The Bile Acid Membrane Receptor TGR5 in Cancer: Friend or Foe?

The G-protein-coupled bile acid receptor, Gpbar1 or TGR5, is characterized as a membrane receptor specifically activated by bile acids. A series of evidence shows that TGR5 induces protein kinase B (AKT), nuclear factor kappa-B (NF-κB), extracellular regulated protein kinases (ERK1/2), signal transducer and activator of transcription 3 (STAT3), cyclic adenosine monophosphate (cAMP), Ras homolog family member A (RhoA), exchange protein activated by cAMP (Epac), and transient receptor potential ankyrin subtype 1 protein (TRPA1) signaling pathways, thereby regulating proliferation, inflammation, adhesion, migration, insulin release, muscle relaxation, and cancer development. TGR5 is widely distributed in the brain, lung, heart, liver, spleen, pancreas, kidney, stomach, jejunum, ileum, colon, brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle. Several recent studies have demonstrated that TGR5 exerts inconsistent effects in different cancer cells upon activating via TGR5 agonists, such as INT-777, ursodeoxycholic acid (UDCA), and taurolithocholic acid (TLCA). In this review, we discuss both the 'friend' and 'foe' features of TGR5 by summarizing its tumor-suppressing and oncogenic functions and mechanisms.

Taurochenodeoxycholic Acid Increases cAMP Content via Specially Interacting with Bile Acid Receptor TGR5.

Taurochenodeoxycholic acid (TCDCA) is one of the main components of bile acids (BAs). TCDCA has been reported as a signaling molecule, exerting anti-inflammatory and immunomodulatory functions. However, it is not well known whether those effects are mediated by TGR5. This study aimed to elucidate the interaction between TCDCA and TGR5. To achieve this aim, first, the TGR5 eukaryotic vector was constructed. The expression level of TGR5 in 293T cells was determined by immunofluorescence, real-time quantitative PCR (RT-PCR, qPCR), and Western blot. The luciferase assay, fluorescence microscopy, and enzyme-linked immunosorbent assay (ELISA) were recruited to check the interaction of TCDCA with TGR5. TCDCA treatment in 293T cells resulted in TGR5 internalization coupled with a significant increase in cAMP luciferase expression. Our results demonstrated that TCDCA was able to bind to the TGR5 receptor and activate it. These results provide an excellent potential therapeutic target for TCDCA research. Moreover, these findings also provide theoretical evidence for further TCDCA research.

Molecular cloning and functional analysis of two phosphate transporter genes from Rhizopogon luteolus and Leucocortinarius bulbiger, two ectomycorrhizal fungi of Pinus tabulaeformis.

Inorganic phosphorus (Pi) is essential for plant growth, and phosphate (P) deficiency is a primary limiting factor in Pinus tabulaeformis development in northern China. P acquisition in mycorrhizal plants is highly dependent on the activities of phosphate transporters of their root-associated fungi. In the current study, two phosphate transporter genes, RlPT and LbPT, were isolated from Rhizopogon luteolus and Leucocortinarius bulbiger, respectively, two ectomycorrhizal fungi forming symbiotic interactions with the P. tabulaeformis. Phylogenetic analysis suggested that the sequence of the phosphate transporter of L. bulbiger is most closely related to a phosphate transporter of Hebeloma cylindrosporum, whereas the phosphate transporter of R. luteolus is most closely related to that of Piloderma croceum. The subcellular localization indicated that RlPT and LbPT were expressed in the plasma membrane. The complementation assay in yeast indicated that both RlPT and LbPT partially compensated for the absence of phosphate transporter activity in the MB192 yeast strain, with a K m value of 57.90 µmol/L Pi for RlPT and 35.87 µmol/L Pi for LbPT. qPCR analysis revealed that RlPT and LbPT were significantly up-regulated at lower P availability, which may enhance P uptake and transport under Pi starvation. Our results suggest that RlPT and LbPT presumably play a key role in Pi acquisition by P. tabulaeformis via ectomycorrhizal fungi.

Exploration of chemical compositions in different germplasm wolfberry using UPLC-MS/MS and evaluation of the in vitro anti-inflammatory activity of quercetin.

