Synthesis and cytotoxic evaluation of glycosyl derivatives of icaritin.

A series of glycosyl alkyl/triazol-linked icaritin derivatives have been designed and synthesised. The target glycosyl derivatives were evaluated for their anticancer activity against three human cancer cell lines. The results of preliminary anticancer tests in vitro revealed that mannose derivatives 10a-10c (100 µM) with different aliphatic chain lengths exhibited increased cytotoxicity against HepG2 and SK-OV-3 cells compared with the parent compound icaritin. The data indicated that the kind of glycosyl groups and linkers affected the anticancer potency significantly. The ADME analysis of derivatives 10a-10c was also performed.

Novel KMT5B variant associated with neurodevelopmental disorder in a Chinese family: A case report.

Background: We report here the clinical and genetic features of KMT5B-related neurodevelopmental disorder caused by a novel heterozygous frameshift variant in KMT5B in a Chinese family. Case presentation: A 7-year-old Chinese boy with mild-to-moderate intellectual disability, significant language impairment, motor disability, and coordination difficulties presented to our hospital because he "could not speak and did not look at others." He was diagnosed with autism spectrum disorder previously owing to developmental delays in cognition, language expression, and understanding. The child also had variable nonspecific features including macrocephaly, wide button-hole space and nasal bridge, low ear, social behavior disorder, and foot deformities. Exome sequencing (ES) revealed that both the proband and his younger brother had inherited a novel heterozygous frameshift variant c.438_439ins[ASD; KT192064.1:1_310] of the KMT5B gene from their father. Bioinformatics analysis showed that the novel mutation affected the structure of the KMT5B pre-SET domain, mainly in the α-helix region. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this type of variant was eventually determined to be likely pathogenic (PVS1+PM2_P). Conclusions: Our investigation expands the mutation spectrum of KMT5B to help us to better understand KMT5B-related neurodevelopmental disorder.

Development of a Triphenylmethyl Alkylation Pre-Column Derivatization Method for HPLC Quantitative Analysis of Chemically Unstable Halogenated Compounds.

The primary limitations of the quantitative analysis of thermally labile halogenated compounds by traditional gas chromatography (GC) are the inadequacy of identifying the insufficiently volatile impurity (often with a high boiling point) and the difficulty in obtaining a standard substance with a reliable standardized assay. Taking the 4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Cl, 1) as an example, we reported a triphenylmethanamino-derivatization method to overcome the challenges of the assay determination of such species. During the quantification of 1, the presence of GC-undetectable polymeric impurity 10 poses a critical challenge in assessing the material quality. Moreover, the standard substance of 1 is not available on the market due to its inherent instability during storage and handling, further complicating the quantitative analysis. In this work, a precolumn HPLC-UV derivatization method based on triphenylmethanamino-alkylation was developed to quantitatively analyze 1. The resulting derivative 2 exhibits excellent crystallinity and superior physical and chemical stability and possesses effective chromophores for UV detection. The conversion from analyte 1 to derivative 2 demonstrates desirable reactivity and purity, facilitating quantitative analysis using the external standard method. The chemical derivatization-chromatographic detection method was optimized and validated, demonstrating its high specificity, good linearity, precision, accuracy, and stability. This method offers a valuable alternative to the general quantitative NMR (qNMR) detection technique, which exhibits reduced specificity in the presence of increased levels of impurities in compound 1.

Self-adjuvanting polymeric nanovaccines enhance IFN production and cytotoxic T cell response.

Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (-1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Cyp2e1 protects against OVA-induced allergic rhinitis through the inhibition of Th2 cell activation and differentiation: Mediated by MAFB.

Allergic rhinitis (AR) is a common allergic disease. Cytochrome P450, family 2, subfamily e, polypeptide 1 (Cyp2e1) is a member of the cytochrome P450 family of enzymes, while its role in AR is still unveiled. In AR mice, T cell-specific overexpression of Cyp2e1 relieved the AR symptoms. Overexpressed-Cyp2e1 restrained the infiltration of eosinophils and mast cells in the nasal mucosa of mice, and the inflammatory cells in nasal lavage fluid (NALF). Cyp2e1 overexpressed mice exhibited decreased goblet cell hyperplasia and mucus secretion as well as decreased MUC5AC expression in nasal mucosa. The epithelial permeability and integrity of nasal mucosa were improved upon Cyp2e1 overexpression in AR mice, as evidenced by decreased fluorescein isothiocyanate-dextran 4 content in serum, increased expression of IL-25, IL-33, and TSLP in NALF, and increased expression of ZO-1 and occluding in nasal mucosa. Cyp2e1 inhibited Th2 immune response by decreasing the expression and secretion of IL-4, IL-5, and IL-13 as well as the expression of GATA-3 in NALF or nasal mucosa. We proved that Cyp2e1 inhibited the differentiation of naïve CD4+ T cells toward the Th2 subtype, which was regulated by MAFB by binding to Cyp2e1 promoter to activate its transcription. Overall, these results show the potential role of Cyp2e1 in alleviating AR symptoms by restraining CD4+ T cells to Th2 cell differentiation. Our findings provide further insight into the AR mechanism.

