Interactions of oleanane pentacyclic triterpenoids with human organic anion transporting polypeptide 1B1 and 1B3.

Oleanane pentacyclic triterpenoids have been widely used in clinical practice. However, studies on their interactions with hepatic transporters remain limited. In this study, we systematically investigated the inhibitory effects of 14 oleanane pentacyclic triterpenoids on organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), two liver-specific uptake transporters. Through fluorescence-based cellular uptake assays, we identified three potent OATP1B1 inhibitors (saikosaponin B1, saikosaponin A and 18ß-glycyrrhetinic acid) and five potent OATP1B3 inhibitors (echinocystic acid, 3-oxo-16α-hydroxy-olean-12-en-28ß-oic acid, chikusetsu saponin IVa, saikosaponin B1 and 18ß-glycyrrhetinic acid). Structural analysis revealed that free oleanane triterpenoids inhibited OATP1B1/1B3 more potently than triterpene glycosides. Despite their similar structures, 18ß-glycyrrhetinic acid exhibited much stronger inhibition on OATP1B1/1B3 than 18α-glycyrrhetinic acid, while both were substrates of OATP1B3. Interestingly, OATP1B3 overexpression significantly increased reactive oxygen species (ROS) levels in HepG2 cells after treatment with 18ß-glycyrrhetinic acid. To conclude, this study highlights the potential interactions of oleanane pentacyclic triterpenoids with OATP1B1/1B3, and provides novel insights into the anti-cancer activity of 18ß-glycyrrhetinic acid.

SF3B3-regulated mTOR alternative splicing promotes colorectal cancer progression and metastasis.

BACKGROUND: Aberrant alternative splicing (AS) is a pervasive event during colorectal cancer (CRC) development. SF3B3 is a splicing factor component of U2 small nuclear ribonucleoproteins which are crucial for early stages of spliceosome assembly. The role of SF3B3 in CRC remains unknown. METHODS: SF3B3 expression in human CRCs was analyzed using publicly available CRC datasets, immunohistochemistry, qRT-PCR, and western blot. RNA-seq, RNA immunoprecipitation, and lipidomics were performed in SF3B3 knockdown or overexpressing CRC cell lines. CRC cell xenografts, patient-derived xenografts, patient-derived organoids, and orthotopic metastasis mouse models were utilized to determine the in vivo role of SF3B3 in CRC progression and metastasis. RESULTS: SF3B3 was upregulated in CRC samples and associated with poor survival. Inhibition of SF3B3 by RNA silencing suppressed the proliferation and metastasis of CRC cells in vitro and in vivo, characterized by mitochondria injury, increased reactive oxygen species (ROS), and apoptosis. Mechanistically, silencing of SF3B3 increased mTOR exon-skipped splicing, leading to the suppression of lipogenesis via mTOR-SREBF1-FASN signaling. The combination of SF3B3 shRNAs and mTOR inhibitors showed synergistic antitumor activity in patient-derived CRC organoids and xenografts. Importantly, we identified SF3B3 as a critical regulator of mTOR splicing and autophagy in multiple cancers. CONCLUSIONS: Our findings revealed that SF3B3 promoted CRC progression and metastasis by regulating mTOR alternative splicing and SREBF1-FASN-mediated lipogenesis, providing strong evidence to support SF3B3 as a druggable target for CRC therapy.

Vector valley Hall edge solitons in distorted type-II Dirac photonic lattices.

Topological edge states have recently garnered a lot of attention across various fields of physics. The topological edge soliton is a hybrid edge state that is both topologically protected and immune to defects or disorders, and a localized bound state that is diffraction-free, owing to the self-balance of diffraction by nonlinearity. Topological edge solitons hold great potential for on-chip optical functional device fabrication. In this report, we present the discovery of vector valley Hall edge (VHE) solitons in type-II Dirac photonic lattices, formed by breaking lattice inversion symmetry with distortion operations. The distorted lattice features a two-layer domain wall that supports both in-phase and out-of-phase VHE states, appearing in two different band gaps. Superposing soliton envelopes onto VHE states generates bright-bright and bright-dipole vector VHE solitons. The propagation dynamics of such vector solitons reveal a periodic change in their profiles, accompanied by the energy periodically transferring between the layers of the domain wall. The reported vector VHE solitons are found to be metastable.

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine.

