Layered NaBa2M3Q3(Q2) (M = Cu or Ag; Q = S or Se) Chalcogenides and Local Ordering in Their Mixed-Anion Compositions.

Three new NaBa2M3Q3(Q2) (M = Ag or Cu; Q = S or Se) chalcogenides were prepared by using solid-state methods and structurally characterized by using single-crystal X-ray diffraction. NaBa2Ag3Se3(Se2) and NaBa2Cu3Se3(Se2) crystallize in monoclinic space group C2/m and have a two-dimensional structure composed of edge-sharing MSe4/4 tetrahedra separated by Na+ and Ba2+ cations, along with (Se2)2- dimers at the center of the spacings between [M3Se3]3- slabs. NaBa2Ag3S3(S2) adopts a related structure with space group C2/m but has additional, crystallographically distinct Ag atoms in the [Ag3S3]3- layer that are linearly coordinated. NaBa2Ag3Se3(Se2) and NaBa2Ag3S3(S2) have indirect band gaps measured to be 1.2 and 1.9 eV, respectively, which is supported by band structures calculated using density functional theory. Mixed-anion NaBa2Cu3Se5-xSx compositions were prepared to probe the presence of anion ordering and heteronuclear (S-Se)2- dimers. Structural analyses of the sulfoselenides indicate that selenium preferentially occupies the Q-Q dimer sites, while Raman spectroscopy reveals a mixture of (S2), (Se2), and heteronuclear (S-Se) units in the sulfur-rich products. The local ordering of the chalcogens is rationalized using simple bonding concepts and adds to a growing framework for understanding ordering phenomena in mixed-anion systems.

Korean red ginseng alleviates benign prostatic hyperplasia by dysregulating androgen receptor signaling and inhibiting DRP1-mediated mitochondrial fission.

Panax ginseng (C.A. Mey.) has been traditionally employed in Korea and China to alleviate fatigue and digestive disorders. In particular, Korean red ginseng (KRG), derived from streamed and dried P. ginseng, is known for its anti-aging and anti-inflammatory properties. However, its effects on benign prostatic hyperplasia (BPH), a representative aging-related disease, and the underlying mechanisms remain unclear. This study aims to elucidate the therapeutic effects of KRG on BPH, with a particular focus on mitochondrial dynamics, including fission and fusion processes. The effects of KRG on cell proliferation, apoptosis, and mitochondrial dynamics and morphology were evaluated in a rat model of testosterone propionate (TP)-induced BPH and TP-treated LNCaP cells, with mdivi-1 as a control. The results revealed that KRG treatment reduced the levels of androgen receptors (AR) and prostate-specific antigens in the BPH group. KRG inhibited cell proliferation by downregulating cyclin D and proliferating cell nuclear antigen (PCNA) levels, and it promoted apoptosis by increasing the ratio of B-cell lymphoma protein 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 expression. Notably, KRG treatment enhanced the phosphorylation of dynamin-related protein 1 (DRP-1, serine 637) compared with that in the BPH group, which inhibited mitochondrial fission and led to mitochondrial elongation. This modulation of mitochondrial dynamics was associated with decreased cell proliferation and increased apoptosis. By dysregulating AR signaling and inhibiting mitochondrial fission through enhanced DRP-1 (ser637) phosphorylation, KRG effectively reduced cell proliferation and induced apoptosis. These findings suggest that KRG's regulation of mitochondrial dynamics offers a promising clinical approach for the treatment of BPH.

GATA2 promotes castration-resistant prostate cancer development by suppressing IFN-ß axis-mediated antitumor immunity.