Prostate cancer-associated transcript 6 (PCAT6) promotes epithelial-mesenchymal transition and stemness and worsens prognosis in patients with colorectal cancer.

Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD­L1­dependent manner.

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

Notoginsenoside Ft1 inhibits colorectal cancer growth by increasing CD8+ T cell proportion in tumor-bearing mice through the USP9X signaling pathway.

The management of colorectal cancer (CRC) poses a significant challenge, necessitating the development of innovative and effective therapeutics. Our research has shown that notoginsenoside Ft1 (Ng-Ft1), a small molecule, markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8+ T cells in tumor-bearing mice, thus restraining tumor growth. Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X, undermining its role in shielding ß-catenin. This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway. These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC, working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8+ T cell prevalence within the tumor environment.

Experimental and Numerical Simulation Research on Controllable Shock Wave-Induced Shale Fracturing under Repeated Action.

Low permeability is a key geological factor constraining the development of shale gas, and reservoir modification to improve its permeability is a prerequisite. Controlled shock wave fracturing can induce the formation of complex fractures in reservoirs and is expected to become an important means of reservoir modification. However, the mechanism of controlled shock wave fracturing in shale and the geological engineering control factors are unclear. Therefore, this article reveals the mechanism and effect of shock wave modification through small-scale experiments and large-scale numerical simulations. Results show that as the impact number increases, a significant increase in large fractures and fracture connectivity within the shale samples is observed, while the correlation between the geometric parameters of the fractures and the number of impacts is weak. High-energy input in the model will cause a larger range of damage to the rock, accompanied by a smaller attenuation index, indicating that the speed of energy attenuation plays a decisive role in rock damage. The influence of crustal stress is greater than the speed of energy attenuation, and higher crustal stress will inhibit the formation of fractures. A moderate increase in the number of controllable shock waves is beneficial for the fracturing effect; however, further increasing the loading number of controllable shock waves will weaken the strengthening effect of the fracturing effect.

Mechanisms and therapeutic strategies for senescence-associated secretory phenotype in the intervertebral disc degeneration microenvironment.

As a permanent state of cell cycle arrest, cellular senescence has become an important factor in aging and age-related diseases. As a central regulator of physiology and pathology associated with cellular senescence, the senescence associated secretory phenotype can create an inflammatory and catabolic environment through autocrine and paracrine ways, ultimately affecting tissue microstructure. As an age-related disease, the correlation between intervertebral disc degeneration and cellular senescence has been confirmed by many studies. Various pathological factors in the microenvironment of intervertebral disc degeneration promote senescent cells to produce and accumulate and express excessive senescence associated secretory phenotype. In this case, senescence associated secretory phenotype has received considerable attention as a potential target for delaying or treating disc degeneration. Therefore, we reviewed the latest research progress of senescence associated secretory phenotype, related regulatory mechanisms and intervertebral disc cell senescence treatment strategies. It is expected that further understanding of the underlying mechanism between cellular senescence pathology and intervertebral disc degeneration will help to formulate reasonable senescence regulation strategies, so as to achieve ideal therapeutic effects. The translational potential of this article: Existing treatment strategies often fall short in addressing the challenge of repairing intervertebral disc Intervertebral disc degeneration（IVD） degeneration. The accumulation of senescent cells and the continuous release of senescence-associated secretory phenotype (SASP) perpetually impede disc homeostasis and hinder tissue regeneration. This impairment in repair capability presents a significant obstacle to the practical clinical implementation of strategies for intervertebral disc degeneration. As a result, we present a comprehensive overview of the latest advancements in research, the associated regulatory mechanisms, and strategies for treating SASP in IVD cells. This article aims to investigate effective interventions for delaying the onset and progression of age-related intervertebral disc degeneration. In an era where the aging population is becoming increasingly prominent, this endeavor holds paramount practical and translational significance.

ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases.

Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.