Traditional Chinese medicine injections have been widely used in China for the treatment of various diseases. Transporter-mediated drug-drug interactions are a major contributor to adverse drug reactions. However, the research on transporter-mediated Traditional Chinese medicine injection-drug interactions is limited. Shuganning injection is a widely used Traditional Chinese medicine injection for treating various liver diseases. In this study, we investigated the inhibitory effect of Shuganning injection and its four main ingredients (baicalin, geniposide, chlorogenic acid, and oroxylin A) on 9 drug transporters. Shuganning injection strongly inhibited organic anion transporter 1 and organic anion transporter 3 with IC50 values < 0.1% (v/v), and moderately inhibited organic anion transporter 2, organic anion transporting-polypeptide 1B1, and organic anion transporting-polypeptide 1B3 with IC50 values < 1.0%. Baicalin, the most abundant bioactive ingredient in the Shuganning injection, was identified as both an inhibitor and substrate of organic anion transporter 1, organic anion transporter 3, and organic anion transporting-polypeptide 1B3. Oroxylin A had the potential to act as both an inhibitor and substrate of organic anion transporting-polypeptide 1B1 and organic anion transporting-polypeptide 1B3. In contrast, geniposide and chlorogenic acid had no significant inhibitory effect on drug transporters. Notably, Shuganning injection markedly altered the pharmacokinetics of furosemide and atorvastatin in rats. Using Shuganning injection as an example, our findings support the implementation of transporter-mediated Traditional Chinese medicine injection-drug interactions in the development of Traditional Chinese medicine injection standards.

Selective Inhibition of Organic Cation Transporter 1 by Benzoylpaeoniflorin Attenuates Hepatic Lipid Accumulation through AMPK Activation.

Organic cation transporter 1 (OCT1) is a liver-specific transporter and plays an essential role in drug disposition and hepatic lipid metabolism. Therefore, inhibition of OCT1 may not only lead to drug-drug interactions but also represent a potential therapy for fatty liver diseases. In this study, we systematically investigated the inhibitory effect of 200 natural products on OCT1-mediated uptake of 4,4-dimethylaminostyryl-N-methylpyridinium (ASP+) and identified 10 potent OCT1 inhibitors. The selectivity of these inhibitors over OCT2 was evaluated using both in vitro uptake assays and in silico molecular docking analyses. Importantly, benzoylpaeoniflorin was identified as the most potent OCT1 inhibitor with the highest selectivity over OCT2. Additionally, benzoylpaeoniflorin prevented lipid accumulation in hepatocytes, with concomitant activation of AMPK and down-regulation of lipogenic genes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). To conclude, our findings are of significant value in understanding OCT1-based natural product-drug interactions and provide a natural source of OCT1 inhibitors which may hold promise for treating fatty liver diseases.

Shunaoxin dropping pill improves cognitive functions of rats with chronic cerebral hypoperfusion via the microbiota-gut-brain axis.

Chronic cerebral hypoperfusion (CCH) is a major risk factor for cognitive decline and degenerative processes. Shunaoxin dropping pill (SNX) has been clinically used to treat cerebrovascular diseases. However, the effect and mechanism of SNX in treating CCH-induced cognitive impairment remain unclear. In this study, CCH was induced in rats using permanent bilateral common carotid artery ligation (2-VO). CCH rats were characterized by impaired spatial learning and memory ability, as well as increased oxidative stress and inflammation in the hippocampus. Additionally, CCH rats had reduced richness and biodiversity of fecal microbiota, which showed a strong correlation with altered serum metabolites. SNX significantly improved the cognitive impairment and restored the dysbiosis of fecal microbiota and serum metabolites in CCH rats. Notably, SNX did not prevent cognitive impairment in antibiotics-treated CCH rats. Our findings suggest that the microbiota-gut-brain axis is a promising therapeutic target for the treatment of CCH-induced cognitive impairment.

The role of hypoxic mesenchymal stem cells in tumor immunity.

The emerging evidence has shown that mesenchymal stem cells (MSCs) not only exert a significant role in the occurrence and development of tumors, but also have immunosuppressive potential in tumor immunity. Hypoxia is a sign of solid tumors, but how functions of hypoxic MSCs alter in the tumor microenvironment (TME) remains less well and comprehensively described. Herein, we mostly describe and investigate recent advances in our comprehension of the emerging effects of different tissue derived MSCs in hypoxia condition on tumor progression and development, as well as bidirectional influence between hypoxic MSCs and immune cells of the TME. Furthermore, we also discuss the potential drug-resistant and therapeutic role of hypoxic MSCs. It can be envisaged that novel and profound insights into the functionality of hypoxic MSCs and the underlying mechanisms in tumor and tumor immunity will promote the meaningful and promising treatment strategies against tumor.