Wolfberry, esteemed as a traditional Chinese medicinal material and functional food, is replete with nutrients and boasts a diverse array of health benefits, including hypoglycemic, antitumor, antioxidant, anti-inflammatory, and immune-enhancing properties. Notably, inflammation is a pivotal factor in the onset and progression of numerous diseases. Despite this, there is a paucity of research on the comprehensive evaluation of the components found in different wolfberries, and the exploration of their primary active components is limited. To address this issue, we conducted a comprehensive targeted metabolomics analysis, employing statistical methods such as principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), KEGG pathway analysis, and volcano plots to delineate the compositional differences among red, black, and yellow wolfberries. Furthermore, we investigated the anti-inflammatory effects of their primary components through in vitro experiments. Our analysis revealed a total of 1,104 chemical compositions in the three wolfberries, with alkaloids, phenolic acids, flavonoids, and lipids being the predominant nutritional components. KEGG enrichment analysis indicated that these compositions were primarily involved in the biosynthesis of secondary metabolites, ABC transport, and galactose metabolism pathway. Moreover, our study demonstrated that quercetin exhibited dose-dependent anti-inflammatory activity in LPS-stimulated HUVECs. It effectively inhibited the production of inflammatory factors such as TNF-α, MCP-1, and IL-1ß, while also down-regulating the gene and protein expression levels of ICAM-1 and VCAM-1. In conclusion, our findings indicate that there are variations in compositions among the three wolfberries, with flavonoids being the most abundant, and in vitro studies also confirmed the anti-inflammatory potential of quercetin. It is worth noting that Lycium ruthenicum contains higher levels of antioxidant components and possesses greater nutritional value, providing valuable insights for the future development and utilization of the three wolfberries.

Predicting the Distribution of Neoceratitis asiatica (Diptera: Tephritidae), a Primary Pest of Goji Berry in China, under Climate Change.

Climate warming affects the growth and development of pests, resulting in changes in their geographical distribution, which increases the difficulty in terms of prevention and control. The fruit fly, Neoceratitis asiatica (Becker), is a predominant frugivorous pest that causes serious yield loss in the goji berry, Lycium barbarum L. In recent years, with the expansion of cultivation area, the damage induced by the pest has become increasingly severe, significantly impeding the production of the goji berry. In this study, the potential suitable habitats of N. asiatica under current and future climate scenarios were simulated and predicted using the optimal MaxEnt model, based on the screening distribution records and environmental factors. The changes in the pest distribution under climate change were determined using ArcGIS. The results showed that the best combination of parameters for MaxEnt were feature combination (FC) = LQPT and regularization multiplier (RM) = 1. The dominant environmental factors influencing pest distribution were mean temperature of driest quarter, mean temperature of coldest quarter and precipitation of coldest quarter. Under different climate conditions, the suitable habitats of the pest primarily ranged between 27°-47° N and 73°-115° E. Under current climate conditions, the area of moderately and highly suitable habitats was 42.18 × 104 km2, and mainly distributed in Inner Mongolia (13.68 × 104 km2), Gansu (9.40 × 104 km2), Ningxia (5.07 × 104 km2), Qinghai (4.10 × 104 km2), and Xinjiang (3.97 × 104 km2) Provinces. Under future climate scenarios, the suitable area was projected to be lower than the current ones, except SSP245-2050s and SSP370-2070s, and the centroids of suitable habitats were mainly shifted to the northeast, except SSP370-2050s and SSP585-2070s. Our results provide valuable guidance for the monitoring and management of N. asiatica, as well as the selection of pest-free goji berry cultivation sites.

Distribution Fitting for Combating Mode Collapse in Generative Adversarial Networks.

Mode collapse is a significant unsolved issue of generative adversarial networks (GANs). In this work, we examine the causes of mode collapse from a novel perspective. Due to the nonuniform sampling in the training process, some subdistributions may be missed when sampling data. As a result, even when the generated distribution differs from the real one, the GAN objective can still achieve the minimum. To address the issue, we propose a global distribution fitting (GDF) method with a penalty term to confine the generated data distribution. When the generated distribution differs from the real one, GDF will make the objective harder to reach the minimal value, while the original global minimum is not changed. To deal with the circumstance when the overall real data is unreachable, we also propose a local distribution fitting (LDF) method. Experiments on several benchmarks demonstrate the effectiveness and competitive performance of GDF and LDF.

Potentially suitable habitats of Daodi goji berry in China under climate change.

