Mechanism of apoptosis in oral squamous cell carcinoma promoted by cardamonin through PI3K/AKT signaling pathway.

Currently, surgical resection remains the primary approach for treating oral squamous cell carcinoma (OSCC), with limited options for effective drug therapy. Cardamonin, a principal compound derived from Myristica fragrans of the Zingiberaceae family, has garnered attention for its potential to suppress the onset and progression of various malignancies encompassing breast cancer, hepatocellular carcinoma, and ovarian cancers. Nevertheless, the involvement of cardamonin in the treatment of OSCC and its underlying mechanisms are yet to be elucidated. This research explored the possible target of cardamonin in treating OSCC via network pharmacological analysis. Subsequently, this research investigated the impact of cardamonin on OSCC cells via in vitro experiments, revealing its capacity to impede the migration, proliferation, and invasion of OSCC cells. Additionally, western blotting analysis demonstrated that cardamonin facilitates apoptosis by regulating the PI3K/AKT pathway. The findings suggest that MMP9 and the PI3K/AKT signaling pathway may serve as the target and pathway of cardamonin in treating OSCC. To summarize, the research findings suggest that cardamonin may facilitate apoptosis in OSCC cells by inhibition of PI3K/AKT pathway activation. These outcomes offer a theoretical basis for the utilization of cardamonin as a natural drug for treating OSCC.

Deepened Photodynamic Therapy through Skin Optical Clearing Technology in the Visible Light Window.

The trade-off that shorter wavelength light facilitates the efficient generation of reactive oxygen species (ROS) from photosensitizer (PS) while facing the drawback of limited penetration depth through skin tissue restricts the further development of photodynamic therapy (PDT). Here, we address this contradiction and achieve visible-light-tailored deep PDT combined with the skin optical clearing technology. With the help of the prepared skin optical clearing gel, the refractive index inhomogeneity between skin tissue components is greatly attenuated, and the light scattering effect within the skin tissue is remarkably reduced. As a consequence, the transmittance of visible light at 600 nm through in vitro porcine skin and in vivo mouse skin after treatment increases from approximately 10 and 40 to 70 and 70%, respectively. Furthermore, in the tumor cell eradication experiment, the local ROS generation efficiency in the experimental group is several times higher than that in the control group owing to improved visible transmittance, which is thus responsible for the complete eradication of tumor cells, even when shaded by skin tissue. The results suggest that this strategy may serve as a valuable supplement to the current deep PDT strategies.

Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells.

BACKGROUND: Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa. PURPOSE: We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells. METHODS: Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling. RESULTS: CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts. CONCLUSIONS: Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.

Ultradeep Photothermal Therapy Strategies.

Photothermal therapy (PTT) mediated by the second near-infrared light (NIR-II) is considered as the most promising PTT in deep tissues due to the superior penetrability of NIR-II through biological tissues. However, the effective therapeutic depth of NIR-II mediated PTT is limited to only several millimeters beneath the skin tissues. So far, deep PTT still cannot satisfy the depth requirement for most common cancers, including but not limited to lung, pancreatic, colorectal, and stomach cancers. Therefore, it is highly desirable to develop ultradeep PTT strategies to enhance the therapeutic depth with clinical availability. This Perspective highlights the latest research progress in regard to ultradeep PTT strategies, including larger laser spot PTT, skin tissue optical clearing technology enhanced PTT, and optical fiber assisted PTT, followed with pertinent evaluations and expectations. In addition, challenges and perspectives in this fast-growing area of ultradeep PTT are discussed.

Aspalathus linearis suppresses cell survival and proliferation of enzalutamide-resistant prostate cancer cells via inhibition of c-Myc and stability of androgen receptor.

Enzalutamide, a nonsteroidal antiandrogen, significantly prolonged the survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patients receiving enzalutamide frequently develop drug resistance. Rooibos (Aspalathus linearis) is a shrub-like leguminous fynbos plant endemic to the Cedarberg Mountains area in South Africa. We evaluated the possibility of using a pharmaceutical-grade green rooibos extract (GRT, containing 12.78% aspalathin) to suppress the proliferation and survival of enzalutamide-resistant prostate cancer (PCa) cells. Treatment with GRT dose-dependently suppressed the proliferation, survival, and colony formation of enzalutamide-resistant C4-2 MDV3100r cells and PC-3 cells. Non-cancerous human cells were more resistant to GRT treatment. GRT suppressed the expression of proteins involved in phosphoinositide 3-kinase (PI3K)-Akt signaling, androgen receptor (AR), phospho-AR (Ser81), cyclin-dependent kinase 1 (Cdk1), c-Myc and Bcl-2 but increased the expression of apoptotic proteins. Overexpression of c-Myc antagonized the suppressive effects of GRT, while knockdown of c-Myc increased the sensitivity of PCa cells to GRT treatment. Expression level of c-Myc correlated to resistance of PCa cells to GRT treatment. Additionally, immunofluorescence microscopy demonstrated that GRT reduced the abundance of AR proteins both in nucleus and cytoplasm. Treatment with cycloheximide revealed that GRT reduced the stability of AR. GRT suppressed protein expression of AR and AR's downstream target prostate specific antigen (PSA) in C4-2 MDV3100r cells. Interestingly, we observed that AR proteins accumulate in nucleus and PSA expression is activated in the AR-positive enzalutamide-resistant PCa cells even in the absence of androgen. Our results suggested that GRT treatment suppressed the cell proliferation and survival of enzalutamide-resistant PCa cells via inhibition of c-Myc, induction of apoptosis, as well as the suppression of expression, signaling and stability of AR. GRT is a potential adjuvant therapeutic agent for enzalutamide-resistant PCa.

Artificial Kidney Capsule Packed with Mesenchymal Stem Cell-Laden Hydrogel for the Treatment of Rhabdomyolysis-Induced Acute Kidney Injury.

Acute kidney injury (AKI) has emerged as a major public health problem affecting millions of people worldwide without specific and satisfactory therapies due to the lack of an effective delivery approach. In the past few decades, hydrogels present infinite potential in localized drug delivery, while their poor adhesion to moist tissue and isotropic diffusion character always restrict the therapeutic efficiency and may lead to unwanted side effects. Herein, we proposed a novel therapeutic strategy for AKI via a customizable artificial kidney capsule (AKC) together with a mesenchymal stem cell (MSC)-laden hydrogel. Specifically, an elastic capsule owning an inner chamber with the same size and shape as the kidney is designed and fabricated through three-dimensional (3D) modeling and printing, serving as an outer wrap for kidney and cell-laden hydrogels. According to the in vitro experiment, the excellent biocompatibility of gelatin-based hydrogel ensures viability and proliferation of MSCs. In vivo mice experiments proved that this concept of AKC-assisted kidney drug delivery could efficiently reduce epithelial cell apoptosis and minimize the damage of the renal tubular structure for mice suffering AKI. Such a strategy not only provides a promising alternative in the treatment of AKI but also offers a feasible and versatile approach for the repair and recovery of other organs.

R-loops mediate transcription-associated formation of human rDNA secondary constrictions.

The ribosomal gene DNA (rDNA) often forms secondary constrictions in the chromosome; however, the molecular mechanism involved remains poorly understood. Here, we report that occurrence of rDNA constriction was increased in the chromosomes in human cancer cell lines compared with normal cells and that decondensed rDNA was significantly enhanced after partial inhibition of rDNA transcription. rDNA transcription was found during the S phase when replication occurred, and thus, DNA replication inhibitors caused constriction formation through hindering rDNA transcription. Inhibition of ataxia ATR (telangiectasia-mutated and RAD3-related) induced rDNA constriction formation. Replication stress or transcription inhibition increased R-loop formation. Topoisomerase I and RNase H1 suppressed secondary constriction formation. These data demonstrate that transcription stress causes the accumulation of stable R-loops (RNA-DNA hybrid) and subsequent constriction formation in the chromosomes.

