Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis.

Lipid metabolic reprogramming of tumor cells has been proven to play a critical role in tumor initiation and development. However, lipid metabolism in cancer-associated fibroblasts (CAFs) has rarely been studied, particularly in CAFs of oral squamous cell carcinoma (OSCC). Additionally, the molecular mechanism by which tumor cells regulate lipid metabolism in fibroblasts is unclear. In this study, we found that phosphorylated ATP citrate lyase (p-ACLY), a key lipid metabolic enzyme, was upregulated in OSCC CAFs. Compared to paracancerous normal fibroblasts, CAFs showed enhanced lipid synthesis, such as elevated cytosolic acetyl-CoA level and accumulation of lipid droplets. Conversely, reduction of p-ACLY level blocked this biological process. In addition, blocking lipid synthesis in CAFs or inhibiting fatty acid uptake by OSCC cells reduced the promotive effects of CAFs on OSCC cell proliferation, invasion, and migration. These findings suggested that CAFs are one of lipid sources required for OSCC progression. Mechanistically, AKT signaling activation was involved in the upregulation of p-ACLY level and lipid synthesis in CAFs. Interleukin-8 (IL8), an exocrine cytokine of OSCC cells, could activate AKT and then phosphorylate ACLY in fibroblasts. This study suggested that the IL8/AKT/p-ACLY axis could be considered as a potential target for OSCC treatment.

FNIII14 Peptide-Enriched Membrane Nanocarrier to Disrupt Stromal Barriers through Reversing CAFs for Augmenting Drug Penetration in Tumors.

Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane nanodelivery system (designated as PMNPs-D) to simultaneously target CAFs and tumor cells for boosted chemotherapy through promoted drug perfusion. In the structure of PMNPs-D, the PLGA-based inner core is loaded with the chemotherapeutic drug doxorubicin, and the outer surface is cloaked by hybrid biomembranes with the insertion of integrin ß1 (ITGB1) inhibiting peptide (i.e., FNIII14). After prolonged blood circulation and actively targeting in tumor sites, PMNPs-D can respond to CAF-overexpressed fibroblast activation protein-α (FAP-α) to trigger the release of FNIII14, which will bind to ITGB1 and inhibit CAFs' biological function in producing the stromal matrix, thereby loosening the condensed stromal structure and enhancing the permeability of nanotherapeutics in tumors. As a result, this tailor-designed nanosystem shows substantial tumor inhibition and metastasis retardation in aggressive adenoid cystic carcinoma (ACC) tumor-harboring mice.

Ab Initio Prediction of Excited-State and Polaron Effects in Transient XUV Measurements of α-Fe2O3.

Transient X-ray and extreme ultraviolet (XUV) spectroscopies have become invaluable tools for studying photoexcited dynamics due to their sensitivity to carrier occupations and local chemical or structural changes. One of the most studied materials using transient XUV spectroscopy is α-Fe2O3 because of its rich photoexcited dynamics, including small polaron formation. The interpretation of carrier and polaron effects in α-Fe2O3 is currently carried out using a semi-empirical method that is not transferrable to most materials. Here, an ab initio, Bethe-Salpeter equation (BSE) approach is developed that can incorporate photoexcited-state effects into arbitrary material systems. The accuracy of this approach is proven by calculating the XUV absorption spectra for the ground, photoexcited, and polaron states of α-Fe2O3. Furthermore, the theoretical approach allows for the projection of the core-valence excitons and different components of the X-ray transition Hamiltonian onto the band structure, providing new insights into old measurements. From this information, a physical intuition about the origins and nature of the transient XUV spectra can be built. A route to extracting electron and hole energies is even shown possible for highly angular momentum split XUV peaks. This method is easily generalized to K, L, M, and N edges to provide a general approach for analyzing transient X-ray absorption or reflection data.

Anisotropic CdSe Tetrapods in Vortex Flow for Removing Non-Specific Binding and Increasing Protein Capture.

