rapidly advancing gene editing technology with significant advantages in various fields, particularly biomedicine. Liver cancer is a severe malignancy that threatens human health and is primarily treated with surgery, radiotherapy, and chemotherapy. However, surgery may not be suitable for advanced cases of liver cancer with distant metastases. Moreover, radiotherapy and chemotherapy have low specificity and numerous side effects that limit their effectiveness; therefore, more effective and safer treatments are required. With the advancement of the biomolecular mechanism of cancer, CRISPR/Cas9 gene editing technology has been widely used in the study of liver cancer to gain insights into gene functions, establish tumor models, screen tumor phenotype-related genes, and perform gene therapy. This review outlines the research progress of CRISPR/Cas9 gene editing technology in the treatment of liver cancer and provides a relevant theoretical basis for its research and application in the treatment of liver cancer.

Biosynthesized tumor acidity and MMP dual-responsive plant toxin gelonin for robust cancer therapy.

Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity via inhibiting intracellular protein synthesis. However, gelonin lacks a translocation domain, and thus its poor cellular uptake leads to low outcomes of antitumor response. Here, tumor acidity and matrix metalloproteinase (MMP) dual-responsive functional gelonin (Trx-PVGLIG-pHLIP-gelonin, TPpG), composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), an MMP-responsive motif PVGLIG hexapeptide and gelonin, was innovatively proposed and biologically synthesized by a gene recombination technique. TPpG exhibited good thermal and serum stability, showed MMP responsiveness and could enter tumor cells under weakly acidic conditions, especially for MMP2-overexpressing HT1080 cells. Compared to low MMP2-expressing MCF-7 cells, TPpG displayed enhanced in vitro antitumor efficacy to HT1080 cells at pH 6.5 as determined by different methods. Likewise, TPpG was much more effective in triggering cell apoptosis and inhibiting protein synthesis in HT1080 cells than in MCF-7 cells. Intriguingly, with enhanced stability and pH/MMP dual responsiveness, TPpG notably inhibited subcutaneous HT1080 xenograft growth in mice and no noticeable off-target side effect was observed. This ingeniously designed strategy aims at providing new perspectives for the development of a smart platform that can intelligently respond to a tumor microenvironment for efficient protein delivery.

[Short-term effectiveness of orthopedic robot-assisted resection for osteoid osteoma].

Objective: To investigate short-term effectiveness and clinical application advantages of orthopedic robot-assisted resection for osteoid osteoma compared with traditional open surgery. Methods: A retrospective analysis was conducted on clinical data of 48 osteoid osteoma patients who met the selection criteria between July 2022 and April 2023. Among them, 23 patients underwent orthopedic robot-assisted resection (robot-assisted surgery group), and 25 patients received traditional open surgery (traditional surgery group). There was no significant difference ( P>0.05) in gender, age, disease duration, lesion location and size, and preoperative visual analogue scale (VAS) score, and musculoskeletal tumor society (MSTS) score between the two groups. The surgical time, intraoperative blood loss, intraoperative lesion localization time, initial localization success rate, infection, and recurrence were recorded and compared. VAS scores before surgery and at 24 hours, 1, 3, 6, and 9 months after surgery and MSTS score before surgery and at 3 months after surgery were assessed. Results: All patients completed the surgery successfully, with no significant difference in surgical time between the two groups ( P>0.05). Compared to the traditional surgery group, the robot-assisted surgery group had less intraoperative blood loss, shorter lesion localization time, and shorter hospitalization time, with significant differences ( P<0.05). The initial localization success rate was higher in the robot-assisted surgery group than in the traditional surgery group, but the difference between the two groups was not significant ( P>0.05). All patients in both groups were followed up, with the follow-up time of 3-12 months in the robot-assisted surgery group (median, 6 months) and 3-14 months in the traditional surgery group (median, 6 months). The postoperative MSTS scores of both groups improved significantly when compared to those before surgery ( P<0.05), but there was no significant difference in the changes in MSTS scores between the two groups ( P>0.05). The postoperative VAS scores of both groups showed a gradually decreasing trend over time ( P<0.05), but there was no significant difference between the two groups after surgery ( P>0.05). During follow-up, except for 1 case of postoperative infection in the traditional surgery group, there was no infections or recurrences in other cases. There was no significant difference in the incidence of postoperative infection between the two groups ( P>0.05). Conclusion: Orthopedic robot-assisted osteoid osteoma resection achieves similar short-term effectiveness when compared to traditional open surgery, with shorter lesion localization time.