3D-QSAR analysis of the interactions of flavonoids with human organic cation transporter 2.

Flavonoids are a class of phenolic and polyphenolic compounds widely distributed in vegetables, fruits, grains and herbs. Organic cation transporter 2 (OCT2) mediates the renal secretion of organic cations and is a key site of drug-drug interactions (DDIs). In this study, we systematically investigated the inhibitory effect of 28 flavonoids on OCT2-mediated uptake of 4-4-dimethylaminostyryl-N-methylpyridinium (ASP+). Among them, scullcapflavone II demonstrated the strongest inhibitory effect on OCT2-mediated uptake of ASP+ (IC50 =11.2 µM) in a competitive manner. Next, 3D-QSAR analyses of flavonoid OCT2 inhibitors were performed using both CoMFA and CoMSIA models. The date revealed that bulky substituents at the C-3 and C-4 positions of ring C as well as the C-7 position of ring A could prevent the interactions of flavonoids with OCT2. In contrast, a hydrophilic and negatively charge substituent on ring A was favorable for the interactions of flavonoids with OCT2. Consequently, baicalin (IC50 =220.2 µM) with a uronic acid substituent on ring A exhibited a stronger inhibition than baicalein (IC50 =294.5 µM); quercetin-3-O-galactoside (IC50 =497.4 µM) was a stronger inhibitor of OCT2 than rhamnetin 3-galactoside (IC50 =1409.0 µM). Taken together, our findings could be valuable in elucidating and predicting the interactions of flavonoids with OCT2.

Application of the PDCA cycle for standardized nursing management in sepsis bundles.

BACKGROUND: To explore the application effect of plan, do, check and action circulation management mode in improving the compliance of sepsis bundle treatment. METHODS: 113 patients with sepsis admitted from January 1 to December 31, 2018 were selected as the control group, and the bundle treatment measures of sepsis were routinely implemented. The above treatment measures were completed within 6 h. 113 patients with sepsis admitted from January 1 to December 31, 2019 were selected as the study group. All clinical staff took the same measures as the control group, supplemented by PDCA cycle management. Objective to compare the changes of compliance of clinical staff to sepsis bundle treatment before and after the implementation of PDCA cycle management. RESULTS: Compared with the control group, the study group achieved the completion rate of sepsis bundle treatment in 1 h from 66.4 to 81.4%, the completion rate in 3 h from 77.0 to 89.4%, and the completion rate in 6 h from 82.3 to 95.6%. The difference was statistically significant (P < 0.05 for all). CONCLUSIONS: The implementation of PDCA cycle management mode can effectively improve the compliance of clinical staff to the bundle treatment of sepsis, improve the treatment efficiency of sepsis, and improve the quality of medical care.

Study on clinical nursing pathway to promote the effective implementation of sepsis bundle in septic shock.

BACKGROUND: There is still a certain gap between the effective implementation and requirements of sepsis bundle. Our aim is to establish the clinical nursing pathway of the cluster treatment of septic shock in the Intensive Care Unit and promote effective implementation of the cluster treatment of septic shock. METHODS: By means of evidence-based method, quality control index requirements and on-site investigation, the implementation process of clinical nursing pathway of the cluster treatment within 6 h of diagnosis of septic shock was established. RESULTS: After the implementation of clinical nursing pathway, the completion rate of septic shock cluster treatment was 81.4% (66.4%) in 1 h, 89.4% (77.0%) in 3 h, 95.5% (82.3%) in 6 h (P < 0.05), which was significantly improved in the experimental group compared with the control group. CONCLUSIONS: The clinical nursing pathway of septic shock cluster treatment is guided by evidence-based nursing, which emphasizes standardization and standardization of septic shock cluster treatment nursing under the guidance of the guideline, and can promote the effective implementation of septic shock cluster treatment, significantly improve efficiency of septic shock treatment and the quality of medical care.

Role of microRNAs in remodeling the tumor microenvironment (Review).

MicroRNAs (miRNAs) are short non­coding RNAs that are known to regulate gene expression at the post­transcriptional level. miRNA expression is often deregulated in several human cancers, affecting the communication between tumor stroma and tumor cells, among other functions. Understanding the role of miRNAs in the tumor microenvironment is crucial for fully elucidating the molecular mechanisms underlying tumor progression and exploring novel diagnostic biomarkers and therapeutic targets. The present review focused on the role of miRNAs in remodeling the tumor microenvironment, with an emphasis on their impact on tumor growth, metastasis and resistance to treatment, as well as their potential clinical applications.

