ALKBH5-mediated upregulation of CPT1A promotes macrophage fatty acid metabolism and M2 macrophage polarization, facilitating malignant progression of colorectal cancer.

m6A modification has been studied in tumors, but its role in host anti-tumor immune response and TAMs polarization remains unclear. The fatty acid oxidation (FAO) process of TAMs is also attracting attention. A co-culture model of colorectal cancer (CRC) cells and macrophages was used to simulate the tumor microenvironment. Expression changes of m6A demethylase genes FTO and ALKBH5 were screened. ALKBH5 was further investigated. Gain-of-function experiments were conducted to study ALKBH5's effects on macrophage M2 polarization, CRC cell viability, proliferation, migration, and more. Me-RIP and Actinomycin D assays were performed to study ALKBH5's influence on CPT1A, the FAO rate-limiting enzyme. AMP, ADP, and ATP content detection, OCR measurement, and ECAR measurement were used to explore ALKBH5's impact on macrophage FAO level. Rescue experiments validated ALKBH5's mechanistic role in macrophage M2 polarization and CRC malignant development. In co-culture, CRC cells enhance macrophage FAO and suppress m6A modification in M2 macrophages. ALKBH5 was selected as the gene for further investigation. ALKBH5 mediates CPT1A upregulation by removing m6A modification, promoting M2 macrophage polarization and facilitating CRC development. These findings indicate that ALKBH5 enhances fatty acid metabolism and M2 polarization of macrophages by upregulating CPT1A, thereby promoting CRC development.

An active piezoelectric plane X-ray focusing mirror with a linearly changing thickness.

X-ray mirrors for synchrotron radiation are often bent into a curved figure and work under grazing-incidence conditions due to the strong penetrating nature of X-rays to most materials. Mirrors of different cross sections have been recommended to reduce the mirror's slope inaccuracy and clamping difficulty in order to overcome mechanical tolerances. With the development of hard X-ray focusing, it is difficult to meet the needs of focusing mirrors with small slope error with the existing mirror processing technology. Deformable mirrors are adaptive optics that can produce a flexible surface figure. A method of using a deformable mirror as a phase compensator is described to enhance the focusing performance of an X-ray mirror. This paper presents an active piezoelectric plane X-ray focusing mirror with a linearly changing thickness that has the ability of phase compensation while focusing X-rays. Benefiting from its special structural design, the mirror can realize flexible focusing at different focusing geometries using a single input driving voltage. A prototype was used to measure its performance under one-dimension and two-dimension conditions. The results prove that, even at a bending magnet beamline, the mirror can easily achieve a single-micrometre focusing without a complicated bending mechanism or high-precision surface processing. It is hoped that this kind of deformable mirror will have a wide and flexible application in the synchrotron radiation field.

Stimulated Raman Scattering Microscopy Reveals Bioaccumulation of Small Microplastics in Protozoa from Natural Waters.

Microplastics (MPs) are pollutants of global concern, and bioaccumulation determines their biological effects. Although microorganisms form a large fraction of our ecosystem's biomass and are important in biogeochemical cycling, their accumulation of MPs has never been confirmed in natural waters because current tools for field biological samples can detect only MPs > 10 µm. Here, we show that stimulated Raman scattering microscopy (SRS) can image and quantify the bioaccumulation of small MPs (<10 µm) in protozoa. Our label-free method, which differentiates MPs by their SRS spectra, detects individual and mixtures of different MPs (e.g., polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, polystyrene, and poly(methyl methacrylate)) in protozoa. The ability of SRS to quantify cellular MP accumulation is similar to that of flow cytometry, a fluorescence-based method commonly used to determine cellular MP accumulation. Moreover, we discovered that protozoa in water samples from Yangtze River, Xianlin Wastewater Treatment Plant, Lake Taihu and the Pearl River Estuary accumulated MPs < 10 µm, but the proportion of MP-containing cells was low (∼2-5%). Our findings suggest that small MPs could potentially enter the food chain and transfer to organisms at higher trophic levels, posing environmental and health risks that deserve closer scrutiny.

Single-incision plus one-port laparoscopy surgery versus conventional multi-port laparoscopy surgery for colorectal cancer: a systematic review and meta-analysis.

