SIAH2 suppresses c-JUN pathway by promoting the polyubiquitination and degradation of HBx in hepatocellular carcinoma.

As an important protein encoded by hepatitis B virus (HBV), HBV X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). It has been shown that seven in absentia homologue 1 (SIAH1) could regulates the degradation of HBx through the ubiquitin-proteasome pathway. However, as a member of SIAH family, the regulatory effects of SIAH2 on HBx remain unclear. In this study, we first confirmed that SIAH2 could reduce the protein levels of HBx depending on its E3 ligase activity. Moreover, SIAH2 interacted with HBx and induced its K48-linked polyubiquitination and proteasomal degradation. Furthermore, we provided evidence that SIAH2 inhibits HBx-associated HCC cells proliferation by regulating HBx. In conclusion, our study identified a novel role for SIAH2 in promoting HBx degradation and SIAH2 exerts an inhibitory effect in the proliferation of HBx-associated HCC through inducing the degradation of HBx. Our study provides a new idea for the targeted degradation of HBx and may have great huge significance into providing novel evidence for the targeted therapy of HBV-infected HCC.

Unveiling the gastric microbiota: implications for gastric carcinogenesis, immune responses, and clinical prospects.

High-throughput sequencing has ushered in a paradigm shift in gastric microbiota, breaking the stereotype that the stomach is hostile to microorganisms beyond H. pylori. Recent attention directed toward the composition and functionality of this 'community' has shed light on its potential relevance in cancer. The microbial composition in the stomach of health displays host specificity which changes throughout a person's lifespan and is subject to both external and internal factors. Distinctive alterations in gastric microbiome signature are discernible at different stages of gastric precancerous lesions and malignancy. The robust microbes that dominate in gastric malignant tissue are intricately implicated in gastric cancer susceptibility, carcinogenesis, and the modulation of immunosurveillance and immune escape. These revelations offer fresh avenues for utilizing gastric microbiota as predictive biomarkers in clinical settings. Furthermore, inter-individual microbiota variations partially account for differential responses to cancer immunotherapy. In this review, we summarize current literature on the influence of the gastric microbiota on gastric carcinogenesis, anti-tumor immunity and immunotherapy, providing insights into potential clinical applications.

Efficacy of acupuncture therapy on cancer-related insomnia: a systematic review and network meta-analysis.

Objectives: Cancer-related insomnia (CRI) takes a toll on many cancer survivors, causing distressing symptoms and deteriorating the quality of life. Acupuncture therapy has been used for CRI already. However, it is still uncertain which acupuncture regime is best for CRI. The primary objective of this review is to conduct a comparative evaluation and ranking of the effectiveness of different acupuncture therapies for CRI. Methods: Randomized controlled trials (RCTs) that were published up to July 31, 2023, from 8 databases (PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and China Biology Medicine disc) were integrated in this study. Trials that met the inclusion criteria were evaluated the risk of bias. Pittsburgh sleep quality index (PSQI) was used to assess the efficacy of different acupuncture therapies as the primary outcome. Then, STATA 15, R, and OpenBUGS were applied to perform the network meta-analysis. PRISMA statements were followed in this network meta-analysis. Results: A total of 37 studies were included in this review, involving 16 interventions with 3,246 CRI participants. Auriculotherapy + moxibustion [surface under the cumulative ranking curve (SUCRA) 98.98%] and auriculotherapy (SUCRA 77.47%) came out top of the ranking, which were more effective than control, medicine, usual care and sham acupuncture. Conclusion: Auriculotherapy + moxibustion and auriculotherapy + acupuncture emerged as the top two acupuncture regimes for CRI and future studies should pay more attention to CRI. Clinical trial registration: https://clinicaltrials.gov/, identifier INPLASY202210095.

Canagliflozin protects against hyperglycemia-induced cerebrovascular injury by preventing blood-brain barrier (BBB) disruption via AMPK/Sp1/adenosine A2A receptor.

Diabetes mellitus causes brain microvascular endothelial cell (MEC) damage, inducing dysfunctional angiogenic response and disruption of the blood-brain barrier (BBB). Canagliflozin is a revolutionary hypoglycemic drug that exerts neurologic and/or vascular-protective effects beyond glycemic control; however, its underlying mechanism remains unclear. In the present study, we hypothesize that canagliflozin ameliorates BBB permeability by preventing diabetes-induced brain MEC damage. Mice with high-fat diet/streptozotocin-induced diabetes received canagliflozin for 8 weeks. We assessed vascular integrity by measuring cerebrovascular neovascularization indices. The expression of specificity protein 1 (Sp1), as well as tight junction proteins (TJs), phosphorylated AMP-activated protein kinase (p-AMPK), and adenosine A2A receptors was examined. Mouse brain MECs were grown in high glucose (30 mM) to mimic diabetic conditions. They were treated with/without canagliflozin and assessed for migration and angiogenic ability. We also performed validation studies using AMPK activator (AICAR), inhibitor (Compound C), Sp1 small interfering RNA (siRNA), and adenosine A2A receptor siRNA. We observed that cerebral pathological neovascularization indices were significantly normalized in mice treated with canagliflozin. Increased Sp1 and adenosine A2A receptor expression and decreased p-AMPK and TJ expression were observed under diabetic conditions. Canagliflozin or AICAR treatment alleviated these changes. However, this alleviation effect of canagliflozin was diminished again after Compound C treatment. Either Sp1 siRNA or adenosine A2A receptor siRNA could increase the expression of TJs. Luciferase reporter assay confirmed that Sp1 could bind to the adenosine A2A receptor gene promoter. Our study identifies the AMPK/Sp1/adenosine A2A receptor pathway as a treatment target for diabetes-induced cerebrovascular injury.

Concentration, speciation and risk effects of multiple environmentally sensitive trace elements in respirable fine-grained fly ash.

Respirable fine-grained fly ash (RFA) is captured very inefficiently by existing air purification devices of power plant, leading to increasing concerns regarding their migration and subsequent interaction with body due to fine particle size and its complex toxic composition. Trace elements of RFA in three groups with five different sizes between 8-13 µm were analyzed in terms of available concentration, speciation and risk effects. The concentration, pollution level and ecological risk level of elements in RFA were related to particle sizes. Chronic non-carcinogenic effect risk (NER) and carcinogenic effect risk (CER) were negatively correlated with particle size. The individual weight of exposed subjects, corresponding trace elements concentration and ingestion rate in RFA were three significant variables influencing CER. NER and CER had a tenfold exaggerated effect when calculated using total element concentration of RFA. In addition to individual differences and exposure conditions, trace element properties, speciation and available concentration were the dominant factor responsible for ecological and environmental effects of trace elements in RFA, following the order As>Ni, Mn>Cr>Pb>Cu>Zn. Results of this work highlight the effects and differences of trace elements in RFA on ecology and health, and provide a basis for further pollution control and human health warning.

Ubiquitin ligase NEDD4 promotes the proliferation of hepatocellular carcinoma cells through targeting PCDH17 protein for ubiquitination and degradation.

Neural precursor cell expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, is commonly upregulated in human hepatocellular carcinoma (HCC) and functions as an oncogenic factor in the progression of HCC, but the molecular mechanism needs be further explored. In this study, we found that NEDD4 could facilitate the proliferation of HCC cells, which was associated with regulating the ERK signaling. Further investigation showed that protocadherin 17 (PCDH17) was a potential substrate of NEDD4, and restoration of PCDH17 could block the facilitation of ERK signaling and HCC cells proliferation induced by NEDD4 overexpression. Whereafter, we confirmed that NEDD4 interacted with PCDH17 and promoted the Lys33-linked polyubiquitination and degradation of it via the proteasome pathway. Finally, NEDD4 protein level was found to be inversely correlated with that of PCDH17 in human HCC tissues. In conclusion, these results suggest that NEDD4 acts as an E3 ubiquitin ligase for PCDH17 ubiquitination and degradation thereby promoting the proliferation of HCC cells through regulating the ERK signaling, which may provide novel evidence for NEDD4 to be a promising therapeutic target for HCC.

Trichostatin A enhances the titanium rods osseointegration in osteoporotic rats by the inhibition of oxidative stress through activating the AKT/Nrf2 pathway.

The use of titanium implants as fixed supports following fractures in patients with OP can often result in sterile loosening and poor osseointegration. Oxidative stress has been shown to play a particularly important role in this process. While TSA has been reported to facilitate in vivo osteogenesis, the underlying mechanisms remain to be clarified. It also remains unclear whether TSA can improve the osseointegration of titanium implants. This study investigated whether TSA could enhance the osseointegration of titanium rods by activating AKT/Nrf2 pathway signaling, thereby suppressing oxidative stress. MC3T3-E1 cells treated with CCCP to induce oxidative stress served as an in vitro model, while an OVX-induced OP rat model was employed for in vivo analysis of titanium rod implantation. In vitro, TSA treatment of CCCP-treated MC3T3-E1 cells resulted in the upregulation of osteogenic proteins together with increased AKT, total Nrf2, nuclear Nrf2, HO-1, and NQO1 expression, enhanced mitochondrial functionality, and decreased oxidative damage. Notably, the PI3K/AKT inhibitor LY294002 reversed these effects. In vivo, TSA effectively enhanced the microstructural characteristics of distal femur trabecular bone, increased BMSCs mineralization capacity, promoted bone formation, and improved the binding of titanium implants to the surrounding tissue. Finally, our results showed that TSA could reverse oxidative stress-induced cell damage while promoting bone healing and improving titanium rods' osseointegration through AKT/Nrf2 pathway activation.

Constitutive photomorphogenic protein 1 ubiquitinates interleukin-1 receptor accessory protein in human liver cancer.

BACKGROUND: Constitutive photomorphogenic protein 1 (COP1) plays a pivotal role in the development and progression of several human cancers and is reported to be upregulated in liver cancer. However, the role of COP1 in human liver cancer is unclear. METHODS: We analyzed the COP1 expression in normal liver and liver cancer tissue samples using western blot and immunohistochemical analysis. We overexpressed and silenced COP1 in HepG2 and Huh7 cells and analyzed the effect on liver cancer cell proliferation. Additionally, COP1 was used as a bait to screen COP1-interacting proteins in a human cDNA library in a yeast two-hybrid screen and the results were confirmed with co-immunoprecipitation (co-IP) assays. Moreover, immunofluorescence staining was performed to assess co-localization. The protein levels of COP1 and mIL1RAcP were determined in clinical samples. RESULTS: COP1 was upregulated in liver cancer samples compared to that in normal tissue samples. COP1 overexpression promoted proliferation of liver cancer cells, while COP1 knockdown exerted the opposite effect. Yeast two-hybrid screen identified interleukin-1 receptor accessory protein (IL1RAP) as a potential COP1-interacting protein. Co-IP assays further confirmed that COP1 interacts with both preIL1RAP and membrane-bound form of IL1RAP (mIL1RAP). Furthermore, COP1 upregulated mIL1RAP protein levels and promoted nuclear translocation and activation of the nuclear factor kappa B (NF-κB) (p50/p65) dimer. Additionally, we demonstrated that COP1 regulated mIL1RAP expression through K63-linked polyubiquitination, suggesting that COP1 plays a role in stabilizing mIL1RAP. Finally, the protein levels of COP1 and mIL1RAcP were found to be positively correlated in clinical samples. CONCLUSION: COP1 regulates IL1RAP, which in turn results in activation of the NF-κB signaling. Our findings suggest that the COP1/IL1RAP/NF-κB axis promotes proliferation of liver cancer cells and is a potential target for the treatment of liver cancer.

Hot and cold tumors: Immunological features and the therapeutic strategies.

The "hotness" or "coldness" of the tumors are determined by the information of the cancer cells themselves, tumor immune characteristics, tumor microenvironment, and signaling mechanisms, which are key factors affecting cancer patients' clinical efficacy. The switch mechanism of "hotness" and "coldness" and its corresponding pathological characteristics and treatment strategies are the frontier and hot spot of tumor treatment. How to distinguish the "hotness" or "coldness" effectively and clarify the causes, microenvironment state, and characteristics are very important for the tumor response and efficacy treatments. Starting from the concept of hot and cold tumor, this review systematically summarized the molecular characteristics, influencing factors, and therapeutic strategies of "hot and cold tumors," and analyzed the immunophenotypes, the tumor microenvironment, the signaling pathways, and the molecular markers that contribute to "hot and cold tumors" in details. Different therapeutic strategies for "cold and hot tumors" based on clinical efficacy were analyzed with drug targets and proteins for "cold and hot tumors." Furthermore, this review combines the therapeutic strategies of different "hot and cold tumors" with traditional medicine and modern medicine, to provide a basis and guidance for clinical decision-making of cancer treatment.

Sodium butyrate enhances titanium nail osseointegration in ovariectomized rats by inhibiting the PKCα/NOX4/ROS/NF-κB pathways.

BACKGROUND: Elevated levels of oxidative stress as a consequence of estrogen deficiency serve as a key driver of the onset of osteoporosis (OP). In addition to increasing the risk of bone fractures, OP can reduce the bone volume proximal to titanium nails implanted to treat these osteoporotic fractures, thereby contributing to titanium nail loosening. Sodium butyrate (NaB) is a short-chain fatty acid produced by members of the gut microbiota that exhibits robust antioxidant and anti-inflammatory properties. METHODS: OP fracture model rats parameters including bone mineral density (BMD), new bone formation, and the number of bonelets around the implanted nail were analyzed via micro-CT scans, H&E staining, and Masson's staining. The protective effects of NaB on such osseointegration and the underlying mechanisms were further studied in vitro using MC3T3-E1 cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce oxidative stress. Techniques including Western immunoblotting, electron microscopy, flow cytometry, alkaline phosphatase (ALP) staining, and osteoblast mineralization assays were employed to probe behaviors such as reactive oxygen species production, mineralization activity, ALP activity, protein expression, and the ability of cells to attach to and survive on titanium plates. RESULTS: NaB treatment was found to enhance ALP activity, mineralization capacity, and Coll-I, BMP2, and OCN expression levels in CCCP-treated MC3T3-E1 cells, while also suppressing PKC and NF-κB expression and enhancing Nrf2 and HO-1 expression in these cells. NaB further suppressed intracellular ROS production and malondialdehyde levels within the cytosol while enhancing superoxide dismutase activity and lowering the apoptotic death rate. In line with these results, in vivo work revealed an increase in BMD in NaB-treated rats that was associated with enhanced bone formation surrounding titanium nails. CONCLUSION: These findings indicate that NaB may represent a valuable compound that can be postoperatively administered to aid in treating OP fractures through the enhancement of titanium nail osseointegration.

Intracerebral Hemorrhage-Induced Brain Injury: the Role of Lysosomal-Associated Transmembrane Protein 5.

Intracerebral hemorrhage (ICH) is a lethal stroke with high mortality or disability. However, effective therapy for ICH damage is generally lacking. Previous investigations have suggested that lysosomal protein transmembrane 5 (LAPTM5) is involved in various pathological processes, including autophagy, apoptosis, and inflammation. In this study, we aimed to identify the expression and functions of LAPTM5 in collagenase-induced ICH mouse models and hemoglobin-induced cell models. We found that LAPTM5 was highly expressed in brain tissues around the hematoma, and double immunostaining studies showed that LAPTM5 was co-expressed with microglia cells, neurons, and astrocytes. Following ICH, the mice presented increased brain edema, blood-brain barrier permeability, and neurological deficits, while pathological symptoms were alleviated after the LAPTM5 knockdown. Adeno-associated virus 9-mediated downregulation of LAPTM5 also improves ICH-induced secondary cerebral damage, including neuronal degeneration, the polarization of M1-like microglia, and inflammatory cascades. Furthermore, LAPTM5 promoted activation of the nuclear factor kappa-B (NF-κB) pathway in response to neuroinflammation. Further investigations indicated that brain injury improved by LAPTM5 knockdown was further exacerbated after the overexpression of receptor-interacting protein kinase 1 (RIP1), which is revealed to trigger the NF-κB pathway. In vitro experiments demonstrated that LAPTM5 silencing inhibited hemoglobin-induced cell function and confirmed regulation between RIP1 and LAPTM5. In conclusion, the present study indicates that LAPTM5 may act as a positive regulator in the context of ICH by modulating the RIP1/NF-κB pathway. Thus, it may be a candidate gene for further study of molecular or therapeutic targets.

Cathepsin K promotes the proliferation of hepatocellular carcinoma cells through induction of SIAH1 ubiquitination and degradation.

Seven in absentia homolog 1 (SIAH1) was reported to be downregulated in hepatocellular carcinoma (HCC) and played an important role in HCC progression; however, the underlying reason remains unknown. Here, we found that Cathepsin K (CTSK), a protein potentially interacting with SIAH1, inhibits SIAH1 protein level. CTSK was highly expressed in HCC tissues. CTSK inhibition or downregulation suppressed HCC cell proliferation, whereas CTSK overexpression had the opposite effect; it promotes HCC cell proliferation by regulating the SIAH1/protein kinase B (AKT) pathway, wherein promotes SIAH1 ubiquitination. Neural precursor cells expressing developmentally downregulated 4 (NEDD4) was found to be a potential upstream ubiquitin ligase of SIAH1. Further, CTSK could mediate SIAH1 ubiquitination and degradation by increasing SIAH1 autoubiquitination and recruiting NEDD4 to ubiquitinate SIAH1. Finally, the roles of CTSK were confirmed in a xenograft mouse model. In conclusion, oncogenic CTSK was upregulated in human HCC tissues and accelerated HCC cell proliferation by downregulating SIAH1.

Mapping port wine stain in vivo by optical coherence tomography angiography and multi-metric characterization.

Port wine stain (PWS) is a congenital cutaneous capillary malformation composed of ecstatic vessels, while the microstructure of these vessels remains largely unknown. Optical coherence tomography angiography (OCTA) serves as a non-invasive, label-free and high-resolution tool to visualize the 3D tissue microvasculature. However, even as the 3D vessel images of PWS become readily accessible, quantitative analysis algorithms for their organization have mainly remained limited to analysis of 2D images. Especially, 3D orientations of vasculature in PWS have not yet been resolved at a voxel-wise basis. In this study, we employed the inverse signal-to-noise ratio (iSNR)-decorrelation (D) OCTA (ID-OCTA) to acquire 3D blood vessel images in vivo from PWS patients, and used the mean-subtraction method for de-shadowing to correct the tail artifacts. We developed algorithms which mapped blood vessels in spatial-angular hyperspace in a 3D context, and obtained orientation-derived metrics including directional variance and waviness for the characterization of vessel alignment and crimping level, respectively. Combining with thickness and local density measures, our method served as a multi-parametric analysis platform which covered a variety of morphological and organizational characteristics at a voxel-wise basis. We found that blood vessels were thicker, denser and less aligned in lesion skin in contrast to normal skin (symmetrical parts of skin lesions on the cheek), and complementary insights from these metrics led to a classification accuracy of ∼90% in identifying PWS. An improvement in sensitivity of 3D analysis was validated over 2D analysis. Our imaging and analysis system provides a clear picture of the microstructure of blood vessels within PWS tissues, which leads to a better understanding of this capillary malformation disease and facilitates improvements in diagnosis and treatment of PWS.

SIAH1/CTR9 axis promotes the epithelial-mesenchymal transition of hepatocellular carcinoma.

SIAH1 has been reported to participate in several human cancers, including hepatocellular carcinoma (HCC). However, the effect of SIAH1 on the epithelial-mesenchymal transition (EMT) has not been reported in HCC cells. Here, we discovered the inhibitory effect of SIAH1 on HCC cell migration and invasion, which was related with regulating EMT. Molecularly, a yeast two-hybrid experiment indicated that Cln Three Requiring 9 (CTR9) was a potential interacting protein of SIAH1, which was further verified by co-immunoprecipitation assays. Furthermore, SIAH1 inhibited the EMT of HCC cells through negatively regulating CTR9. Importantly, CTR9 was ubiquitinated and degraded by SIAH1 via the proteasome pathway in HCC cells. Additionally, it was showed that SIAH1 mainly mediated the K48-linked polyubiquitination on CTR9. Finally, the protein level of CTR9 was found to be inversely correlated with SIAH1 in human HCC tissues. Summed up all together, these findings reveal that SIAH1/CTR9 axis promotes the EMT of HCC cells and is a promising therapeutic target for HCC therapy.

Label-free, multi-parametric assessments of cell metabolism and matrix remodeling within human and early-stage murine osteoarthritic articular cartilage.

Osteoarthritis (OA) is characterized by the progressive deterioration of articular cartilage, involving complicated cell-matrix interactions. Systematic investigations of dynamic cellular and matrix changes during OA progression are lacking. In this study, we use label-free two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) imaging to assess cellular and extracellular matrix features of murine articular cartilage during several time points at early stages of OA development following destabilization of medial meniscus surgery. We detect significant changes in the organization of collagen fibers and crosslink-associated fluorescence of the superficial zone as early as one week following surgery. Such changes become significant within the deeper transitional and radial zones at later time-points, highlighting the importance of high spatial resolution. Cellular metabolic changes exhibit a highly dynamic behavior, and indicate metabolic reprogramming from enhanced oxidative phosphorylation to enhanced glycolysis or fatty acid oxidation over the ten-week observation period. The optical metabolic and matrix changes detected within this mouse model are consistent with differences identified in excised human cartilage specimens from OA and healthy cartilage specimens. Thus, our studies reveal important cell-matrix interactions at the onset of OA that may enable improved understanding of OA development and identification of new potential treatment targets.

Exosomes from Adipose-Derived Stem Cells Alleviate Dexamethasone-Induced Bone Loss by Regulating the Nrf2/HO-1 Axis.

The widespread use of therapeutic glucocorticoids has increased the incidences of glucocorticoid-induced osteoporosis (GIOP). Oxidative stress and mitochondrial dysfunction are major causes of GIOP; therefore, alleviation of excess oxidative stress in osteoblasts is a potential therapeutic strategy for osteoporosis. Exosomes derived from ADSCs (ADSCs-Exos), as novel cell-free therapeutics, can modulate various biological processes, such as immunomodulation, reduce oxidative damage, and promote tissue repair as well as regeneration. In this study, ADSCs-Exos restored the viability and osteogenic potential of MC3T3-E1 cells by attenuating apoptosis, oxidative damage, intracellular ROS generation, and mitochondrial dysfunction. Moreover, after pretreatment with ADSCs-Exos, Nrf2 expressions were upregulated in Dex-stimulated osteoblasts. Inhibitory assays showed that silencing Nrf2 partially eliminated the protective effects of ADSCs-Exos. The rat model assays confirmed that ADSCs-Exos alleviated the Dex-induced increase in oxidation levels, restored bone mass of the distal femur, and increased the expressions of Nrf2 and osteogenic markers in bone tissues. Thus, ADSCs-Exos alleviated apoptosis and oxidative stress by regulating Nrf2/HO-1 expressions after Dex and prevented the development of GIOP in vivo.