Efficient removal of naphthenic acids from real petroleum wastewater by natural pyrite activated persulfate system.

The petroleum wastewater (PWW) contains a diverse range of recalcitrant organic contaminants. Of particular concern is the removal of naphthenic acids (NAs) due to the high toxicity and persistence. Persulfate (PS) based oxidation processes have shown promising in treating refractory wastewater, while the high costs of prepared catalysts limited their widespread implementation. This study aims to develop a cost-effective natural pyrite activated PS system for PWW treatment. The removal of NAs by pyrite/PS system was initially investigated. More than 90% of cyclohexanoic acid (CHA), a model NA, was removed in pyrite/PS system (2.0 g/L pyrite, 4.0 mM PS) at initial pH of 3-11. Scavenging experiments revealed that Fe(II) on pyrite surface was the reactive site for PS activation to generate reactive species, including sulfate radical (SO4·-), Fe(IV) and hydroxyl radical (·OH) for CHA degradation. Reactions of Fe(III) with S helped restore Fe(II) and enhance PS activation, resulting in the sustained catalytic activity of pyrites over five cycles. Cl-, SO42- and NO3- below 10 mM had minimal impact on CHA degradation in pyrite/PS system. However, over 1 mM of HCO3- inhibited 80% of CHA removal due to the buffer effect to maintain the high solution pH. Removing HCO3- from real PWW restored the removal of CHA and of total organic carbon (TOC) to over 90% and 71.3% in pyrite/PS system, respectively. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) results indicated that O2‒6 species including NAs were primarily eliminated through mineralization and oxygen addition. Besides, O3-5S, NO3-5S and N3O2‒4 species were the most susceptible to oxidation in PWW, resulting in the increase of the oxidation level (i.e., O/Cwa) from 0.41 to 0.56 after treatment. This study provides valuable insights into the treatment of NAs in real PWW, and potential application of natural minerals in the treatment of industrial wastewater.

Characteristics of dissolved organic matter in point-source wastewaters at a petrochemical plant: Molecular constituents and contributions to the influent of wastewater treatment plant.

Dissolved organic matter (DOM) in point-source petrochemical wastewaters (PCWs) from different operating units is closely linked to the efficiency of wastewater treatment plant (WWTP). However, systematic studies on DOM characters of point-source PCWs and their influences on WWTP influents were seldom conducted. In this study, DOM in three low-salinity point-source PCWs and four high-salinity point-source PCWs at a typical petrochemical plant were comprehensively characterized at a molecular level. Orbitrap mass spectrometry results indicated that point-source PCWs had diverse DOM constituents tightly related to the corresponding petrochemical processes. Phenols in oily wastewaters (OW), phenols and N-containing compounds in coal partial oxidation wastewater (POXW), and naphthenic acids (NAs) and aromatic acids in crude oil electric desalting unit wastewater (EDW) were characteristic DOM constituents for low-salinity point-source PCWs. While S-containing compounds (mercaptans, thiophenes) and NAs in spent caustic liquors (SCL), alcohols and esters in butanol-octanol plant wastewater (BOW), high molecular weight aromatic ketones in phenol-acetone plant wastewater (PAW), and oxygenated NAs as well as short chain N-containing compounds in concentrate from reverse osmosis unit (ROC) were characteristic DOM constituents for high-salinity point-source PCWs. Spearman correlation analysis indicated that though with relative low pollutant contents (OW) and discharge volume (EDW), N/O/S-containing compounds of OW and EDW greatly contributed to the polar DOM constituents of low-salinity influent in WWTP (R > 0.5, P < 0.001). While N-containing compounds of ROC mainly contributed to the polar DOM of high-salinity influent (R > 0.5, P < 0.001). Though N-/S-containing species in PAW had low contents, they also posed obvious impacts on DOM constituents of high-salinity influent. Interestingly, some O-/S-containing species were newly formed during the confluent process of high-salinity point-source PCWs. The results strengthened the combined contributions of pollutants contents, discharge emission and DOM constituents of point-source PCWs to the water matrix of WWTP influents, which would provide reference for the management of PCW streams.

Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.

The interaction between apigenin and PKM2 restrains progression of colorectal cancer.

Apigenin, a flavonoid that widely existed in vegetables and fruits, possesses anticarcinogenic, low toxicity, and no mutagenic properties, suggesting that apigenin is a potential therapeutic agent for tumors. However, the underlying anti-cancer molecular target of apigenin is still unclear. Therefore, to reveal the direct target and amino acid site of apigenin against colorectal cancer is the focus of this study. In the present study, the results proved that the anti-CRC activity of apigenin was positively correlated with pyruvate kinase M2 (PKM2) expression, characterized by the inhibition of cell proliferation and increase of apoptotic effects induced by apigenin in LS-174T cells of knock down PKM2. Next, pull-down and MALDI-TOF/TOF analysis determined that apigenin might interact directly with PKM2 in HCT-8 cells. Further, the study confirmed that lysine residue 433 (K433) was a key amino acid site for PKM2 binding to apigenin. Apigenin restricted the glycolysis of LS-174T and HCT-8 cells by targeting the K433 site of PKM2, thereby playing an anti-CRC role in vivo and in vitro. Meanwhile, apigenin markedly attenuated tumor growth without any adverse effects. Taken together, these findings reveal that apigenin is worthy of consideration as a promising PKM2 inhibitor for the prevention of CRC.

Oat ß-D-glucan ameliorates type II diabetes through TLR4/PI3K/AKT mediated metabolic axis.

Diabetes is one of the major global public health problems. Our previous results found that oat ß-D-glucan exhibited ameliorative effects on diabetic mice, but the underlying mechanism is unclear. The present study indicates that oat ß-D-glucan increased glycogen content, decreased glycogen synthase (GS) phosphorylation and increased hepatic glycogen synthase kinase 3ß (GSK3ß) phosphorylation for glycogen synthesis via PI3K/AKT/GSK3-mediated GS activation. Moreover, oat ß-D-glucan inhibited gluconeogenesis through the PI3K/AKT/Foxo1-mediated phosphoenolpyruvate carboxykinase (PEPCK) decrease. In addition, oat ß-D-glucan enhanced glucose catabolism through elevated protein levels of COQ9, UQCRC2, COXIV and ATP5F complexes involved in oxidative phosphorylation, as well as that of TFAM, a key regulator of mitochondrial gene expression. Importantly, our results showed that oat ß-D-glucan maintained hepatic glucose balance via TLR4-mediated intracellular signal. After TLR4 blocking with anti-TLR4 antibody, oat ß-D-glucan had almost no effect on high glucose-induced HepG2 cells. These data revealed that oat ß-D-glucan maintains glucose balance by regulating the TLR4/PI3K/AKT signal pathway.

Potent Intestinal Mucosal Barrier Enhancement of Nostoc commune Vaucher Polysaccharide Supplementation Ameliorates Acute Ulcerative Colitis in Mice Mediated by Gut Microbiota.