OBJECTIVE: The efficacy of single-incision plus one-port laparoscopic surgery (SILS + 1) versus conventional laparoscopic surgery (CLS) for colorectal cancer treatment remains unclear. This study compares the short-term and long-term outcomes of SILS + 1 and CLS using a high-quality systematic review and meta-analysis. METHOD: Literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, drawing from PubMed, Embase, Web of Science, and the Cochrane Library until December 10, 2023. Statistical analysis was conducted using RevMan and Stata. RESULT: The review and meta-analysis included seven studies with 1740 colorectal cancer patients. Compared to CLS, SILS + 1 showed significant improvements in operation time (WMD = - 18.33, P < 0.00001), blood loss (WMD = - 21.31, P < 0.00001), incision length (WMD = - 2.07, P < 0.00001), time to first defecation (WMD = - 14.91, P = 0.009), time to oral intake (WMD = - 11.46, P = 0.04), and time to ambulation (WMD = - 11.52, P = 0.01). There were no significant differences in lymph node harvest, resection margins, complications, anastomotic leakage, hospital stay, disease-free survival, overall survival, and postoperative recurrence. CONCLUSIONS: Compared to CLS, SILS + 1 demonstrates superiority in shortening the surgical incision and promoting postoperative recovery. SILS + 1 can provide a safe and feasible alternative to CLS.

Patent Foramen Ovale Closure for Migraineurs with Massive Right-to-Left Shunt and White Matter Lesions: An Exploration on Curative Effects.

Objective: This study aims to investigate the therapeutic efficacy of patent foramen ovale (PFO) closure in migraine patients with a massive right-to-left shunt (RLS) and white matter lesions (WMLs). Methods: The research focused on migraine patients with a massive RLS who underwent PFO closure in our hospital from June 2020 to June 2021. The study included 51 patients without WMLs (control group, CG) and 27 patients with WMLs (observation group, OG). A 12-month postoperative follow-up survey was conducted to assess headache episodes (frequency and duration), evaluated using the Headache Impact Test-6 (HIT-6) and the Pain Intensity Visual Analog Scale (VAS). The psychological state was also evaluated using the Hamilton Anxiety and Depression Scale (HAMA, HAMD). Adverse reactions during the follow-up were recorded. Results: No significant differences in perioperative and prognostic adverse reactions were observed between OG and CG (P > .05). Both groups showed a reduction in postoperative headache episodes and pain intensity. However, the OG exhibited higher frequency and duration of headache episodes and elevated HIT-6 and VAS scores, resulting in lower clinical efficacy (P < .05). Postoperatively, both groups demonstrated reductions in HAMA and HAMD, with CG showing lower scores compared to OG (P < .05). Logistic regression analysis identified the course of the disease, HIT-6 score, and the presence of WMLs as independent risk factors for the efficacy of PFO closure (P < .05). Conclusions: PFO closure proves effective and safe in treating migraine patients with RLS. However, for those with WMLs, clinical attention should be directed toward the treatment of WMLs.

Mixed crushing and competitive leaching of all electrode material components and metal collector fluid in the spent lithium battery.

Hydrometallurgy is a primary method for recovering cathode electrode materials from spent lithium-ion batteries (LIBs). Most of the current research materials are pure cathode electrode materials obtained through manual disassembly. However, the spent LIBs are typically broken as a whole during the actual industrial recycling which makes the electrode materials combined with the collector fluid. Therefore, the competitive leaching between metal collector fluid and electrode material was examined. The pyrolysis characteristics of the electrode materials were analyzed to determine the pyrolysis temperature. The electrode sheet was pyrolyzed and then crushed for competitive leaching. The effect of pyrolysis was analyzed by XPS. The competitive leaching behavior was studied based on leaching agent concentration, leaching time and leaching temperature. The composition and morphology of the residue were determined to prove the competitive leaching results by XRD-SEM. TG results showed that 500 °C was the suitable pyrolysis temperature. XPS analysis demonstrated that pyrolysis can completely remove PVDF. Li and Co were preferentially leached during the competitive leaching while the leaching rates were 90.10% and 93.40% with 50 min leaching at 70 °C. The Al and Cu had weak competitive leachability and the leaching rate was 29.10% and 0.00%. XRD-SEM analysis showed that Li and Co can be fully leached with residual Al and Cu remaining. The results showed that the mixed leaching of electrode materials is feasible based on its excellent selective leaching properties.

(111) Facet-oriented Cu2Mg Intermetallic Compound with Cu3-Mg Sites for CO2 Electroreduction to Ethanol with Industrial Current Density.

The efficient ethanol electrosynthesis from CO2 is challenging with low selectivity at high CO2 electrolysis rates, due to the competition with H2 and other reduction products. Copper-based bimetallic electrocatalysts are potential candidates for the CO2-to-ethanol conversion, but the secondary metal has mainly been focused on active components (such as Ag, Sn) for CO2 electroreduction, which also promote selectivity of ethylene or other reduction products rather than ethanol. Limited attention has been given to alkali-earth metals due to their inherently active chemical property. Herein, we rationally synthesized a (111) facet-oriented nano Cu2Mg (designated as Cu2Mg(111)) intermetallic compound with high-density ordered Cu3-Mg sites. The in situ Raman spectroscopy and density function theory calculations revealed that the Cu3 - δ $_{^{\rm{{\rm \delta} }} }$ --Mg- δ $_{^{\rm{{\rm \delta} }} }$ + active sites allowed to increase *CO surface coverage, decrease reaction energy for *CO-CO coupling, and stabilize *CHCHOH intermediates, thus promoting the ethanol formation pathway. The Cu2Mg(111) catalyst exhibited a high FEC2H5OH of 76.2±4.8 % at 600 mA⋅cm-2, and a peak value of |jC2H5OH| of 720±34 mA⋅cm-2, almost 4 times of that using conventional Cu2Mg with (311) facets, comparable to the best reported values for the CO2-to-ethanol electroreduction.

Nobiletin, an active component of Wenyang Yiqi formula, alleviates constipation associated depression through targeting MAPT to inhibit the MAPK signaling pathway.

BACKGROUND: Slow transit constipation (STC) is a common gastrointestinal disorder that is often accompanied by depression. Nobiletin is a natural compound that has been shown to have anti-inflammatory and anti-depressant effects. PURPOSE: To study the effects of nobiletin extracted from Wenyang Yiqi Formula 19 (WYF) on STC accompanied by depression and the related mechanism in STC mouse models. METHODS: In this study, the effects of nobiletin on STC accompanied by depression were investigated in both an STC animal model and an in vitro study. The animal model was induced by loperamide, and the in vitro study used Interstitial cells of Cajal (ICCs) isolated from STC mice. The efficacy of nobiletin was assessed by comparing various parameters, including stool particle counts, moisture content, intestinal propulsive rate, colon histopathology, microtubule-associated protein-tau (MAPT) expression in colon tissue, serum levels of TNF-α, IL-1ß, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins among three experimental groups. RESULTS: Nobiletin treatment significantly improved stool particle counts, moisture content, intestinal propulsive rate, and colon histopathology in the STC animal model. Nobiletin also decreased MAPT expression in colon tissue and serum levels of TNF-α, IL-1ß, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins. In the in vitro study, nobiletin treatment reversed the increased cell proliferation and cell apoptosis observed in ICC isolated from the STC model. CONCLUSION: The findings of this study indicate that nobiletin exhibits promising therapeutic potential in addressing STC accompanied by depression. This potential may be attributed to its ability to regulate the function of ICC by targeting MAPT.

Erratum: [Corrigendum] Downregulated caveolin­1 expression serves a potential role in coronary artery spasm by inducing nitric oxide production in vitro.

[This corrects the article DOI: 10.3892/etm.2018.6646.].