Identification of nucleic acid aptamers against lactate dehydrogenase via SELEX and high-throughput sequencing.

Nucleic acid aptamers are small fragments of DNA or RNA molecules binding specifically to targets, which can be obtained through in vitro screening via systematic evolution of ligands by exponential enrichment (SELEX). Lactate dehydrogenase (LDH) is an important tumor marker, whose level in patients is of great significance for diagnosis of many diseases. Here, we report the identification of LDH aptamers by 9 rounds of screening from a length-mixed single-stranded DNA library using the SELEX technology. After the 3rd and 7th rounds of aptamer screening, affinity was significantly improved, and fluorescence quantitative analysis showed stronger affinity for the aptamers selected from the 7th to 9th rounds of screening. After high-throughput sequencing, motif analysis, and secondary structure prediction, we finally chose and further investigated 15 candidate LDH aptamer sequences with obvious differences in secondary structure in the 7th to 9th rounds of screening. Among them, LDH7-1, LDH7-9, LDH8-2, and LDH9-1 were shown to bind to LDH protein with high affinity and specificity with Kd < 25 nM. This study provides new ideas for rapid detection of LDH protein content and enzyme activity, thus contributing to the development of rapid medical detection.

Challenges and opportunities for ovarian cancer management in the epidemic of Covid-19: lessons learned from Wuhan, China.

China and the rest of the world are experiencing an outbreak of the 2019 novel coronavirus disease (COVID-19). Patients with cancer are more susceptible to viral infection and are more likely to develop severe complications, as compared to healthy individuals. The growing spread of COVID-19 presents challenges for the clinical care of patients with gynecological malignancies. Ovarian debulking surgery combined with the frequent need for chemotherapy is most likely why ovarian cancer was rated as the gynecologic cancer most affected by COVID-19. Therefore, ovarian cancer presents a particular challenging task. Concerning the ovarian cancer studies with confirmed COVID-19 reported from large-scale general hospitals in Wuhan, we hold that the treatment plan was adjusted appropriately and an individualized remedy was implemented. The recommendations discussed here were developed mainly based on the experience from Wuhan. We advise that the management strategy for ovarian cancer patients should be adjusted in the light of the local epidemic situation and formulated according to the pathological type, tumor stage and the current treatment phase. Online medical service is an effective and convenient communication platform during the pandemic.

Effect of pH or Metal Ions on the Oil/Water Interfacial Behavior of Humic Acid Based Surfactant.

Humic acid, a kind of widespread organic macromolecule on earth, is naturally formed through the microbial biodegradation of plant, animal, and microorganism residues. Because of the large number of active functional groups (phenolic hydroxyl and carboxyl), humic acid has been considered as a biocompatible, green, and low-cost biosurfactant recently. In this work, based on the sensitivity of humic acid to the external chemical environment, the oil/water interfacial behavior of sodium humate at different pH or in the presence of metal ions is closely investigated. Sodium humate is significantly enriched toward the oil/water interface at either low pH or high metal-ion concentration to adjust the properties of the prepared emulsion, but the mechanisms are proved to be different when considering the influence of pH and metal ions. Besides, to the best of our knowledge, humic acid based surfactant is proposed as a Pickering emulsifier for the first time, known as solid surfactant. This work promises the great potential of humic acid as a natural environment-responsive surfactant and has important implications for the application of humic acid based surfactant in industry and understanding of the role of humic acid in the natural environment.

A Transcriptome Analysis: Various Reasons of Adverse Pregnancy Outcomes Caused by Acute Toxoplasma gondii Infection.

BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular parasite, which can affect the pregnancy outcomes in infected females by damaging the uterus, and the intrauterine environment as well as and the hypothalamus resulting in hormonal imbalance. However, the molecular mechanisms underlying the parasite-induced poor pregnancy outcomes and the key genes regulating these mechanisms remain unclear. Therefore, this study aimed to analyze the gene expression in the mouse's uterus following experimentally-induced acute infection with T. gondii RH strain. Three groups of female mice were intraperitoneally injected with tachyzoites as follow; 3 days before pregnancy (FBD6), after pregnancy (FAD6), and after implantation (FID8) as the experimental groups. Another corresponding three groups served as control, were injected with normal saline at the same time. Transcriptome analysis of the total RNA extracted from both infected and non-infected mouse uterus samples was performed using RNA sequencing (RNA-Seq). RESULTS: The three experimental groups (FBD6, FAD6, and FID8) had a total of 4,561, 2,345, and 2,997 differentially expressed genes (DEGs) compared to the controls. The significantly upregulated and downregulated DEGs were 2,571 and 1,990 genes in FBD6, 1,042 and 1,303 genes in FAD6 and 1,162 and 1,835 genes in FID8 group, respectively. The analysis of GO annotation, and KEGG pathway showed that DEGs were mainly involved in anatomical structure development, transport, cell differentiation, embryo development, hormone biosynthetic process, signal transduction, immune system process, phagosome, pathways in cancer, and cytokine-cytokine receptor interaction pathways. CONCLUSION: T. gondii infection can induce global transcriptomic changes in the uterus that may cause pregnancy hypertension, destruct the intrauterine environment, and hinder the normal development of placenta and embryo. Our results may help to understand the molecular mechanisms of the acute T. gondii infection, which could promote the development of new therapeutics or prophylactics for toxoplasmosis in pregnancy.

Solar activation of fungus coated in photothermal cloth.

Bioorthogonal reactions based on manipulating the physicochemical and biological behavior of natural cells have gained tremendous attention for meeting the demands for multifunctional microorganisms without decreasing cell viability. Described herein is a novel bioorthogonal method for microorganism (Aspergillus oryzae) modification which coats the microorganism with a photothermal conversion cloth for staying bioactive in cold environments. Two steps, including ferric ions primarily binding to the microorganism cell surface, followed by in situ polymerization of pyrrole, are adopted to actualize highly efficient polypyrrole modification on the microorganism surfaces. The production of α-amylase by Aspergillus oryzae and α-amylase catalytic ability are two representative indexes of cold adaptation as confirmed by a starch decomposition test. This strategy for coating microorganisms with photothermal cloth is biocompatible and cost-effective, and can achieve non-contact modulation, which also offers great promise for generating living cell-polymer hybrid structures based on other microorganism systems for low-temperature environmental adaptation.

RhB-encapsulating silica nanoparticles modified with PEG impact the vascular endothelial function in endothelial cells and zebrafish model.

Silica nanoparticles (SiNPs) have been widely used in human health related products, such as food additives, cosmetics and even drug delivery, gene therapy or bioimaging. Recently, a first-in-human clinical trial based on polyethylene glycol (PEG)-modified SiNPs had been approved by US FDA to trace melanoma. However, as a nano-based drug delivery system, its biocompatibility and vascular toxicity are still largely unknown. Thus, we synthesized the fluorescent SiNPs to explore the biocompatibility and vascular endothelial function, and compare different biological effects caused by PEG-modified and unmodified SiNPs in cells and zebrafish model. The characterizations of SiNPs and PEG-modified SiNPs were analyzed by TEM, SEM, AFM and DLS, which exhibited relatively good stable and dispersive. Compared with SiNPs, PEG-modified SiNPs had markedly reduced the inflammatory response and vascular damage in Tg (fli-1: EGFP) and Tg (mpo: GFP) transgenic zebrafish lines, respectively. Consistent with the in vivo results, the PEG-modified SiNPs had been found to significantly decline the levels of ROS, inflammatory cytokines and mitochondrial-mediated apoptosis in vascular endothelial cells compared to SiNPs, and the ROS scavenger NAC could effectively alleviate the above adverse effects induced by nanoparticles. Our results suggested that the PEG-modified SiNPs could become more safety via increasing the biocompatibility and decreasing cellular toxicities in living organisms.