Castration-resistant prostate cancer (CRPC) nearly inevitably develops after long-term treatment with androgen deprivation therapy (ADT), leading to significant mortality. Investigating the mechanisms driving CRPC development is imperative. Here, we determined that the pioneer transcription factor GATA2, which is frequently amplified in CRPC patients, inhibits interferon (IFN)-ß-mediated antitumor immunity, thereby promoting CRPC progression. Employing a genetically engineered mouse model (GEMM), we demonstrated that GATA2 overexpression hindered castration-induced cell apoptosis and tumor shrinkage, facilitating tumor metastasis and CRPC development. Notably, GATA2 drives castration resistance predominantly via repressing castration-induced activation of IFN-ß signaling and CD8+ T-cell infiltration. This finding aligns with the negative correlation between GATA2 expression and IFNB1 expression, as well as CD8+ T-cell infiltration in CRPC patients. Mechanistically, GATA2 recruited PIAS1 as corepressor, and reprogramed the cistrome of IRF3, a key transcription factor of the IFN-ß axis, in an androgen-independent manner. Furthermore, we identified a novel silencer element that facilitated the function of GATA2 and PIAS1 through looping to the IFNB1 promoter. Importantly, depletion of GATA2 augmented antitumor immunity and attenuated CRPC development. Consequently, our findings elucidate a novel mechanism wherein GATA2 promotes CRPC progression by suppressing IFN-ß axis-mediated antitumor immunity, underscoring GATA2 as a promising therapeutic target for CRPC.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Electron-Phonon Interaction Mediated Gigantic Enhancement of Thermoelectric Power Factor Induced by Topological Phase Transition.

We propose an effective strategy to significantly enhance the thermoelectric power factor (PF) of a series of 2D semimetals and semiconductors by driving them toward a topological phase transition (TPT). Employing first-principles calculations with an explicit consideration of electron-phonon interactions, we analyze the electronic transport properties of germanene across the TPT by applying hydrogenation and biaxial strain. We reveal that the nontrivial semimetal phase, hydrogenated germanene with 8% biaxial strain, achieves a considerable 4-fold PF enhancement, attributed to the highly asymmetric electronic structure and semimetallic nature of the nontrivial phase. We extend the strategy to another two representative 2D materials (stanene and HgSe) and observe a similar trend, with a marked 7-fold and 5-fold increase in PF, respectively. The wide selection of functional groups, universal applicability of biaxial strain, and broad spectrum of 2D semimetals and semiconductors render our approach highly promising for designing novel 2D materials with superior thermoelectric performance.

An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.

First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.

TRPC4 deletion elicits behavioral defects in sociability by dysregulating expression of microRNA-138-2.

To investigate whether the defects in transient receptor potential canonical 4 (TRPC4), which is strongly expressed in the hippocampus, are implicated in ASD, we examined the social behaviors of mice in which Trpc4 was deleted (Trpc4-/-). Trpc4-/- mice displayed the core symptoms of ASD, namely, social disability and repetitive behaviors. In microarray analysis of the hippocampus, microRNA (miR)-138-2, the precursor of miR-138, was upregulated in Trpc4-/- mice. We also found that binding of Matrin3 (MATR3), a selective miR-138-2 binding nuclear protein, to miR-138-2 was prominently enhanced, resulting in the downregulation of miR-138 in Trpc4-/- mice. Some parameters of the social defects and repetitive behaviors in the Trpc4-/- mice were rescued by increased miR-138 levels following miR-138-2 infusion in the hippocampus. Together, these results suggest that Trpc4 regulates some signaling components that oppose the development of social behavioral deficits through miR-138 and provide a potential therapeutic strategy for ASD.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer

Purpose Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. Methods PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. Results In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. Conclusion Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Fulvestrant alleviates cisplatin-induced acute kidney injury via repression of BNIP3-mediated apoptosis and autophagy.

Cisplatin-induced acute kidney injury (AKI) is a clinical disease characterized by a sudden loss of renal function within a few hours or days, due to cisplatin uptake. Fulvestrant is an oestrogen receptor alpha (ERα) antagonist used for endocrine therapy. However, the role of fulvestrant in cisplatin-induced AKI remains unclear. In this study, we investigated the effects of fulvestrant on the regulation of apoptotic cell death and autophagic response in cisplatin-induced AKI. The human kidney proximal tubule epithelial cell line (HK-2) was co-treated with fulvestrant and cisplatin. C57BL/6 mice were subcutaneously injected with fulvestrant and cisplatin was administered via intraperitoneal injection. First, cisplatin treatment increased ERα expression, apoptosis, and autophagy in HK-2 cells. Fulvestrant treatment decreased apoptosis and autophagy, which were accompanied by cisplatin treatment in HK-2 cells. Consistent with in vitro results, cisplatin treatment significantly increased ERα expression in vivo. Additionally, cisplatin treatment increased renal injury, apoptosis, and autophagy. Surprisingly, compared to that in the cisplatin-treated mice group, reduced cisplatin-induced renal injury, apoptosis, and autophagy was observed in the cisplatin+fulvestrant-treated mice group. In summary, these results suggest that fulvestrant plays an important role in cisplatin-induced AKI by decreasing apoptosis and autophagy.