Diagnostic value of contrast-enhanced ultrasound in judging the survival of graft after heteroautoplasty for secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is one of the common complications of end-stage renal disease-uremia, and is mainly manifested as parathyroid hyperplasia and abnormal secretion of parathyroid hormone (PTH). OBJECTIVE: To investigate the value and advantages of contrast-enhanced ultrasound (CEUS) in evaluating the survival of autografts after parathyroidectomy + parathyroid autotransplantation. METHODS: In this study, 125 patients with renal failure due to polycystic kidney disease, chronic nephritis, diabetic nephropathy, lupus nephritis, and atherosclerotic nephropathy were enrolled as the participants and each of them had 4 secondary hyperactive parathyroid glands and underwent parathyroid autotransplantation. One parathyroid gland was taken from each patient and equally divided into 4 parts and placed in the subcutaneous fat of one forearm for transplantation. CEUS was performed 14 days after the transplantation to observe the micro blood supply of the graft and assess the survival and secretory function of the transplanted parathyroid. The grafts were divided into the partial survival group and the total survival group based on the enhancement characteristics. The survival of the grafts was determined by comparing the parathyroid hormone level in bilateral elbow cephalic veins 1 month after surgery. RESULTS: Among the 125 patients, 112 had linear or punctate enhancement of 2-4 parathyroid glands 14 days after surgery, and 13 patients had linear or punctate enhancement of 0-1 parathyroid gland. There were statistically significant differences in the perfusion pattern, enhancement uniformity, and parathyroid hormone levels in the cephalic veins at the elbow on both the graft and non-graft sides among all groups (P< 0.05). CONCLUSION: Compared to the detection of the difference in the parathyroid hormone level in the cephalic vein of bilateral elbows 1 month after surgery, CEUS can reflect the parathyroid survival after transplantation more quickly and accurately 2 weeks later, and provide a more rapid and agile non-invasive clinical diagnosis method.

Network Pharmacology Combined with Molecular Docking Approach to Investigate the Mechanism of ChuShiWeiLing Decoction against Perianal Eczema.

BACKGROUND: ChuShiWeiLing Decoction (CSWLD) is a famous classical Chinese prescription for the treatment of eczema with desirable effect in clinical practice. It has gradually exerted good curative effects on perianal eczema (PE) in recent years, but its specific mechanism is not elucidated yet. OBJECTIVE: This research explores the underlying pharmacological mechanism of CSWLD in addressing PE through network pharmacology combined with molecular docking strategy. METHODS: The key chemical compounds and potential target genes of CSWLD were screened by bioinformatics. The major targets of CSWLD were discovered using network modules. Functional annotation of Gene Ontology (GO) was undertaken, as well as pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular docking of core protein-ligand interactions was modeled using AutoDock software. Pymol software was used to perform a molecular dynamics simulation for the ideal core protein-ligand that was discovered by molecular docking. RESULTS: A total of 2,853 active compounds and 922 targets of CSWLD were collected. The target with a higher degree was identified through the PPI network, namely TNF, IL6, ALB, STAT3, EGFR, TLR4, CXCL8 and PTPRC. GO and KEGG analyses suggested that CSWLD treatment of PE mainly involves cellular activation, activation of leukocytes, and adhesion among leukocytes. The molecular docking results showed that wogonin, hederagenin and quercetin of CSWLD could bind to IL-6 and TNF, respectively. CONCLUSION: Our results indicated that the bioactives, potential targets, and molecular mechanism of CSWLD against PE.

Thromboxane A2 Modulates de novo Synthesis of Adrenal Corticosterone in Mice via p38/14-3-3γ/StAR Signaling.

Prostanoids are endogenous lipid bioactive mediators that play essential roles in physiological processes such as glucocorticoid secretion. Here, it is found that the thromboxane (Tx)A2 receptor (TP) is highly expressed in the adrenal cortex of mice. Both global and adrenocortical-specific deletion of the TP receptor lead to increased adiposity in mice by elevating corticosterone synthesis. Mechanistically, the TP receptor deletion increases the phosphorylation of steroidogenic acute regulatory protein (StAR) and corticosterone synthesis in adrenal cortical cells by suppressing p-p38-mediated phosphorylation of 14-3-3γ adapter protein at S71. The activation of the p38 in the adrenal cortical cells by forced expression of the MKK6EE gene attenuates hypercortisolism in TP-deficient mice. These observations suggest that the TxA2/TP signaling regulates adrenal corticosterone homeostasis independent of the hypothalamic-pituitary-adrenal axis and the TP receptor may serve as a promising therapeutic target for hypercortisolism.

High-strength alginate fibers wet-spun from pre-crosslinked sodium alginate solutions.