Introduction: Goji berry (Lycium barbarum L.) is a famous edible and medicinal herb worldwide with considerable consumption. The recent cultivation of goji berries in the Daodi region was seriously reduced due to increased production costs and the influence of policy on preventing nongrain use of arable land in China. Consequently, production of Daodi goji berry was insufficient to meet market demands for high-quality medicinal materials. Searching for regions similar to the Daodi region was necessary. Methods: The MaxEnt model was used to predicted the current and future potential regions suitable for goji berry in China based on the environmental characteristics of the Daodi region (including Zhongning County of Zhongwei prefecture-level city, and its surroundings), and the ArcGIS software was used to analyze the changes in its suitable region. Results: The results showed that when the parameters were FC = LQHP and RM = 2.1, the MaxEnt model was optimal, and the AUC and TSS values were greater than 0.90. The mean temperature and precipitation of the coldest quarter were the most critical variables shaping the distribution of Daodi goji berries. Under current climate conditions, the suitable habitats of the Daodi goji berry were 45,973.88 km2, accounting for 0.48% of China's land area, which were concentrated in the central and western Ningxia Province (22,589.42 km2), and the central region of Gansu Province (18,787.07 km2) bordering western Ningxia. Under future climate scenarios, the suitable area was higher than that under current climate conditions and reached the maximum under RCP 6.0 (91,256.42 km2) in the 2050s and RCP 8.5 (82,459.17 km2) in the 2070s. The expansion regions were mainly distributed in the northeast of the current suitable ranges, and the distributional centroids were mainly shifted to the northeast. The moderately and highly suitable overlapping habitats were mainly distributed in Baiyin (7,241.75 km2), Zhongwei (6,757.81 km2), and Wuzhong (5, 236.87 km2) prefecture-level cities. Discussion: In this stduy, MaxEnt and ArcGIS were applied to predict and analyze the suitable habitats of Daodi goji berry in China under climate change. Our results indicate that climate warming is conducive to cultivating Daodi goji berry and will not cause a shift in the Daodi region. The goji berry produced in Baiyin could be used to satisfy the demand for high-quality medicinal materials. This study addresses the insufficient supply and guides the cultivation of Daodi goji berry.

Effect of Lycium barbarum polysaccharides on cell signal transduction pathways.

Lycium barbarum polysaccharide (LBP), is a major active ingredient Lycium barbarum (LB), which exhibits several beneficial effects through NF-κB, PI3K-Akt-mTOR, p38-MAPK, Wnt-ß-catenin, PI3K-Akt-GSK-3ß, and MyD88 signal pathway, including anti-oxidation, and anti-aging, hypolipidemic and hypoglycemic, radiation, anti-tumor, and neuroprotection. Today, many researching papers are published on the LBP in physiology and pathology; however, the review of the LBP taking part in the signal transduction pathway in physiology and pathology is rear searched. Therefore, this research topic is a collection of reviews and original research articles that focus on the methods of the LBP extraction and its effects on the signal transduction pathway. The aim of this study is to provide theoretical evidence for in-depth analysis of the mechanisms of LBP in clinical clinical research studies.

Multiple analyses of various factors affecting the plantlet regeneration of Picea mongolica (H. Q. Wu) W.D. Xu from somatic embryos.

Picea mongolica, a native species with excellent industrial wood quality and strong sand-fixing capacity, may be utilized in construction of urban green spaces in arid areas in China. However, now the sustainability of the ecosystems where this species grows is at serious risk due to a lack of natural regeneration. In this study, we developed an efficient regeneration system and comprehensively analyzed various factors affecting somatic embryogenesis (SE) using zygotic embryos as explants. We identified the optimal plant growth regulators (PGRs) performance and the best donor trees (k81) for the generation of somatic embryos (SEMs). Additionally, we confirmed that the positive developmental window of SEMs initiation was at the end of July to early August, which is when zygotic embryos was at the late embryogeny. In this time period, specific transcripts associated with the regulation of epigenetic modifications, plant hormone-related genes, and embryonic development-related transcription factors play important roles for early SEMs initiation. These results may provide a valuable resource for vegetative propagation of Picea mongolica. Our results may help to establish a reliable protocol for plantlet regeneration, which may facilitate urban greening applications and industrialization in arid areas.

Taurochenodeoxycholic acid mediates cAMP-PKA-CREB signaling pathway.

Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.

Successful management of giant condyloma acuminatum of vulva with the combination of surgery and photodynamic therapy: Report of two cases.

Patients with condylomata acuminata of the vulva usually have increased difficulty to achieve complete response to treatment and also have a higher risk for disease recurrence. Treatment for this disease varies, including surgical excision, cryotherapy, electrocautery, CO2 laser therapy, topical therapy, and photodynamic therapy (PDT), but none of these alone provides a satisfactory outcome, especially for giant condyloma acuminatum (GCA). We reported two cases of GCA successfully cured with surgical removal, electrocautery and photodynamic therapy.