Ulcerative colitis (UC) is evolving into a global burden with a substantially increasing incidence in developing countries. It is characterized by inflammation confined to mucosa and is recognized as an intestinal barrier disease. The intestinal microbiota plays a crucial role in UC pathogenesis. N. commune has long been appreciated as a healthy food and supplement worldwide and polysaccharides account for 60%. Here, we examined the amelioration of N. commune polysaccharides against acute colitis in mice induced by DSS and assessed the mediating role of gut microbiota. An integrated analysis of microbiome, metabolomics, and transcriptomics fully elaborated it markedly enhanced intestinal mucosal barrier function, including: increasing the relative abundance of Akkermansia muciniphila, uncultured_bacterium_g__norank_f__Muribaculaceae, and unclassified_g__norank_f__norank_o__Clostridia_UCG-014; decreasing microbiota-derived phosphatidylcholines and thromboxane 2 levels mapped to arachidonic acid metabolism; improving mucin2 biosynthesis and secretion; enhancing ZO-1 and occludin expression; reducing neutrophil infiltration; regulating the level of colitis-related inflammatory cytokines; involving inflammation and immune function-associated signaling pathways. Further, the mediation effect of gut microbiota was evaluated by administering a cocktail of antibiotics. In conclusion, our results demonstrated that N. commune polysaccharides predominantly reinforced the gut microbiota-mediated intestinal mucosal barrier to confer protection against UC and exhibited dramatic prebiotic-like functions, providing an alternative or complementary treatment for UC.

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: The objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. CONCLUSIONS: Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

Incidence of acute kidney injury after hematopoietic stem cell transplantation in children: a systematic review and meta-analysis.

While acute kidney injury (AKI) has been reported after hematopoietic stem cell transplantation (HCT) in children, the incidence of this condition in the pediatric population has not been fully addressed. To assess the incidence of pediatric AKI after HCT treatment,we conducted a systematic literature review. Databases PubMed, Embase, Cochrane Library, and WOS were searched as of June 2022 to identify studies on the incidence and the risk of death in AKI children undergoing HCT. Random effects and generic inverse variance methods were used, and effect estimates were subsequently derived from individual studies. Twelve cohort studies with 2 159 HCT cases were included in this analysis. The combined estimated incidence of AKI and severe AKI (stage AKI III) was 51% (95% confidence interval (CI) 39-64%) and 12% (95%CI 4-24%), respectively. The estimated incidence of AKI based on RIFLE (pRIFLE), AKIN, and KDIGO criteria was 61% (95%CI 40-82% score I 95.1%), 64% (95%CI 49-79% score I 90.4%), and 51% (95%CI 2-100% score 99.0%), respectively. However, we found no significant correlation between the years of publication of the included studies and the incidence of AKI.  Conclusions: AKI affects approximately half of the children after HCT. With the advancements in medical techniques, it is expected that AKI in this population will decrease gradually. What is Known: • Hematopoietic stem cell transplantation is recognized as a treatment for malignant and non-malignant diseases in children. • Hematopoietic stem cell transplantation causes acute kidney injury in children. What is New: • This metanalysis showed that the overall frequency of post-HCT AKI in children is 51%. • The frequency of severe AKI after HCT was found to be 12%.

The bound polyphenols of foxtail millet (Setaria italica) inner shell inhibit breast cancer by promoting lipid accumulation-induced autophagic death.

Foxtail millet is a traditional excellent crop with high nutritional value in the world, belong to cereals. The bran of foxtail millet is rich in polyphenol that has antioxidant, anti-inflammatory, and anti-tumorigenic effects. Previously, we extracted bound polyphenols from the inner shell of foxtail millet bran (BPIS). Here, we report that BPIS specifically induced breast cancer cell death and elevated the autophagy level simultaneously. The addition of an autophagy inhibitor blocked BPIS-induced breast cancer cell death, indicating that excessive autophagy induced cell death. Furthermore, oil red O and BODIPY staining also confirmed that lipids, which are important inducers of autophagy, accumulated in breast cancer cells treated with BPIS. Lipidomics research revealed that glycerophospholipids were the main accumulated lipids induced by BPIS. Further study showed that elevated PCYT1A expression was responsible for glycerophospholipid accumulation, and BPIS contained ferulic acid and p-coumaric acid, which induced PCYT1A expression and breast cancer cell death. Collectively, our results revealed that BPIS resulted in autophagic death by enhancing lipid accumulation in breast cancer cells, and BPIS contains ferulic acid and p-coumaric acid, which provided new insights into developing nutraceuticals and drugs for breast cancer patients.

Tumor-secreted GRP78 induces M2 polarization of macrophages by promoting lipid catabolism.

Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination. Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.

The Pathogenesis of Diabetes.

Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia is the main hallmark of diabetes. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Understanding the molecular processes involved in the development of diabetes can provide clinical care with much-needed updates. This review provides the current global state of diabetes, the mechanisms involved in glucose homeostasis and diabetic insulin resistance, and the long-chain non-coding RNA (lncRNA) associated with diabetes.

Integrated analysis of metabolomic and transcriptomic profiling reveals the effect of Buyang Huanwu decoction on Parkinson's disease in mice.

BACKGROUND: Parkinson's disease (PD) is a common, complex, and chronic neurodegenerative disorder involved in multi-system. At present, medicine for PD has many limitations. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicinal (TCM) formulae, is used in the treatment of PD clinically in China. However, the therapeutic mechanism is still unknown. PURPOSE: We aimed to explore the pharmacological mechanism of BHD alleviating PD through an integrated liver metabolome and brain transcriptome analysis. METHODS: The mice with PD were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests and immunohistochemistry were used to evaluate the neuroprotective effects of BHD. The non-targeted metabolomics analysis was conducted to profile differentially accumulated metabolites (DAMs) in the liver using a UHPLC-Q-Exactive MS/MS method. The differentially expressed genes (DEGs) in the brain were investigated by transcriptomic analysis on an Illumina sequencing platform. The correlations of DAMs and DEGs were investigated using an integrated metabolomic and transcriptomic approach. RESULTS: The results of behavioral tests and immunohistochemistry proved the alleviated effects of BHD on PD symptoms. A total of 14 and 36 DAMs were detected in the groups treated with low- (L group) and high-dose (H group) BHD respectively under the positive ion mode. Compared with the PD model group (M group), three enriched pathways including metabolic pathways, ABC transporters, and biosynthesis of amino acids were common in the L and H group. Transcriptomic analysis proved that BHD could regulate the expression of numerous genes, some of which were targeted by Ben-Ldopa such as Creb5, Gm45623, Ccer2, Cd180, Fosl2, Crip3, and Noxred1. Based on the integrated metabolomic and transcriptomic analysis, 7 metabolite-gene pairs were found in four comparisons, including C vs M, M vs P, M vs L, and M vs H, and 6 enriched pathways containing purine metabolism, glycine/serine/threonine metabolism, phenylalanine metabolism, carbon fixation in photosynthetic organisms, thiamine metabolism, and ABC transporters were overlapped. CONCLUSIONS: Though the underlying pharmacological mechanism of BHD is still lacking, we provided evidence that BHD could improve dopaminergic neurons in MPTP-induced PD mice by regulating liver metabolism and brain transcriptome. The correlation between the liver and the brain was preliminarily revealed in this study.

A novel lncRNA 495810 promotes the aerobic glycolysis in colorectal cancer by stabilizing pyruvate kinase isozyme M2.

Aberrant expression of long non­coding RNA (lncRNA) plays an important role in malignant progression of colon cancer and has become a new therapeutic target. In the present study, it was found that the expression of a novel lncRNA 495810 was significantly upregulated in colon cancer and correlated with poor prognosis in patients with colorectal cancer. The highly expressed lncRNA 495810 promoted the proliferation and inhibited apoptosis of CRC cells. Furthermore, the results of gene enrichment analysis indicated that 495810­targeted genes were enriched in the glycolysis pathway and overexpression of 495810 enhanced aerobic glycolysis in colon cancer cells. More importantly, the expression of lncRNA 495810 was positively correlated with the glycolytic rate­limiting enzyme pyruvate kinase isozyme M2 (PKM2). Notably, the data suggested that lncRNA 495810 physically interacted with PKM2 protein and enhanced PKM2 protein stability via the ubiquitin­proteasome pathway. The present findings suggested that lncRNA 495810, a glycolysis­related oncogenic lncRNA, is a potential biomarker for predicting prognosis and a therapeutic target for colon cancer.