Non-specific binding (NSB) is one of the important issues in biosensing performance. Herein, we designed a strategy for removing non-specific binding including anti-mouse IgG antibody and bovine serum albumin (BSA) by utilizing anisotropic cadmium selenide tetrapods (CdSe TPs) in a vortex flow. The shear force on the tetrapod nanoparticles was increased by controlling the rotation rate of the vortex flow from 0 rpm to 1000 rpm. As a result, photoluminescence (PL) signals of fluorescein (FITC)-conjugated protein, anti-mouse IgG antibody-FITC and bovine serum albumin (BSA)-FITC, were reduced by 35% and 45%, respectively, indicating that NSB can be removed under vortex flow. In particular, simultaneous NSB removal and protein capture can be achieved even with mixture solutions of target antibodies and anti-mouse IgG antibodies by applying cyclic mode vortex flow on anisotropic CdSe TPs. These results demonstrate successfully that NSB can be diminished by rotating CdSe TPs to generate shear force under vortex flow. This study opens up new research protocols for utilization of anisotropic nanoparticles under vortex flow, which increases the feasibility of protein capture and non-specific proteins removal for biosensors.

Characterization of high-harmonic emission from ZnO up to 11 eV pumped with a Cr:ZnS high-repetition-rate source.

We report the measurement of high-order harmonics from a ZnO crystal with photon energies up to 11 eV generated by a high-repetition-rate femtosecond Cr:ZnS laser operating in the mid-infrared at 2-3 µm, delivering few-cycle pulses with multi-watt average power and multi-megawatt peak power. High-focus intensity is achieved in a single pass through the crystal without a buildup cavity or nanostructued pattern for field enhancement. We measure in excess of 108 high-harmonic photons/second.

Direct Measurement of Anharmonic Decay Channels of a Coherent Phonon.

We report channel-resolved measurements of the anharmonic coupling of the coherent A_{1g} phonon in photoexcited bismuth to pairs of high wave vector acoustic phonons. The decay of a coherent phonon can be understood as a parametric resonance process whereby the atomic displacement periodically modulates the frequency of a broad continuum of modes. This coupling drives temporal oscillations in the phonon mean-square displacements at the A_{1g} frequency that are observed across the Brillouin zone by femtosecond x-ray diffuse scattering. We extract anharmonic coupling constants between the A_{1g} and several representative decay channels that are within an order of magnitude of density functional perturbation theory calculations.

TL1-A can engage death receptor-3 and activate NF-kappa B in endothelial cells.

BACKGROUND: Death receptors (DRs) play an important role in renal pathology. We have shown that DR3 is inducibly expressed on renal tubular epithelial cells in the setting of inflammatory injuries. In this study we investigate the expression of DR3 in renal endothelial cells and their response to TL1A, the only known ligand of DR3. METHODS: We did RT-PCR, flow cytometry and subcellular immunoblotting to examine the expression and function of DR3 in cells in vitro. We did organ culture of human and mouse tissue to examine expression and signal of DR3 in vivo. RESULTS: DR3 is expressed in some interstitial vascular endothelial cells (EC) in human kidney in situ; these EC also respond to its ligand TL1A by activating NF-κB. Very low levels of DR3 can be detected on the cell surface of cultured human umbilical vein (HUV) EC, which do not respond to TL1A. HUVEC transfected to overexpress DR3 become responsive to TL1A, assessed by IκBα degradation and E-selectin induction, indicating that the signaling components needed for DR3 responsiveness are expressed. TL1A induces NF-κB activation in EC in renal and cardiac tissue from wild type but not DR3 knock-out mice. CONCLUSION: TL1A and DR3 activate NF-κB in vascular endothelial cells, and can be an important regulator of renal interstitial vascular injury.

Nanoparticles as drug delivery systems in the treatment of oral squamous cell carcinoma: current status and recent progression.

Oral squamous cell carcinoma (OSCC) is a common human malignancy with an estimated incidence of around 377,713 new cases worldwide in 2020. Despite the advance in clinical management, some of OSCC patients still miss the opportunity of completable resection of tumor, and have to accept medical therapies, e.g., chemotherapy, radiotherapy, or immunotherapy when the disease develops into the advanced stage. However, these therapies have been reported to be far from ideal due to the low efficiency of conventional delivery approaches. To obtain a better therapeutic effect, considerable attempts have been made toward to develop an effective drug delivery system (DDS). Nanoparticles (NPs) including inorganic NPs, polymer NPs, lipid NP, extracellular vesicles and cell membrane-based NPs have been evaluated as the better DDS candidates that can specifically accumulate in the tumor microenvironment along with a large amount of blood vessels. Emerging evidence suggested that NPs formulated with anticancer drugs including chemotherapeutic drugs, radiotherapy and immunotarget antibodies could remarkably improve the release and increase concentration of these drugs at the tumor site and show a better therapeutic efficacy, suggesting that NPs might serve as promising DDSs in the treatment of OSCC. Therefore, we have conducted this review to summarize recent progression and current status of diverse NPs as DDSs in this research field.

Endothelial cells-directed angiogenesis in colorectal cancer: Interleukin as the mediator and pharmacological target.

Enhanced angiogenesis is a cancer hallmark and critical for colorectal cancer (CRC) invasion and metastasis. Upon exposure to proangiogenic factors, therefore, targeting tumor-associated proangiogenic factors/receptors hold great promise as a therapeutic modality to treat CRC, particularly metastatic CRC. Accumulating evidence from numerous studies suggests that tumor endothelial cells (ECs) are not only the target of proangiogenic factors, but also function as the cellular source of proangiogenic factors. Studies showed that ECs can produce different proangiogenic factors to participate in the regulation of angiogenesis process, in which ECs-derived interleukins (ILs) show a potential stimulatory effect on angiogenesis via either an direct action on their receptors expressed on progenitor of ECs or an indirect way through enhanced production of other proangiogenic factors. Although a great deal of attention is given to the effects of tumor-derived and immune cell-derived ILs, few studies describe the potential effects of vascular ECs-derived ILs on the tumor angiogenesis process. This review provides an updated summary of available information on proangiogenic ILs, such as IL-1, IL-6, IL-8, IL-17, IL-22, IL-33, IL-34, and IL-37, released by microvascular ECs as potential drivers of the tumor angiogenesis process and discusses their potential as a novel candidate for antiangiogenic target for the treatment of CRC patients.

Triple-Peak Photoluminescence of DNA-Hybrid Alq3 Crystals Emitting a Depressed Single Peak upon Bio-Recognition.

The green organic semiconductor, tris-(8-hydroxyquinoline)aluminum (Alq3), was hybridized with DNA growing in the shape of hexagonal prismatic crystals. In this study, we applied hydrodynamic flow to the fabrication of Alq3 crystals doped with DNA molecules. The hydrodynamic flow in the Taylor-Couette reactor induced nanoscale pores in the Alq3 crystals, especially at the side part of the particles. The particles exhibited distinctly different photoluminescence emissions divided into three parts compared to common Alq3-DNA hybrid crystals. We named this particle a "three-photonic-unit". After treatment with complementary target DNA, the three-photonic-unit Alq3 particles doped with DNAs were found to emit depressed luminescence from side parts of the particles. This novel phenomenon would expand the technological value of these hybrid crystals with divided photoluminescence emissions toward a wider range of bio-photonic applications.

Measuring Photoexcited Electron and Hole Dynamics in ZnTe and Modeling Excited State Core-Valence Effects in Transient Extreme Ultraviolet Reflection Spectroscopy.

Transient extreme ultraviolet (XUV) spectroscopy is becoming a valuable tool for characterizing solar energy materials because it can separate photoexcited electron and hole dynamics with element specificity. Here, we use surface-sensitive femtosecond XUV reflection spectroscopy to separately measure photoexcited electron, hole, and band gap dynamics of ZnTe, a promising photocathode for CO2 reduction. We develop an ab initio theoretical framework based on density functional theory and the Bethe-Salpeter equation to robustly assign the complex transient XUV spectra to the material's electronic states. Applying this framework, we identify the relaxation pathways and quantify their time scales in photoexcited ZnTe, including subpicosecond hot electron and hole thermalization, surface carrier diffusion, ultrafast band gap renormalization, and evidence of acoustic phonon oscillations.

Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications.

The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential.

Cancer cells corrupt normal epithelial cells through miR-let-7c-rich small extracellular vesicle-mediated downregulation of p53/PTEN.

Tumor volume increases continuously in the advanced stage, and aside from the self-renewal of tumor cells, whether the oncogenic transformation of surrounding normal cells is involved in this process is currently unclear. Here, we show that oral squamous cell carcinoma (OSCC)-derived small extracellular vesicles (sEVs) promote the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of normal epithelial cells but delay their apoptosis. In addition, nuclear-cytoplasmic invaginations and multiple nucleoli are observed in sEV-treated normal cells, both of which are typical characteristics of premalignant lesions of OSCC. Mechanistically, miR-let-7c in OSCC-derived sEVs is transferred to normal epithelial cells, leading to the transcriptional inhibition of p53 and inactivation of the p53/PTEN pathway. In summary, we demonstrate that OSCC-derived sEVs promote the precancerous transformation of normal epithelial cells, in which the miR-let-7c/p53/PTEN pathway plays an important role. Our findings reveal that cancer cells can corrupt normal epithelial cells through sEVs, which provides new insight into the progression of OSCC.

Exploring Links Between Industrialization, Urbanization, and Chinese Inflammatory Bowel Disease.

Background: Evidence is emerging that the incidence of inflammatory bowel diseases (IBD) is dramatically increased in China, but with a geographic variation. Objectives: We performed a review to summarize the link of accelerated industrialization, urbanization to changing trends in the incidence of IBD over the last three decades. Methods: An electronic database search was performed in PubMed, Medline, EMBASE and Google Scholar (for English literature) and the China Science Periodical Database in Wanfang Data (for Chinese literature) from January 1990 to June 2020. Results: By systematically analyzing the changing trends of gross domestic product (GDP) or GDP per capita, population migration from rural areas to cities and increasing incidence of IBD in parallel in different Chinese regions, an association between accelerated industrialization and urbanization and rising rate of IBD was shown. In which, rates of IBD incidence were higher in provinces with a high value of GDP per capita than those provinces with a low value of GDP per capita. Analysis of available epidemiological data revealed that the incidence of IBD was rising in parallel with increasing trends of both gross products of industry and urban population in Yunnan Province in a 14-year interval. Further evidence suggested that industrialization- and urbanization-induced subsequent changes in environmental factors, e.g., Westernized dietary habits and obesity, and work-related stress, might contribute to the increased risk of IBD in China. In addition, the preliminary results showed that urbanization and Westernized dietary habits might induce significant changes in gut microbiota profile that are possibly to increase the risk for IBD in Chinese. Conclusions: Existing evidence to suggest that accelerated industrialization/urbanization is associated with the increasing incidence of IBD in China, which provides novel insights to study the possible mechanisms for the recent increasing incidence of IBD in newly industrialized and urbanized developing countries. In the future, the interaction between relevant environmental factors e.g., air/water pollution and IBD susceptibility genes in Chinese should be examined.

Unfractionated heparin attenuates endothelial barrier dysfunction via the phosphatidylinositol-3 kinase/serine/threonine kinase/nuclear factor kappa-B pathway.

BACKGROUND: Vascular endothelial dysfunction is considered a key pathophysiologic process for the development of acute lung injury. In this study, we aimed at investigating the effects of unfractionated heparin (UFH) on the lipopolysaccharide (LPS)-induced changes of vascular endothelial-cadherin (VE-cadherin) and the potential underlying mechanisms. METHODS: Male C57BL/6 J mice were randomized into three groups: vehicle, LPS, and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received subcutaneous injection of 8 U UFH 0.5 h before LPS injection. The lung tissue of the mice was collected for assessing lung injury by measuring the lung wet/dry (W/D) weight ratio and observing histological changes. Human pulmonary microvascular endothelial cells (HPMECs) were cultured and used to analyze the effects of UFH on LPS- or tumor necrosis factor-alpha (TNF-α)-induced vascular hyperpermeability, membrane expression of VE-cadherin, p120-catenin, and phosphorylated myosin light chain (p-MLC), and F-actin remodeling, and on the LPS-induced activation of the phosphatidylinositol-3 kinase (PI3K)/serine/threonine kinase (Akt)/nuclear factor kappa-B (NF-κB) signaling pathway. RESULTS: In vivo, UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes (neutrophil infiltration and erythrocyte effusion, alveolus pulmonis collapse, and thicker septum), decreased the lung W/D, and increased protein concentration (LPS vs. LPS + UFH: 0.57 ±â€Š0.04 vs. 0.32 ±â€Š0.04 mg/mL, P = 0.0092), total cell count (LPS vs. LPS + UFH: 9.57 ±â€Š1.23 vs. 3.65 ±â€Š0.78 × 10/mL, P = 0.0155), polymorphonuclear neutrophil percentage (LPS vs. LPS + UFH: 88.05% ±â€Š2.88% vs. 22.20% ±â€Š3.92%, P = 0.0002), and TNF-α (460.33 ±â€Š23.48 vs. 189.33 ±â€Š14.19 pg/mL, P = 0.0006) in the bronchoalveolar lavage fluid. In vitro, UFH pre-treatment prevented the LPS-induced decrease in the membrane expression of VE-cadherin (LPS vs. LPS + UFH: 0.368 ±â€Š0.044 vs. 0.716 ±â€Š0.064, P = 0.0114) and p120-catenin (LPS vs. LPS + UFH: 0.208 ±â€Š0.018 vs. 0.924 ±â€Š0.092, P = 0.0016), and the LPS-induced increase in the expression of p-MLC (LPS vs. LPS + UFH: 0.972 ±â€Š0.092 vs. 0.293 ±â€Š0.025, P = 0.0021). Furthermore, UFH attenuated LPS- and TNF-α-induced hyperpermeability of HPMECs (LPS vs. LPS + UFH: 8.90 ±â€Š0.66 vs. 15.84 ±â€Š1.09 Ω·cm, P = 0.0056; TNF-α vs. TNF-α + UFH: 11.28 ±â€Š0.64 vs. 18.15 ±â€Š0.98 Ω·cm, P = 0.0042) and F-actin remodeling (LPS vs. LPS + UFH: 56.25 ±â€Š1.51 vs. 39.70 ±â€Š1.98, P = 0.0027; TNF-α vs. TNF-α + UFH: 55.42 ±â€Š1.42 vs. 36.51 ±â€Š1.20, P = 0.0005) in vitro. Additionally, UFH decreased the phosphorylation of Akt (LPS vs. LPS + UFH: 0.977 ±â€Š0.081 vs. 0.466 ±â€Š0.035, P = 0.0045) and I kappa B Kinase (IKK) (LPS vs. LPS + UFH: 1.023 ±â€Š0.070 vs. 0.578 ±â€Š0.044, P = 0.0060), and the nuclear translocation of NF-κB (LPS vs. LPS + UFH: 1.003 ±â€Š0.077 vs. 0.503 ±â€Š0.065, P = 0.0078) in HPMECs, which was similar to the effect of the PI3K inhibitor, wortmannin. CONCLUSIONS: The protective effect of UFH against LPS-induced pulmonary endothelial barrier dysfunction involves VE-cadherin stabilization and PI3K/Akt/NF-κB signaling.