Facing the severe problem of microplastic pollution, there is an urgent need to develop biodegradable fibers to replace the petrochemical fibers. Sodium alginate, a biomass polysaccharide, has gained widespread attentions recently for the fiber manufacture. However, the limited mechanical strength of alginate fibers restricts their usages as load-bearing fabrics and reinforcement fibers. Here, we develop a novel strategy to prepare alginate multifilaments using pre-crosslinked sodium alginate solutions. The increase in the pre-crosslinking ratio effectively hinders the disentanglement of sodium alginate chains at high stretches, causing an increase in the shear viscosity of the solution ascertained from the capillarity-driven thinning process from 4.5 Pa·s to 9.9 Pa·s and facilitating the high alignment and orientation of sodium alginate chains. The resultant fibers possess a breaking strength of 474 MPa, elongation at break of 16 %, Young's modulus of 14.4 GPa, and toughness of 51.8 MJ/m3, exceeding most biomass fibers without reinforcement additives. The high orientation degree of 0.865 and high spinnability of alginate multifilaments enable their applications in multi-channel encryption fabrics that exhibit distinct information under various optical conditions. This rheological regulation of spinning solutions provides a facile yet effective strategy to enhance the mechanical performance and broaden application scenarios of alginate fibers.

LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis.

Purpose: The study aims to explore the roles and underlying mechanisms of long noncoding RNAs endogenous bornavirus-like nucleoprotein (lncRNA EBLN3P) in colon cancer, emphasizing the potential impact of these insights on advancing colon cancer treatment strategies. By shedding light on lncRNA EBLN3P's involvement, this research could contribute to the development of novel therapeutic approaches, enhancing the efficacy of interventions for colon cancer patients. Methods: We employed quantitative reverse transcription polymerase chain reaction to assess the levels of lncRNA EBLN3P, zinc finger protein (ZFP91), and miR-519d-3p, alongside CCK-8 and EdU assays for cell proliferation, flow cytometry for apoptosis, and Transwell and wound healing assays for migration and invasion. The in vivo function of lncRNA EBLN3P was investigated through a xenograft model, and protein levels were evaluated via Western blot analysis. Results: LncRNA EBLN3P was found to be upregulated in colon cancer tissues and cells, promoting cell proliferation and metastasis while inhibiting apoptosis. Downregulation of lncRNA EBLN3P reduced tumor size, volume, and weight in a mouse model. MiR-519d-3p, which negatively interacts with lncRNA EBLN3P, was found to be downregulated in colon cancer tissues and cell lines. Its upregulation hindered cancer cell proliferation and metastasis while enhancing apoptosis. ZFP91, a binding partner of miR-519d-3p, was upregulated in colon cancer and inversely related to miR-519d-3p levels. Rescue experiments indicated that the effects of lncRNA EBLN3P silencing could be reversed by miR-519d-3p suppression, but were mitigated by ZFP91 downregulation. Conclusion: LncRNA EBLN3P facilitates colon cancer progression via the miR-519d-3p/ZFP91 axis, presenting a novel understanding of lncRNA EBLN3P's role and offering potential therapeutic insights for colon cancer treatment. This study fills a critical gap by linking lncRNA EBLN3P with the miR-519d-3p/ZFP91 axis in the context of colon cancer, thereby broadening our understanding of the molecular mechanisms underlying colon cancer progression.

Long non­coding RNA DANCR aggravates breast cancer through the miR­34c/E2F1 feedback loop.