The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity.

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

The Emerging Role of YAP/TAZ in Tumor Immunity.

Yes-associated protein (YAP)/WW domain-containing transcription regulator 1 (TAZ) is an important transcriptional regulator and effector of the Hippo signaling pathway that has emerged as a critical determinant of malignancy in many human tumors. YAP/TAZ expression regulates the cross-talk between immune cells and tumor cells in the tumor microenvironment through its influence on T cells, myeloid-derived suppressor cells, and macrophages. However, the mechanisms underlying these effects are poorly understood. An improved understanding of the role of YAP/TAZ in tumor immunity is essential for exploring innovative tumor treatments and making further breakthroughs in antitumor immunotherapy. This review primarily focuses on the role of YAP/TAZ in immune cells, their interactions with tumor cells, and how this impacts on tumorigenesis, progression, and therapy resistance.

Pressure ulcer healing promoted by adequate protein intake in rats.

The effect of protein intake on rat pressure ulcer healing was evaluated. One hundred rats were numbered according to body weight and then they were randomly divided into 4 groups (n=25) using the random number table. After rat models of stage II pressure ulcer were established, they were fed with feed containing different protein levels (10, 15, 20 and 25%). Healing time, pressure ulcer area, body weight, albumin (ALB) and hemoglobin (Hb) levels among groups were compared. Hematoxylin and eosin (H&E) staining was also performed to observe pressure ulcer tissue structure. In the healing process of pressure ulcer, rats with 20% protein intake had the shortest healing time and the smallest pressure ulcer area. Body weight, ALB and Hb levels were much closer to the normal level. H&E staining result also suggested that the pressure ulcer healing degree of rats with 20% protein intake was much better than the others. Adequate protein intake is therefore conducive to pressure ulcer healing, while excessive or insufficient protein intake has negative impact on healing.

Generation and characterization of a IgG monoclonal antibody specific for GM3 (NeuGc) ganglioside by immunizing ß3Gn-T5 knockout mice.

A murine monoclonal antibody (MAb-1) specific for GM3 has been generated by immunizing ß3Gn-T5 knockout mice with purified GM3 ganglioside. The binding specificity of MAb-1 (IgG3 subclass) was established by an enzyme-linked immunosorbent assay (ELISA) and FACS and the antibody showed high binding specificity with GM3. Cell viability assay showed that MAb-1 significantly suppressed cell growth. Immunohistochemistry analysis revealed that MAb-1 was strongly expressed in human ovarian cancer tissues, whereas it was hardly expressed in normal tissues. Finally, antibody-dependent cellular cytotoxicity (ADCC) activities were determined by measuring lactate dehydrogenase (LDH) releasing assay and the results showed high ADCC activities in two representative ovarian cancer cell lines (OVHM and ID8). All of these data indicate that MAb-1 may be potentially used as a therapeutic antibody against ovarian cancers in clinical trials.

YAP signaling in gastric cancer-derived mesenchymal stem cells is critical for its promoting role in cancer progression.

Cancer-associated mesenchymal stem cells (MSCs) are critically involved in tumor development and progression. However, the mechanisms of action for MSCs in cancer remain largely unknown. Herein, we reported that the expression of Yes-associated protein 1 (YAP) was higher in gastric cancer derived mesenchymal stem cells (GC­MSCs) than that in bone marrow derived MSCs (BM­MSCs). YAP knockdown not only inhibited the growth, migration and invasion, and stemness of GC­MSCs, but also suppressed their promoting effect on gastric cancer growth in vitro and in vivo. In addition, the interference of YAP expression in GC­MSCs also attenuated the promoting role of gastric cancer cells in endothelial cell tube formation and migration. Mechanistically, YAP knockdown reduced the activation of ß-catenin and its target genes in gastric cancer cells by GC­MSCs. Taken together, these findings suggest that YAP activation in GC­MSCs plays an important role in promoting gastric cancer progression, which may represent a potential target for gastric cancer therapy.

miR-155-5p inhibition promotes the transition of bone marrow mesenchymal stem cells to gastric cancer tissue derived MSC-like cells via NF-κB p65 activation.

Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-κB p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKKε) were identified as targets of miR-155-5p and important for miRNA inhibitor activating NF-κB p65 in the transition. Inactivation of NF-κB by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-κB p65 and phospho-NF-κB p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-κB p65 protein was increased and activated. NF-κB inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-κB p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy.