Abstract
Thyroid hormone (TH) has long been believed to play a minor role in male reproduction. However, evidences from experimental model of thyrotoxicosis or hypothyroidism suggests its role in ...spermatogenesis. Cellular action of TH requires membrane transport via specific transporters such as monocarboxylate transporter 8 (MCT8).
SLC16A2
(encodes for MCT8) inactivating mutation in humans can lead to Allan-Herndon Dudley-syndrome, a X-linked psychomotor and growth retardation. These patients present cryptorchidism which suggests a role of MCT8 during spermatogenesis. In this study, we found that Mct8 is highly expressed during early postnatal development and decreases its expression in the adulthood of testis of wild-type male rats. Histological analysis revealed that spermatogonia largely lacks MCT8 expression while spermatocytes and maturing spermatids highly express MCT8. To further understand the role of Mct8 during spermatogenesis, we generated
Slc16a2
(encodes MCT8) knockout rats using CRISPR/Cas9. Serum THs (T3 and T4) level were significantly altered in
Slc16a2
knockout rats when compared to wild-type littermates during early to late postnatal development. Unlike
Slc16a2
knockout mice,
Slc16a2
knockout rats showed growth delay during early to late postnatal development. In adult Slc16a2 knockout rats, we observed reduced sperm motility and viability. Collectively, our data unveil a functional involvement of MCT8 in spermatogenesis, underscoring the importance of TH signaling and action during spermatogenesis.
Although nanomedicines have been intensively investigated for cancer therapy in the past, poor accumulation of nanomedicines in tumor sites remains a serious problem. Therefore, a novel drug delivery ...system is required to enhance accumulation and penetration of nanomedicines at the tumor site. Recently, high-intensity focused ultrasound (HIFU) has been highlighted as a non-invasive therapeutic modality, and showed enhanced therapeutic efficacy in combination with nanomedicines. Cavitation effect induced by the combination of HIFU and microbubbles results in transiently enhanced cell membrane permeability, facilitating improved drug delivery efficiency into tumor sites. Therefore, we introduce the acoustic cavitation and thermal/mechanical effects of HIFU in conjunction with microbubble to overcome the limitation of conventional drug delivery. The cavitation effect maximized by the strong acoustic energy of HIFU induced the preferential accumulation of nanomedicine locally released from the nanomedicines-microbubble complex in the tumor. In addition, the mechanical effect of HIFU allowed the accumulated nanomedicines to penetrate into deeper tumor region. The preferential accumulation and deeper penetration of nanomedicines by HIFU showed enhanced therapeutic efficacy, compared to low frequency ultrasound (US). These overall results demonstrate that the strategy combined nanomedicines-microbubble complex with HIFU is a promising tools for cancer therapy.
The therapeutic strategy using HIFU in conjunction with a nanomedicines-microbubble complex allows the locally preferential accumulation of nanomedicines in the tumor and enhanced penetration of nanomedicines into deeper tumor region. Display omitted
To overcome the limitations of single therapy, chemotherapy has been studied to be combined with photodynamic therapy. However, nanomedicine combining anticancer drug and photosensitizer still cannot ...address the insufficiency of drug delivery and the off-targeting effect. To address drug delivery issue, we have developed a doxorubicin encapsulating human serum albumin nanoparticles/chlorin e6 encapsulating microbubbles (DOX-NPs/Ce6-MBs) complex system. Microbubbles enable ultrasound-triggered local delivery via sonoporation for maximizing the drug delivery to a target site. In both in vitro and in vivo experiments, the developed DOX-NPs/Ce6-MBs drug delivery complex could be confirmed to transfer drugs deeply and effectively into cancerous tumors through the following three steps; (1) the local release of nanoparticles due to the cavitation of DOX-NPs/Ce6-MBs; (2) the enhanced extravasation of DOX-NPs and Ce6-liposome/micelle due to the sonoporation phenomenon; (3) the improved penetration of extravasated nanomedicines into the deep tumor region due to the mechanical energy of ultrasound. As a result, the developed DOX-NPs/Ce6-MBs complex with ultrasound irradiation showed increased therapeutic effects compared to the case where no ultrasound irradiation was applied. The DOX-NPs/Ce6-MBs was concluded from this study to be the optimal drug delivery system for external-stimuli local combination (chemotherapy + PDT) therapy.
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•Nanoparticle/Microbubble complex can be an excellent carrier for multiple drugs.•Microbubble in the complex can be used for both drug carrier and sonoporation.•Sonoporation effects can improve local delivery efficiency of multiple drugs.•Combination therapy can be improved by increasing tissue penetration of drugs.
Exosomes, which are released from all cells and take part in cell-to-cell communication, have been utilized as drug delivery vehicles in many recent studies. Immunotherapy is an emerging technology ...which uses patients' innate immune systems. In immunotherapy, immune cells are stimulated through antibodies, the other immune cells and genetic modifications for the purposes of, for instance, cancer therapy. In this study, tumor-derived re-assembled exosome (R-Exo) was simultaneously utilized as both a drug delivery carrier and an immunostimulatory agent. A chlorin e6 photosensitizer was loaded into tumor-derived exosomes during exosomal re-assembly. After this modification, R-Exo retains its original average size and has the same membrane proteins, which allows for targeting of tumor cells. Chlorin e6-loaded R-Exo (Ce6-R-Exo) can be visualized by photoacoustic imaging and can efficiently generate reactive oxygen species inside tumor cells under laser irradiation. In addition, Ce6-R-Exo increased the release of cytokines from immune cells, which indicates that these modified exosomes can be used as an immunotherapeutic agent. In conclusion, we developed a novel strategy that enables photoacoustic imaging-guided photodynamic and immune-combination therapy for the treatment of cancer with tumor-derived Ce6-R-Exo.
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Cancer recurrence is the main cause of chemotherapeutic treatment failure. The mechanisms driving cancer recurrence may be due to very rare subpopulation cells, cancer stem-like cells (CSCs). ...Therefore, the early detection and better treatment of cancer stem-like cells are of great interest. In this study, we investigated how to eliminate the side population cells (SP), which have the characteristics of cancer stem-like cells, and also show chemotherapy resistance. Fluorescence-activated cell sorting (FACS) were used to sort SP and non-SP cells from human liver cancers, Huh-7 Hyaluronic acid (HA), which is an abundant component in the extracellular matrix, is known to involve in proliferation of normal and cancer cells. Herein, we investigated the effect of HA component on chemotherapy against SP cells. Cell growth inhibitory effects of the paclitaxel (PTX) chemotherapy combined with the HA component on SP cells of Huh-7 was determined using the trypan blue dye exclusion test. PTX combined with HA was found to show more increased inhibition of cell growth in both SP and non-SP cells, compared to free PTX treatment. In conclusion, SP cells of Huh-7 shows chemotherapeutic drug resistance due to the over-expressed efflux pumps. HA proposed one of possibilities to overcome the limitation of chemotherapy against cancer stem-like cells.
Biomedical imaging-guided cancer therapy should have capabilities of both accurate tumor diagnosis and high therapeutic efficacy for the personalized treatment. Various biomedical imaging-guided ...cancer therapies are currently being investigated to overcome current limitations that include low sensitivity of diagnosis and poor drug delivery to the tumor site. Here, we report the development of a multifunctional theranostic contrast agent demonstrating high sensitive photoacoustic and ultrasound imaging and effective local delivery of anticancer drug to a tumor site. A microbubble (porphyrin-MB) was developed using phospholipid–porphyrin conjugates to enhance ultrasound and photoacoustic signal intensities simultaneously. Paclitaxel-loaded human serum albumin nanoparticles (PTX-HSA-NPs) were then conjugated onto the surface of the microbubble. The developed PTX-HSA-NPs conjugated porphyrin-MB (porphyrin-MB-NPs) provided sensitive, dual modal images of a tumor at 700nm optimal laser wavelength for photoacoustic imaging and 5–14MHz operating frequency for the ultrasound imaging. In addition, porphyrin-MB-NPs efficiently suppressed tumor growth by ultrasound exposure. Exposure to the focused ultrasound triggered the collapse of porphyrin-MB-NPs, resulting in the local release of PTX-HSA-NPs and enhanced penetration into the tumor site. The increased preferential accumulation and penetration of PTX-HSA-NPs suppressed tumor growth 10-fold more than without exposure to ultrasound. In conclusion, the developed porphyrin-MB-NPs establish a new paradigm in simultaneous bi-functional ultrasound/photoacoustic imaging diagnosis and locally triggered release of nanomedicine and enhanced chemotherapy efficiency.
The porphyrin-microbubble, onto the surface of which paclitaxel-loaded human serum albumin nanoparticles were conjugated, provide simultaneous bi-functional ultrasound/photoacoustic imaging diagnosis and locally triggered release of nanomdicine and enhanced chemotherapy efficiency. Display omitted
This paper presents a single-slope analog-to-digital converter (SS-ADC) with a proposed zero-crossing (ZC)-prediction-based power-gating technique for low-power complementary ...metal-oxide-semiconductor (CMOS) image sensor applications. The proposed ZC prediction utilizes the DC gain difference between the preamplifier and main comparator in the SS-ADC without an additional ramp signal. For a consistent prediction with a low power operation, the constant charge bias amplifier (CQBA) is implemented as a preamplifier, which exhibits input level independent output common mode and gain response. The proposed SS-ADC is demonstrated for a 110-nm CMOS image sensor process, assuming a 640\times 480 image resolution, a 10-bit ADC resolution, and 120 frames/s. The simulation results show that the CQBA output common mode and gain response only vary by 1% and 6.4%, respectively. Furthermore, the overall power consumption of the sensor is reduced by about 80% compared with the static comparator by the prediction-based power-gating, achieving high energy efficiency (51. 5 pJ/pixel of the Figure of merit).