Three Birds with One Stone: Injectable CaC2 Nanobombs with Triple Effects for Minimally Invasive Tumor Chemical Ablation.

Percutaneous chemical ablation (PCA) is the oldest and most established technique for treating small solid tumors in organs. It has been widely used in clinics even on an outpatient basis. However, compared with the emerging microwave or magnetic hyperthermal ablation, PCA is faced with relatively poor necrosis results and needs to repeat multiple sessions. Inspired by the three effects in the bomb's explosive process, we herein expect to combine calcium carbide (CaC2) nanoparticles into the PCA technique to generate local explosion within tumor tissues, leading to three killing effects against tumors to further improve the ablation efficacy of PCA. Through an efficient wet milling procedure with poly(ethylene glycol), three kinds of nanobombs including CaC2, calcium oxide (CaO), and calcium hydroxide (Ca(OH)2) were fabricated, and they all exhibited desirable suspension stability. Among these nanobombs, in particular CaC2 nanobombs showed a synergistic effect that the generation of ethyne gas bubbles could facilitate the most rapid diffusion of hyperthermia. Also, CaC2 nanobombs offered the powerful ability to cause the sudden rise of local high temperature and pH value. According to the in vivo mice tumor excision trial, the tumors of 75% of cases that received CaC2 treatment were destroyed and eradicated, exhibiting the excellent ablation ability of CaC2 nanobombs against small solid tumors planted in mice.

Metformin treatment alleviates polycystic ovary syndrome by decreasing the expression of MMP-2 and MMP-9 via H19/miR-29b-3p and AKT/mTOR/autophagy signaling pathways.

In this study, we aimed to investigate the molecular pathway(s) underlying the effect of metformin (MET) on the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Real-time polymerase chain reaction, Western blot analysis, and gelatin zymography were used to assay the effects of MET on MMP and AMPK signaling pathways. In addition, HTOG cells were treated with miR-29b-3p/a scramble control, H19/a negative control, or MET/PBS to explore possible signaling pathway(s) underlying the inhibitory effect of MET on MMP-2/MMP-9. A rat model of polycystic ovary syndrome (PCOS) was also established to validate the molecular mechanism(s) of MET in vivo. The administration of MET suppressed the expression of MMP-9/MMP-2 and mTOR while increasing the expression of Akt and AMPK, indicating that MET reduced the expression of MMPs via the AMPK signaling pathway. Meanwhile, the H19/miR-29b-3p/MMP-9 and H19/miR-29b-3p/MMP-2 signaling pathways were implicated in PCOS, in which the interactions between H19/miR-29b-3p and MMP-9/MMP-2/miR-29b-3p were confirmed. Furthermore, the administration of MET suppressed the expression of H19 while elevating the expression of miR-29b-3p. And the role of MET in PCOS was also confirmed in vivo via examining the activity of H19 and AMPK signaling pathways in cell or serum samples collected from PCOS rats. MET exhibits a therapeutic effect in the treatment of PCOS by reducing the expression of MMPs.

Dark Ionic Liquid for Flexible Optoelectronics.

Owing to a wide visual angle, few aberrations, and great depth of focus, flexible optoelectronics have become one subject of intense investigation for rescue equipment and endoscopy tools. Ionic liquids are rising as a kind of fluidic "semiconductor" with advantages of high flexibility and self-healing. However, challenges in the molecular design of photoresponsive ionic liquids impede the exploration of ionic liquids as intrinsic flexible liquid optoelectronics. This work demonstrated an imidazole-based ionic liquid covalently linked with a polypyrrole oligomer by alkyl chains. Such an ionic liquid has wide absorption from the visible light range to the near-infrared light range. The imidazole moiety acts as an electrical conductor which is thermally responsive. On the other hand, the polypyrrole segment serving as a light antenna is able to convert light energy to thermal heat. The alkyl linker tailors the energy transfer between polypyrrole and an imidazole cation. Negligible molecular aggregation and phase separation are attributed to the preservation of the fluidic nature at room temperature. This photoresponsive ionic liquid is successfully exploited as a flexible light detector that is adaptable to special sensing tests in bending states.