Emerging scientific evidence has suggested that the long non­coding (lnc)RNA differentiation antagonizing non­protein coding RNA (DANCR) serves a significant role in human tumorigenesis and cancer progression; however, the precise mechanism of its function in breast cancer remains to be fully understood. Therefore, the objective of the present study was to manipulate DANCR expression in MCF7 and MDA­MB­231 cells using lentiviral vectors to knock down or overexpress DANCR. This manipulation, alongside the analysis of bioinformatics data, was performed to investigate the potential mechanism underlying the role of DANCR in cancer. The mRNA and/or protein expression levels of DANCR, miR­34c­5p and E2F transcription factor 1 (E2F1) were assessed using reverse transcription­quantitative PCR and western blotting, respectively. The interactions between these molecules were validated using chromatin immunoprecipitation and dual­luciferase reporter assays. Additionally, fluorescence in situ hybridization was used to confirm the subcellular localization of DANCR. Cell proliferation, migration and invasion were determined using 5­ethynyl­2'­deoxyuridine, wound healing and Transwell assays, respectively. The results of the present study demonstrated that DANCR had a regulatory role as a competing endogenous RNA and upregulated the expression of E2F1 by sequestering miR­34c­5p in breast cancer cells. Furthermore, E2F1 promoted DANCR transcription by binding to its promoter in breast cancer cells. Notably, the DANCR/miR­34c­5p/E2F1 feedback loop enhanced cell proliferation, migration and invasion in breast cancer cells. Thus, these findings suggested that targeting DANCR may potentially provide a promising future therapeutic strategy for breast cancer treatment.

Conductive and alignment-optimized porous fiber conduits with electrical stimulation for peripheral nerve regeneration.

Autologous nerve transplantation (ANT) is currently considered the gold standard for treating long-distance peripheral nerve defects. However, several challenges associated with ANT, such as limited availability of donors, donor site injury, mismatched nerve diameters, and local neuroma formation, remain unresolved. To address these issues comprehensively, we have developed porous poly(lactic-co-glycolic acid) (PLGA) electrospinning fiber nerve guide conduits (NGCs) that are optimized in terms of alignment and conductive coating to facilitate peripheral nerve regeneration (PNR) under electrical stimulation (ES). The physicochemical and biological properties of aligned porous PLGA fibers and poly(3,4-ethylenedioxythiophene):polystyrene sodium sulfonate (PEDOT:PSS) coatings were characterized through assessments of electrical conductivity, surface morphology, mechanical properties, hydrophilicity, and cell proliferation. Material degradation experiments demonstrated the biocompatibility in vivo of electrospinning fiber films with conductive coatings. The conductive NGCs combined with ES effectively facilitated nerve regeneration. The designed porous aligned NGCs with conductive coatings exhibited suitable physicochemical properties and excellent biocompatibility, thereby significantly enhancing PNR when combined with ES. This combination of porous aligned NGCs with conductive coatings and ES holds great promise for applications in the field of PNR.

Hepatic perivascular epithelioid cell tumors: The importance of preoperative diagnosis.

Accurate preoperative diagnosis is highly important for the treatment of perivascular epithelioid cell tumors (PEComas) because PEComas are mainly benign tumors and may not require surgical intervention. By analyzing the causes, properties and clinical manifestations of PEComas, we summarize the challenges and solutions in the diagnosis of PEComas.

Mechanism and treatment of diarrhea associated with tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have become first-line drugs for cancer treatment. However, their clinical use is seriously hindered since many patients experience diarrhea after receiving TKIs. The mechanisms of TKI-associated diarrhea remain unclear. Most existing therapies are symptomatic treatments based on experience and their effects are unsatisfactory. Therefore, clarification of the mechanisms underlying diarrhea is critical to develop effective anti-diarrhea drugs. This article summarizes several potential mechanisms of TKI-associated diarrhea and reviews current treatment progress.

Coupling experimental with simulation studies into the impact factors and reaction mechanism of sawdust char pressured hydrogasification on K-modified transition metal composite catalysts.

The utilization of biomass char was hindered by the low gasification activity due to thick ring structures and unclear gasification mechanism. Herein, the mechanism was elucidated by experimental and DFT to improve the activity. The results demonstrated that temperature increased the gasification activity but did not changed the order of gasification activity of samples. Pressure dominated the position of the highest point of instantaneous CH4 yield, and high pressure enhanced carbon conversion by 81.72 % and 7.32 times. Moreover, KNi exhibited an uppermost catalytic activity with the instantaneous CH4 yield 1.89 times higher than that of raw char at 750 °C. The formation of the CxNi structure lowered the activation barrier for the ring opening reaction. Possible transformation pathways of Ni species were as follows: Ni(NO3)2·6H2O â†’ NiO â†’ Ni. KNi changed the reaction pathways and the most energy-consuming step. The study could shed light on the hydrogasification reaction mechanism.

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation.

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.