Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

[The Expression of METTL14 in Patients with Newly Diagnosed Acute Myeloid Leukemia and Its Clinical Significance].

OBJECTIVE: To detect the expression of RNA methyltransferase 14(METTL14) in bone marrow of patients with newly diagnosed acute myeloid leukemia (AML), and to investigate the clinical and prognostic significance of METTL14 expression in newly diagnosed AML. METHODS: Bone marrow samples were collected from 100 patients with newly diagnosed AML as observation group and 60 patients with iron deficiency anemia AML as control group. And collected the clinical data of the AML patients. Real-time quantitative PCR (qRT-PCR) was used to detect the expression level of METTL14 in AML and IDA patients. The relationship between the expression level of METTL14 and clinicopathological features, prognosis was analyzed. Kaplan-Meier curves were used to analyze the effect of METTL14 on overall survival (OS) in AML patients. Cox risk regression model was used to analyze the prognostic factors affecting in patients with AML. RESULTS: Compared with the control group, the expression of METTL14 was significantly increased in AML patients (P < 0.05). Compared with the METTL14 low-expression group, patients in the METTL14 high-expression group had advanced age, high bone marrow cell number, poor efficacyand poor prognosis(P < 0.05). The overall survival time of patients with the METTL14 high-expression group was significantly shorter than that of the low-expression group (P < 0.05). The high expression of METTL14 was an independent risk factor for poor prognosis in AML. CONCLUSION: METTL14 is significantly overexpressed in AML patients, and its correlated with poor clinicopathological features and poor prognosis. It can be used as a prognostic marker and potential therapeutie target for AML patients.

Efficient regioselective enzymatic acylation of troxerutin: difference characterization of in vitro cellular uptake and cytotoxicity.

In this study, we developed a multi-site acylation strategy to improve the lipophilicity and cellular uptake of troxerutin, a natural flavonoid with many health-promoting bioactivities. By clarifying the acylation properties of troxerutin catalyzed by lipases from different sources, a series of troxerutin ester derivatives acylated at different sites was synthesized, including troxerutin dipropyl (TDP), tripropyl (TTP), tetrapropyl (TEP), dibutyl (TDB), monohexyl (TMH), monooctyl (TMO) and monodecyl (TMD) esters. Interestingly, the troxerutin esters acylated at multiple sites with shorter fatty chains (TDP, TTP and TEP) had similar lipophilicity to the mono-acylated esters bearing longer fatty chains (TMH, TMO and TMD, respectively) and meanwhile demonstrated surprisingly lower cytotoxicity than that of the long fatty-chain mono-esters. In particular, the multi-acylated esters with shorter fatty chains showed remarkably higher cellular uptake than the mono-esters with long fatty chains. In vitro gastrointestinal digestion suggested that the multi-acylated esters of troxerutin were more resistant to gastrointestinal degradation than the mono-esters. These results indicated that multi-site acylation with short fatty chains could be an effective alternative to introducing one-site mono-acylation for the modification of troxerutin and other flavonoid compounds.

Genome-Wide Identification and Drought Stress Response Pattern of the NF-Y Gene Family in Cymbidium sinense.

Cymbidium sinense, a type of orchid plant, is more drought-resistant and ornamental than other terrestrial orchids. Research has shown that many members of the NUCLEAR FACTOR Y (NF-Y) transcription factor family are responsive to plant growth, development, and abiotic stress. However, the mechanism of the NF-Y gene family's response to abiotic stress in orchids has not yet been reported. In this study, phylogenetic analysis allowed for 27 CsNF-Y genes to be identified (5 CsNF-YAs, 9 CsNF-YBs, and 13 CsNF-YC subunits), and the CsNF-Ys were homologous to those in Arabidopsis and Oryza. Protein structure analysis revealed that different subfamilies contained different motifs, but all of them contained Motif 2. Secondary and tertiary protein structure analysis indicated that the CsNF-YB and CsNF-YC subfamilies had a high content of alpha helix structures. Cis-element analysis showed that elements related to drought stress were mainly concentrated in the CsNF-YB and CsNF-YC subfamilies, with CsNF-YB3 and CsNF-YC12 having the highest content. The results of a transcriptome analysis showed that there was a trend of downregulation of almost all CsNF-Ys in leaves under drought stress, while in roots, most members of the CsNF-YB subfamily showed a trend of upregulation. Additionally, seven genes were selected for real-time reverse transcription quantitative PCR (qRT-PCR) experiments. The results were generally consistent with those of the transcriptome analysis. The regulatory roles of CsNF-YB 1, 2, and 4 were particularly evident in the roots. The findings of our study may make a great contribution to the understanding of the role of CsNF-Ys in stress-related metabolic processes.