As a molecular imaging modality, photoacoustic (PA) imaging has been in the spotlight because it can provide an optical contrast image of physiological information and a relatively deep imaging ...depth. However, its sensitivity is limited despite the use of exogenous contrast agents due to the background PA signals generated from nontargeted absorbers, such as blood and boundaries between different biological tissues. In addition, clutter artifacts generated in both in-plane and out-of-plane imaging region degrade the sensitivity of PA imaging. We propose a method to eliminate the nontargeted PA signals. For this study, we used a dual-modal ultrasound (US)-PA contrast agent that is capable of generating both the backscattered US and PA signals in response to the transmitted US and irradiated light, respectively. The US images of the contrast agents are used to construct a masking image that contains the location information about the target site and is applied to the PA image acquired after contrast agent injection. In vitro and in vivo experimental results demonstrated that the masking image constructed using the US images makes it possible to completely remove nontargeted PA signals. The proposed method can be used to enhance the clear visualization of the target area in PA images.
Photoacoustic imaging is the latest promising diagnostic modality that has various advantages such as high spatial resolution, deep penetration depth, and use of non-ionizing radiation. It also ...employs a non-invasive imaging technique and optically functionalized imaging. The goal of this study was to develop a nanomedicine for simultaneous cancer therapy and diagnosis based on photoacoustic imaging. Human serum albumin nanoparticles loaded with melanin and paclitaxel (HMP-NPs) were developed using the desolvation technique. The photoacoustic-based diagnostic and chemotherapeutic properties of HMP-NPs were evaluated through in vitro and in vivo experiments. The size and zeta potential of the HMP-NPs were found to be 192.8±21.11nm and -22.2±4.39mV, respectively. In in vitro experiments, HMP-NPs produced increased photoacoustic signal intensity because of the loaded melanin and decreased cellular viability because of the encapsulated paclitaxel, compared to the free human serum albumin nanoparticles (the control). In vivo experiments showed that the HMP-NPs efficiently accumulated inside the tumor, resulting in the enhanced photoacoustic signal intensity in the tumor site, compared to the normal tissues. The in vivo chemotherapy study demonstrated that HMP-NPs had the capability to treat cancer for an extended period. In conclusion, HMP-NPs were simultaneously capable of photoacoustic diagnostic and chemotherapy against cancer.
Metastatic lung adenocarcinoma (LuAC) presents a significant clinical challenge due to the short latency and the lack of efficient treatment options. Therefore, identification of molecular ...vulnerabilities in metastatic LuAC holds great importance in the development of therapeutic drugs against this disease. In this study, we performed a genome-wide siRNA screening using poorly and highly brain-metastatic LuAC cell lines. Using this approach, we discovered that compared to poorly metastatic LuAC (LuAC-Par) cells, brain-metastatic LuAC (LuAC-BrM) cells exhibited a significantly higher vulnerability to c-FLIP (an inhibitor of caspase-8)-depletion-induced apoptosis. Furthermore, in vivo studies demonstrated that c-FLIP knockdown specifically inhibited growth of LuAC-BrM, but not the LuAC-Par, tumors, suggesting the addiction of LuAC-BrM to the function of c-FLIP for their survival.
Our in vitro and in vivo analyses also demonstrated that LuAC-BrM is more sensitive to c-FLIP-depletion due to ER stress-induced activation of the c-JUN and subsequent induction of stress genes including ATF4 and DDIT3. Finally, we found that c-JUN not only sensitized LuAC-BrM to c-FLIP-depletion-induced cell death but also promoted brain metastasis in vivo, providing strong evidence for c-JUN's function as a double-edged sword in LuAC-BrM. Collectively, our findings not only reveal a novel link between c-JUN, brain metastasis, and c-FLIP addiction in LuAC-BrM but also present an opportunity for potential therapeutic intervention.
•A genome-wide siRNA screening revealed that brain-metastatic lung adenocarcinoma cells (LuAC) exhibit greater c-FLIP dependency for their survival than poorly-metastatic LuAC cells.•The selective vulnerability of brain-metastasis LuAC to c-FLIP depletion is conferred by ER stress-induced activation of the c-JUN pathway in LuAC-BrM, with AFT4 and DDIT3 functioning as downstream mediators.•c-JUN promotes brain metastasis in LuAC, thus functioning as a double-edged sword in brain-metastatic LuAC.
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