Mispacking of the F87 sidechain drives aggregation-promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer.

Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The X-ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation-prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless, 19F-NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4-7% (ΔG ~ 1.5-1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (ΔG ~ 1.6 kcal/mol). Our data provide a molecular-level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.

Gut microbiome-metabolites axis: A friend or foe to colorectal cancer progression.

An expanding corpus of research robustly substantiates the complex interrelation between gut microbiota and the onset, progression, and metastasis of colorectal cancer. Investigations in both animal models and human subjects have consistently underscored the role of gut bacteria in a variety of metabolic activities, driven by dietary intake. These activities include amino acid metabolism, carbohydrate fermentation, and the generation and regulation of bile acids. These metabolic derivatives, in turn, have been identified as significant contributors to the progression of colorectal cancer. This thorough review meticulously explores the dynamic interaction between gut bacteria and metabolites derived from the breakdown of amino acids, fatty acid metabolism, and bile acid synthesis. Notably, bile acids have been recognized for their potential carcinogenic properties, which may expedite tumor development. Extensive research has revealed a reciprocal influence of gut microbiota on the intricate spectrum of colorectal cancer pathologies. Furthermore, strategies to modulate gut microbiota, such as dietary modifications or probiotic supplementation, may offer promising avenues for both the prevention and adjunctive treatment of colorectal cancer. Nevertheless, additional research is imperative to corroborate these findings and enhance our comprehension of the underlying mechanisms in colorectal cancer development.

Numerical simulation of cavitation-vortex interaction mechanism in an advanced rotational hydrodynamic cavitation reactor.

Hydrodynamic cavitation (HC), a promising technology for enhancing processes, has shown distinct effectiveness and versatility in various chemical and environmental applications. The recently developed advanced rotational hydrodynamic cavitation reactors (ARHCRs), employing cavitation generation units (CGUs) to induce cavitation, have demonstrated greater suitability for industrial-scale applications than conventional devices. However, the intricate interplay between vortex and cavitation, along with its spatial-temporal evolution in the complex flow field of ARHCRs, remains inadequately elucidated. This study investigated the interaction mechanism between cavitation and vortex in a representative interaction-type ARHCR for the first time using the "simplified flow field strategy" and the Q-criterion. The findings reveal that the flow instability caused by CGUs leads to intricate helical and vortex flows, subsequently giving rise to both sheet and vortex cavitation. Subsequently, utilizing the Q-criterion, the vortex structures are identified to be concentrated inside and at CGU edges with evolution process of mergence and separation. These vortex structures directly influence the shape and dimensions of cavities, establishing a complex interaction with cavitation. Lastly, the vorticity transport equation analysis uncovered that the stretching and dilatation terms dominate the vorticity transport process. Simultaneously, the baroclinic term focuses on the vapor-liquid interface, characterized by significant alterations in density and pressure gradients. These findings contribute to a better comprehension of the cavitation-vortex interaction in ARHCRs.

Improving fourth harmonic generation performance by elevating the operation temperature of ADP crystal.

In current inertial confinement fusion (ICF) facilities, potassium dihydrogen phosphate (KH2PO4, KDP) type crystals are the only nonlinear optical (NLO) materials that can satisfy the aperture requirement of the ICF laser driver. Ammonium dihydrogen phosphate (NH4H2PO4, ADP) crystal is a typical isomer of KDP crystal, with a large nonlinear optical coefficient, high ultraviolet transmittance, and large growth sizes, which is an important deep ultraviolet (UV) NLO material. In this paper, we investigated the effect of ADP temperature on its fourth-harmonic-generation (FHG) performance. When the temperature of the ADP crystal was elevated to 48.9 °C, the 90° phase-matched FHG of the 1064 nm laser was realized. Compared with the 79° phase-matched FHG at room temperature (23.0 °C), the output energy at 266 nm, conversion efficiency, angular acceptance, and laser-induced damage threshold (LIDT) increased 113%, 71%, 623%, 19.6%, respectively. It shows that elevating ADP temperature is an efficient method to improve its deep UV frequency conversion properties, which may also be available to other NLO crystals. This discovery provides a very valuable technology for the future development of UV, deep UV lasers in ICF facilities.

Phase Separation and Aggregation of α-Synuclein Diverge at Different Salt Conditions.