A mechanism for the treatment of cardiovascular and renal disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. CVD and kidney disease are closely related, with kidney injury increasing CVD mortality. The pathogenesis of cardiovascular and renal diseases involves complex and diverse interactions between multiple extracellular and intracellular signaling molecules, among which transient receptor potential vanilloid 1 (TRPV1)/ transient receptor potential ankyrin 1(TRPA1) channels have received increasing attention. TRPV1 belongs to the vanilloid receptor subtype family of transient receptor potential (TRP) ion channels, and TRPA1 belongs to the TRP channel superfamily. TRPV1/TRPA1 are jointly involved in the management of cardiovascular and renal diseases, and play important roles in regulating vascular tension, promoting angiogenesis, anti-fibrosis, anti-inflammation, and anti-oxidation. The mechanism of TRPV1 / TRPA1 is mainly related to regulation of intracellular calcium influx and release of nitric oxide (NO) and calcitonin gene-related peptide (CGRP). Therefore, this study takes TRPV1 / TRPA1 channel as the research object, analyzes and summarizes the process and mechanism of TRPV1 / TRPA1 affecting cardiovascular and renal diseases, and lays a foundation for the treatment of cardio-renal diseases.

Divergent Biosynthesis of Bridged Polycyclic Sesquiterpenoids by a Minimal Fungal Biosynthetic Gene Cluster.

The bridged polycyclic sesquiterpenoids derived from sativene, isosativene, and longifolene have unique structures, and many chemical synthesis approaches with at least 10 steps have been reported. However, their biosynthetic pathway remains undescribed. A minimal biosynthetic gene cluster (BGC), named bip, encoding a sesquiterpene cyclase (BipA) and a cytochrome P450 (BipB) is characterized to produce such complex sesquiterpenoids with multiple carbon skeletons based on enzymatic assays, heterologous expression, and precursor experiments. BipA is demonstrated as a versatile cyclase with (-)-sativene as the dominant product and (-)-isosativene and (-)-longifolene as minor ones. BipB is capable of hydroxylating different enantiomeric sesquiterpenes, such as (-)-longifolene and (+)-longifolene, at C-15 and C-14 in turn. The C-15- or both C-15- and C-14-hydroxylated products are then further oxidized by unclustered oxidases, resulting in a structurally diverse array of sesquiterpenoids. Bioinformatic analysis reveals the BipB homologues as a discrete clade of fungal sesquiterpene P450s. These findings elucidate the concise and divergent biosynthesis of such intricate bridged polycyclic sesquiterpenoids, offer valuable biocatalysts for biotransformation, and highlight the distinct biosynthetic strategy employed by nature compared to chemical synthesis.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Anion-Counterion Strategy toward Organic Cocrystal Engineering for Near-Infrared Photothermal Conversion and Solar-Driven Water Evaporation.

An anion-counterion strategy is proposed to construct organic mono-radical charge-transfer cocrystals for near-infrared photothermal conversion and solar-driven water evaporation. Ionic compounds with halogen anions as the counterions serve as electron donors, providing the necessary electrons for efficient charge transfer with unchanged skeleton atoms and structures as well as the broad red-shifted absorption (200-2000 nm) and unprecedented photothermal conversion efficiency (~90.5 %@808 nm) for the cocrystals. Based on these cocrystals, an excellent solar-driven interfacial water evaporation rate up to 6.1±1.1 kg ⋅ m-2 ⋅ h-1 under 1 sun is recorded due to the comprehensive evaporation effect from the cocrystal loading in polyurethane foams and chimney addition, such performance is superior to the reported results on charge-transfer cocrystals or other materials for solar-driven interfacial evaporation. This prototype exhibits the great potential of cocrystals prepared by the one-step mechanochemistry method in practical large-scale seawater desalination applications.

Development of PI3Kγ selective inhibitors: the strategies and application.

The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.

Primary Structural Units "D+A-" Ion Pairs Dominating Near-Infrared Photothermal Conversion of Organic Ionic Cocrystals.

The specific stacking mode of D/A blocks is often considered to largely determine the physicochemical properties of cocrystals. However, this rule may fail when encountering a large degree of (integer or near-integer) charge transfer situations. Herein, we explore the extensive correlations between the possible smallest structural units, stacking modes, and near-infrared photothermal conversion (NIR-PTC) properties of F4TCNQ-based cocrystals with typical features of integer-charge-transfer. Surprisingly, these cocrystals with distinct stacking modes display analogous D-A interactions, broad red-shift absorption, ultrafast (1-3 ps) relaxation dynamics of excited states, and excellent NIR-PTC properties. This supports that the resulting "D+A-" ion pairs from integer-charge-transfer may serve as the primary structural units beneath the secondary stacking modes to dominate the property of cocrystals. The stacking modes play an important but only secondary role. This work provides new insights into the structure-dynamics-property correlations and modular design of organic cocrystals for PTC and other applications.

Glutathione depletion and dihydroorotate dehydrogenase inhibition actuated ferroptosis-augment to surmount triple-negative breast cancer.

Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH2) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.

Comparing the survival rates of patients with stage IIIC endometrial cancer undergoing sandwich therapy to those undergoing sequential chemotherapy and radiotherapy: a meta-analysis.

BACKGROUND: The use of additional treatment after surgery for stage IIIC endometrial cancer (EC) according to the Federation of Gynecology and Obstetrics (FIGO) is still a topic of discussion. This meta-analysis examined the effects of sandwich treatment and sequential treatment on the survival of individuals diagnosed with stage IIIC EC. METHODS: We examined the literature from various databases regarding the overall survival (OS) and adverse effects of the two additional therapies following surgery in individuals diagnosed with stage IIIC EC. Revman 5.4.1 was utilized to combine hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI) for OS and toxicities. RESULTS: The findings comprised of five retrospective investigations involving a combined total of 800 individuals. The patients who underwent sandwich treatment did not demonstrate a notable improvement in survival rates over a period of 3 years. Upon eliminating the impact of extensive samples, it was discovered that sandwich therapy exhibited a superior 5-year overall survival compared to patients receiving sequential therapy. The effectiveness of sandwich therapy was superior to sequential therapy in terms of a 3-year OS for non-endometrioid histology, although the outcome did not reach statistical significance. The toxicities of both treatments were similar. CONCLUSIONS: In terms of long-term survival, sandwich therapy was found to be more advantageous than sequential therapy for patients with stage IIIC EC, with no significant disparity observed in the 3-year OS and toxicities between the two treatments. Sandwich therapy exhibited a tendency towards improved effectiveness in patients with histology other than endometrioid.

Genome-Wide Identification of PEBP Gene Family in Two Dendrobium Species and Expression Patterns in Dendrobium chrysotoxum.

The PEBP gene family plays a significant role in regulating flower development and formation. To understand its function in Dendrobium chrysotoxum and D. nobile flowering, we identified 22 PEBP genes (11 DchPEBPs and 11 DnoPEBPs) from both species. We conducted analyses on their conserved domains and motifs, phylogenetic relationships, chromosome distribution, collinear correlation, and cis elements. The classification results showed that the 22 PEBPs were mainly divided into three clades, as follows: FT, MFT, and TFL1. A sequence analysis showed that most PEBP proteins contained five conserved domains, while a gene structure analysis revealed that 77% of the total PEBP genes contained four exons and three introns. The promoter regions of the 22 PEBPs contained several cis elements related to hormone induction and light response. This suggests these PEBPs could play a role in regulating flower development by controlling photoperiod and hormone levels. Additionally, a collinearity analysis revealed three pairs of duplicate genes in the genomes of both D. chrysotoxum and D. nobile. Furthermore, RT-qPCR has found to influence the regulatory effect of DchPEBPs on the development of flower organs (sepals, petals, lip, ovary, and gynostemium) during the flowering process (bud, transparent stage, and initial bloom). The results obtained imply that DchPEBP8 and DchPEBP9 play a role in the initial bloom and that DchPEBP7 may inhibit flowering processes. Moreover, DchPEBP9 may potentially be involved in the development of reproductive functionality. PEBPs have regulatory functions that modulate flowering. FT initiates plant flowering by mediating photoperiod and temperature signals, while TFL1 inhibits flowering processes. These findings provide clues for future studies on flower development in Dendrobium.