A Polypyrrole Elastomer Based on Confined Polymerization in a Host Polymer Network for Highly Stretchable Temperature and Strain Sensors.

For the purpose of stretchable electronics, broad interests have been paid to elastic conductors by which high tensile strain over 100% can be readily achieved. Here, a scalable-processing, dyeing-like strategy for highly stretchable polypyrrole elastomer (1450% in strain) is conceived without particular topological design. This approach effectively improves the mechanical properties of the classic insoluble polypyrrole by confined polymerization within an elastic polymer network. In terms of the easy processing, it is technically possible to prepare stretchable electronics with arbitrary shape and size for wearable electronics with low cost. The mechanism of interpenetrated networks coexisting with microphase separation is comprehensively illustrated at molecular scale. The as-fabricated polypyrrole elastomers are utilized as temperature or strain sensors for automatic fishing and region-distinct dual signal sensing. Further integration of multiple sensors offers immediate alarm for old people falling at home, which thereby proves its promising potential in practical applications.

Second Near-Infrared Conjugated Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy.

Photothermal conversion in the second near-infrared (NIR-II) window allows deeper penetration and higher exposure to lasers, but examples of NIR-II photothermal agents are mainly formulated by inorganic compounds. In view of the underlying influence of inorganic materials, a novel NIR-II photothermal nanoagent based on a narrow band gap D-A conjugated polymer (TBDOPV-DT) with 2,2-bithiophene as the donor and thiophene-fused benzodifurandione-based oligo( p-phenylenevinylene) as the acceptor has been developed. More importantly, TBDOPV-DT nanoparticles (TBDOPV-DT NPs) are demonstrated to combine excellent photoacoustic imaging (PAI) and photothermal therapy (PTT) ability. TBDOPV-DT NPs exhibit dramatic photostability and heating reproducibility with a photothermal conversion efficiency of 50%. Especially, the NPs possess a remarkable PTT effect toward cancer cells in vitro and can eliminate tumor cells completely in vivo under 1064 nm laser irradiation, while no appreciable side effects have been observed. This study achieves PAI-guided cancer therapy and sheds light on the future of using organic polymer NPs for the NIR-II PTT of cancer.

Preparation of T-2-glucoronide with Rat Hepatic Microsomes and Its Use along with T-2 for Activation of the JAK/STAT Signaling Pathway in RAW264.7 Cells.

T-2 toxin (T-2), one of the most toxic trichothecene A-type mycotoxins, is biotransformed in animal tissues to modified T-2s (mT-2s) including T-2-glucuronide (T-2-GlcA). In this study, the optimal conditions for T-2-GlcA synthesis were established, and the JAK/STAT pathway in RAW264.7 cells was used to study the toxicity of T-2-GlcA. Because many mT-2 standards are not readily available, optimal conditions for T-2-GlcA synthesis in vitro were established by incubating T-2 with rat liver microsomes, UDPGA, and 0.2% Triton X-100 for 90 min. qRT-PCR and Western blot results showed 21- and 760-fold increases in IL-6 mRNA expression induced by T-2-GlcA and T-2, respectively. Similar differences were observed in JAK3, SOCS2/3, and CIS mRNA expression. T-2-GlcA induced a dose-responsive decrease in STAT1 mRNA expression, whereas the result with T-2 was the opposite. Moreover, the phosphorylation of STAT3 induced by T-2-GlcA was higher than that by T-2, whereas the phosphorylation of STAT1 was to the contrary. Overall, the results show that T-2-GlcA was somewhat toxic, but activation of the JAK/STAT pathway in RAW264.7 was higher by T-2.