The coacervation and structural rearrangement of the protein alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks of Parkinson's disease. While aggregation is recognized as the key element of amyloid diseases, liquid-liquid phase separation (LLPS) and its interplay with aggregation have gained increasing interest. Previous work showed that factors promoting or inhibiting amyloid formation have similar effects on phase separation. Here, we provide a detailed scanning of a wide range of parameters including protein, salt and crowding concentrations at multiple pH values, revealing different salt dependencies of aggregation and phase separation. The influence of salt on aggregation under crowded conditions follows a non-monotonic pattern, showing increased effects at medium salt concentrations. This behavior can be elucidated through a combination of electrostatic screening and salting-out effects on the intramolecular interactions between the N-terminal and C-terminal regions of αSyn. By contrast, we find a monotonic salt dependence of phase separation due to the intermolecular interaction. Furthermore, we observe the time evolution of the two distinct assembly states, with macroscopic fibrillar-like bundles initially forming at medium salt concentration but subsequently converting into droplets after prolonged incubation. The droplet state is therefore capable of inhibiting aggregation or even dissolving the aggregates through a variety of heterotypic interactions, thus preventing αSyn from its dynamically arrested state.

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via ß1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9.

BACKGROUND: Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered protein expressed in human tissues, especially in malignant tissues; however, its role in CSC expansion has not been studied. This study aimed to determine the role of TMEM120B in transcriptional coactivator with PDZ-binding motif (TAZ)-mediated CSC expansion and chemotherapy resistance. METHODS: Both bioinformatics analysis and immunohistochemistry assays were performed to examine expression patterns of TMEM120B in lung, breast, gastric, colon, and ovarian cancers. Clinicopathological factors and overall survival were also evaluated. Next, colony formation assay, MTT assay, EdU assay, transwell assay, wound healing assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, RNA-sequencing assay, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of TMEM120B interaction on proliferation, invasion, stemness, chemotherapy sensitivity, and integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography-tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between TMEM120B, myosin heavy chain 9 (MYH9), and CUL9. RESULTS: TMEM120B expression was elevated in lung, breast, gastric, colon, and ovarian cancers. TMEM120B expression positively correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Overexpression of TMEM120B promoted breast cancer cell proliferation, invasion, and stemness by activating TAZ-mTOR signaling. TMEM120B directly bound to the coil-coil domain of MYH9, which accelerated the assembly of focal adhesions (FAs) and facilitated the translocation of TAZ. Furthermore, TMEM120B stabilized MYH9 by preventing its degradation by CUL9 in a ubiquitin-dependent manner. Overexpression of TMEM120B enhanced resistance to docetaxel and doxorubicin. Conversely, overexpression of TMEM120B-∆CCD delayed the formation of FAs, suppressed TAZ-mTOR signaling, and abrogated chemotherapy resistance. TMEM120B expression was elevated in breast cancer patients with poor treatment outcomes (Miller/Payne grades 1-2) than in those with better outcomes (Miller/Payne grades 3-5). CONCLUSIONS: Our study reveals that TMEM120B bound to and stabilized MYH9 by preventing its degradation. This interaction activated the ß1-integrin/FAK-TAZ-mTOR signaling axis, maintaining stemness and accelerating chemotherapy resistance.

Sulfarotene Inhibits Colorectal Cancer via Mitigating Natural-Killer-Cell-Induced Stemness.

Tumor cell stemness stands out as a pivotal factor driving tumor recurrence or metastasis and significantly contributes to the mortality of patients with colorectal cancer (CRC). Recent research has unveiled a link between immune-active cells and the induction of tumor cell stemness, ultimately leading to heightened resistance to treatment. In this study, stemness in CRC cell lines was assessed after co-culture with natural killer (NK) cells, both with and without sulfarotene administration. Furthermore, a CRC xenograft model was utilized to scrutinize the in vivo efficacy of sulfarotene in overcoming stemness induced by NK cell activation. As a result, CRC cells exhibited significant stemness after NK cell co-culture, as evidenced by the upregulation of several stemness markers associated with cancer stem cells. Moreover, these cells demonstrated remarkable resistance to commonly used chemotherapy agents for CRC, such as oxaliplatin and irinotecan. Importantly, sulfarotene effectively reversed the altered stemness of CRC cells in both in vitro and in vivo assays. In conclusion, sulfarotene emerges as a promising therapeutic strategy for overcoming colorectal cancer resistance to NK cells by effectively inhibiting stemness remodeling. This study underscores the potential of sulfarotene in augmenting NK-cell-mediated immune surveillance, proposing a novel immunotherapeutic approach against colorectal cancer.

HSK3486 Inhibits Colorectal Cancer Growth by Promoting Oxidative Stress and ATPase Inhibitory Factor 1 Activation.

BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.