Up-to-date literature review and issues of sedation during digestive endoscopy.

Sedation is common during digestive endoscopy to provide comfort and pain relief for patients. However, the use of sedation in endoscopy also poses potential risks, and recent issues have been raised regarding its safety and administration. This literature review paper will discuss the most recent developments in the field of sedation in digestive endoscopy, including the adverse events that might be associated with sedation and how to manage it, the legal issues associated with administration, the impact of COVID-19 on sedation practices, and sedation in special situations. It will also touch upon the current guidelines and recommendations for sedation, including the importance of patient selection and monitoring and the need for training and certification for endoscopists administering sedation. The review will also analyse studies evaluating the safety and efficacy of various sedation techniques, including propofol, midazolam, and others. It will examine the benefits and drawbacks of these agents.

Genome-based identification of the CYP75 gene family in Orchidaceae and its expression patterns in Cymbidium goeringii.

With a great diversity of species, Orchidaceae stands out as an essential component of plant biodiversity, making it a primary resource for studying angiosperms evolution and genomics. This study focuses on 13 published orchid genomes to identify and analyze the CYP75 gene family belonging to the cytochrome P450 superfamily, which is closely related to flavonoid biosynthetic enzymes and pigment regulation. We found 72 CYP75s in the 13 orchid genomes and further classified them into two classes: CYP75A and CYP75B subfamily, the former synthesizes blue anthocyanins, while the latter is involved in the production of red anthocyanins. Furthermore, the amount of CYP75Bs (53/72) greatly exceeds the amount of CYP75As (19/72) in orchids. Our findings suggest that CYP75B genes have a more important evolutionary role, as red plants are more common in nature than blue plants. We also discovered unique conserved motifs in each subfamily that serve as specific recognition features (motif 19 belong to CYP75A; motif 17 belong to CYP75B). Two diverse-colored varieties of C. goeringii were selected for qRT-PCR experiments. The expression of CgCYP75B1 was significantly higher in the purple-red variant compared to the yellow-green variant, while CgCYP75A1 showed no significant difference. Based on transcriptomic expression analysis, CYP75Bs are more highly expressed than CYP75As in floral organs, especially in colorful petals and lips. These results provide valuable information for future studies on CYP75s in orchids and other angiosperms.

Genome Mining of Linaridins Provides Insights into the Widely Distributed LinC Oxidoreductases.

Linaridins are a family of underexplored ribosomally synthesized and post-translationally modified peptides despite the prevalence of their biosynthetic gene clusters (BGCs) in microbial genomes, as shown by bioinformatic studies. Our genome mining efforts reveal that 96 putative oxidoreductase genes, namely, LinC, are encoded in linaridin BGCs. We heterologously expressed two such LinC-containing linaridin BGCs, yan and ydn, from Streptomyces yunnanensis and obtained three new linaridins, named yunnanaridins A-C (1-3). Their structures are characterized by Z-configurations of the dehydrobutyrines and the presence of a variety of epimerized amino acid residues. Yunnanaridin A (1) is the sixth member of the family of type-B linaridins, whereas yunnanaridins B (2) and C (3) represent the first examples of expressed type-C linaridins. Interestingly, heterologous expression of the same BGCs with LinC in-frame knockouts produced the same compounds. This work expands the structural diversity of linaridins and provides evidence for the notion that the widespread LinCs may not be involved in linaridin biosynthesis.

Research advances on the gene regulation of floral development and color in orchids.