Melatonin Repairs Osteoporotic Bone Defects in Iron-Overloaded Rats through PI3K/AKT/GSK-3ß/P70S6k Signaling Pathway.

It was found recently that iron overload can cause osteoporosis in rats. Through in vitro and in vivo experimentations, the purpose of the present study was to validate and confirm the inhibitory effects of melatonin on iron death of osteoporosis and its role in bone microstructure improvements. Melatonin (100 mol/L) was administered to MC3T3-E1 cells induced by iron overload in vitro for 48 hours. The expression of cleaved caspase-3 and cleaved PARP and the production of ROS (reactive oxygen species) and mitochondrial damage were all exacerbated by iron overload. On the other hand, melatonin restored these impacts in MC3T3-E1 cells produced by iron overload. By evaluating the expression of PI3K/AKT/GSK-3ß/P70S6k signaling pathway-related proteins (RUNX2, BMP2, ALP, and OCN) using RT-PCR and Western blot, osteogenic-related proteins were identified. Alizarin red S and alkaline phosphatase were utilized to evaluate the osteogenic potential of MC3T3-E1 cells. Melatonin significantly improved the osteogenic ability and phosphorylation rates of PI3K, AKT, GSK-3ß, and P70S6k in iron overload-induced MC3T3-E1 cells. In vivo, melatonin treated iron overload-induced osteoporotic bone defect in rats. Rat skeletal microstructure was observed using micro-CT and bone tissue pathological section staining. ELISA was utilized to identify OCN, PINP, CTX-I, and SI in the serum of rats. We discovered that melatonin increased bone trabecular regeneration and repair in osteoporotic bone defects caused by iron overload. In conclusion, melatonin enhanced the osteogenic ability of iron overload-induced MC3T3-E1 cells by activating the PI3K/AKT/GSK-3ß/P70S6k signaling pathway and promoting the healing of iron overload-induced osteoporotic bone defects in rats.

Identification of human ovarian cancer relying on collagen fiber coverage features by quantitative second harmonic generation imaging.

Ovarian cancer has the highest mortality rate among all gynecological cancers, containing complicated heterogeneous histotypes, each with different treatment plans and prognoses. The lack of screening test makes new perspectives for the biomarker of ovarian cancer of great significance. As the main component of extracellular matrix, collagen fibers undergo dynamic remodeling caused by neoplastic activity. Second harmonic generation (SHG) enables label-free, non-destructive imaging of collagen fibers with submicron resolution and deep sectioning. In this study, we developed a new metric named local coverage to quantify morphologically localized distribution of collagen fibers and combined it with overall density to characterize 3D SHG images of collagen fibers from normal, benign and malignant human ovarian biopsies. An overall diagnosis accuracy of 96.3% in distinguishing these tissue types made local and overall density signatures a sensitive biomarker of tumor progression. Quantitative, multi-parametric SHG imaging might serve as a potential screening test tool for ovarian cancer.

High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant mortality and frequent recurrence. Prior efforts to transcriptionally classify HNSCC into groups of varying prognoses have identified four accepted molecular subtypes of the disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigate the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identify samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to the AT subtype are more resistant to enhancer-blocking bromodomain inhibitors (BETi). Examination of nascent transcripts reveals that both AT TCGA tumors and cell lines express higher levels of enhancer RNA (eRNA) transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, investigation of higher-order chromatin structure suggests more enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways are upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with higher enhancer activity, resistance to enhancer blockade, and increased signaling through pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.