A critical review on saline wastewater treatment by membrane bioreactor (MBR) from a microbial perspective.

This work has reviewed from a microbial perspective and listed the typical studies on MBR techniques for saline wastewater treatments. When the salinity of influent is lower than 10 g/L NaCl, conventional MBR can be easily applied with adjusted operating conditions. For better biodegradation and anti-fouling ability at higher salinities (10-100 g/L), modified and hybrid MBR systems may need to be wisely designed according to the change in the microbial community and contents of EPS/SMP. To treat hypersaline wastewaters with salinities of up to 100 g/L NaCl, inoculation of halophilic bacteria has been applied in MBR works. Microbial community structures in some typical works have been discussed from a microbial perspective to benefit the identification and isolation of halophilic bacteria for future works. The following aspects are also suggested in future MBR research for saline wastewater treatment: (1) The structure design of MBR and the manufacture of advanced membranes; (2) The maintenance of the microbial biodiversity for anti-membrane fouling; (3) The metabolic mechanism for halophilic (or salt-tolerant) microorganisms against salinity shocks; (4) The revolution stage and process of microorganisms during saline wastewater treatment in MBR; (5) The effects of characteristics (cell structure, shape and metabolic pathways) of microorganisms on the salt tolerance; (6) Applying halophilic microorganisms for salinities over 150 g/L NaCl.

Fenofibrate, a PPARα agonist, protect proximal tubular cells from albumin-bound fatty acids induced apoptosis via the activation of NF-kB.

Albumin-bound fatty acids is the main cause of renal damage, PPARα is responsible in the metabolism of fatty acids. Previous study found that PPARα played a protective role in fatty acids overload associated tubular injury. The aim of the present study is to investigate whether fenofibrate, a PPARα ligands, could contribute to the renoprotective action in fatty acids overload proximal tubule epithelial cells. We observed in HK-2 cells that fenofibrate significantly inhibited fatty acids bound albumin (FA-BSA) induced up-regulation of MCP-1 and IL-8. Treatment with fenofibrate attenuated renal oxidative stress induced by FA-BSA as evidenced by decreased MDA level, increased SOD activity and catalase, GPx-1 expression. FA-BSA induced apoptosis of HK-2 cells were also obviously prevented by fenofibrate. Furthermore, fenofibrate significantly increased the expression of PPARα mRNA and protein in FA-BSA treated cells. Finally, the activation of NF-kB induced by FA-BSA was markedly suppressed by fenofibrate. Taken together, our study describes a renoprotective role of fenofibrate in fatty acids associated tubular toxicity, and the transcriptional activation of PPARα and suppression of NF-kB were at least partially involved.