Orchidaceae is one of the largest monocotyledon families and contributes significantly to worldwide biodiversity, with value in the fields of landscaping, medicine, and ecology. The diverse phenotypes and vibrant colors of orchid floral organs make them excellent research objects for investigating flower development and pigmentation. In recent years, a number of orchid genomes have been published, laying the molecular foundation for revealing flower development and color presentation. In this article, we review transcription factors, the structural genes responsible for the floral pigment synthesis pathways, the molecular mechanisms of flower morphogenesis, and the potential relationship between flower type and flower color. This study provides a theoretical reference for the research on molecular mechanisms related to flower morphogenesis and color presentation, genetic improvement, and new variety creation in orchids.

Genome-Wide Identification of TCP Gene Family in Dendrobium and Their Expression Patterns in Dendrobium chrysotoxum.

The TCP gene family are plant-specific transcription factors that play important roles in plant growth and development. Dendrobium chrysotoxum, D. nobile, and D. huoshanense are orchids with a high ornamental value, but few studies have investigated the specific functions of TCPs in Dendrobium flower development. In this study, we used these three Dendrobium species to analyze TCPs, examining their physicochemical properties, phylogenetic relationships, gene structures, and expression profiles. A total of 50 TCPs were identified across three Dendrobium species; they were divided into two clades-Class-I (PCF subfamily) and Class-II (CIN and CYC/TB1 subfamilies)-based on their phylogenetic relationships. Our sequence logo analysis showed that almost all Dendrobium TCPs contain a conserved TCP domain, as well as the existence of fewer exons, and the cis-regulatory elements of the TCPs were mostly related to light response. In addition, our transcriptomic data and qRT-PCR results showed that DchTCP2 and DchTCP13 had a significant impact on lateral organs. Moreover, changes in the expression level of DchTCP4 suggested its important role in the phenotypic variation of floral organs. Therefore, this study provides a significant reference for the further exploration of TCP gene functions in the regulation of different floral organs in Dendrobium orchids.

Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis: A trans-cellular crosstalk.

BACKGROUND: Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis (NASH). However, the underlining mechanism is still unclear, where adipose tissue (AT) derived exosomes may actively participate. MicroRNAs (miRNAs) are commonly secreted from exosomes for cell communication. Though the regulation of miR-103 on insulin sensitivity has been reported, the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices. AIM: To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods. METHODS: The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control. The effect of miR-103 on NASH progression was also explored by antagonizing miR-103, including steatosis and inflammation degree changes. The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog (PTEN) was confirmed by dual-luciferase reporter assay. The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells. Finally, the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments. RESULTS: The expression of miR-103 was increased in NASH mice, compared to the control, and inhibition of miR-103 could alleviate NASH. The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN. MiR-103-anta decreased p-AMPKa, p-mammalian target of rapamycin (mTOR), and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice. Similar results were also observed in NASH-like cells, and further experiments showed PTEN silencing inhibited the effect of miR-103-anta. AT derived-exosome miR-103 aggravated NASH and increased the expressions of p-AMPKa, p-mTOR, and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice. CONCLUSION: AT derived-exosome increased the levels of miR-103 in the liver, and miR-103 aggravated NASH. Mechanically, miR-103 could interact with PTEN and inhibit autophagy.

The Impact of Cellular Therapies on Gastrointestinal Diseases: Applications and Challenges.

Gastrointestinal diseases are highly prevalent, and their burden significantly impacts the quality of life of affected individuals. Inflammatory and immune-mediated intestinal diseases usually have a chronic course without adequate therapeutic modalities. Although much has been reported to comprehend these diseases, many remain resistant and refractory to conventional treatment approaches. Therefore, recent approaches to cellular therapy using stem cells, like hematopoietic stem cells and mesenchymal stem cells, and other cellular immunosuppressive modalities, like T-regulatory cells, were introduced and investigated in treating gastrointestinal diseases. We aimed to conduct a literature review to discuss the applications and challenges of cellular therapeutics in gastrointestinal diseases. Evidence from published clinical trials supports the safety and efficacy of cellular treatment in different immune-mediated and inflammatory gastrointestinal diseases. They can offer a longer duration of remission, being able to adjust the dysregulated immune system. However, there are various challenges to be considered by future trials, including the limitations of current clinical trials, challenges in retrieval and application of these therapeutics, and their mutagenesis potential.