Suspended particulate matter-bound per- and polyfluoroalkyl substances (PFASs) in a river-coastal system: Possible correlation with transparent exopolymer particles.

The transport and ultimate fate of per- and polyfluoroalkyl substances (PFASs) are generally considered to be influenced by partitioning behavior between water, suspended particulate matters (SPM), and sediments. This study examined the distribution and partitioning of the PFASs in the water, SPM, and sediments in a densely populated urban river-coastal system. The total concentrations of eight PFASs (∑8 PFASs) in the water phase, SPM, and sediments varied from 0.59 to 7.40 ng/L, 0.54 to 9.08 ng/g, and 0.05 to 0.13 ng/g, respectively. The PFAS concentrations in the water and SPM phase decreased as the salinity increased, confirming contaminant inputs from the upstream of the river to the estuary zone. Notably, the positive correlation between SPM-bound PFASs and transparent exopolymer particles (TEPs) content, providing first evidence that TEPs may accumulate and concentrate more PFASs on the SPM. Collectively, this results offers useful information about roles of TEPs in determining environmental fate of PFASs.

Humoral and cellular immunity in three different types of COVID-19 vaccines against SARS-CoV-2 variants in a real-world data analysis.

BACKGROUND: An effective vaccine response is currently a critical issue in the control of COVID-19. Little is known about humoral and cellular immunity comparing protein-based vaccine with other types of vaccines. The relevance of basal immunity to antibody production is also unknown. METHODS: Seventy-eight individuals were enrolled in the study. The primary outcome were the level of spike-specific antibodies and neutralizing antibodies measured by ELISA. Secondary measures included memory T cells and basal immunity estimated by flow cytometry and ELISA. Correlations for all parameters were calculated using the nonparametric Spearman correlation method. RESULTS: We observed that two doses of mRNA-based Moderna mRNA-1273 (Moderna) vaccine produced the highest total spike-binding antibody and neutralizing ability against the wild-type (WT), Delta, and Omicron variants. The protein-based MVC-COV1901 (MVC) vaccine developed in Taiwan produced higher spike-binding antibodies against Delta and Omicron variants and neutralizing ability against the WT strain than the adenovirus-based AstraZeneca-Oxford AZD1222 (AZ) vaccine. Moderna and AZ vaccination produced more central memory T cells in PBMC than the MVC vaccine. However, the MVC vaccine had the lowest adverse effects compared to the Moderna and AZ vaccines. Surprisingly, the basal immunity represented by TNF-α, IFN-γ, and IL-2 prior to vaccination was negatively correlated with the production of spike-binding antibodies and neutralizing ability. CONCLUSION: This study compared memory T cells, total spike-binding antibody levels, and neutralizing capacity against WT, Delta, and Omicron variants between the MVC vaccine and the widely used Moderna and AZ vaccines, which provides valuable information for future vaccine development strategies.

Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α.

Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.

Silencing of LLGL2 Suppresses the Estradiol-Induced BPH-1 Cell Proliferation through the Regulation of Autophagy.

Lethal giant larvae (Lgl) is an apical-basal polarity gene first identified in Drosophila. LLGL2 is one of the mammalian homologs of Lgl. However, little is known about its function in the prostate. In this study, to explore the new role of LLGL2 in the prostate, we examined the proliferative activity of a BPH-1 cell line, a well-established model for the human prostate biology of benign prostatic hyperplasia (BPH). The expression of LLGL2 was dose-dependently increased in BPH-1 cells after treatment with 17ß-estradiol (E2). Additionally, E2 treatment increased the proliferation of the BPH-1 cells. However, the knockdown of LLGL2 with siRNA significantly suppressed the proliferation of the E2-treated BPH-1 cells. Moreover, si-llgl2 treatment up-regulated the expression of LC-3B, ATG7, and p-beclin, which are known to play a pivotal role in autophagosome formation in E2-treated BPH-1 cells. Overexpression of LLGL2 was able to further prove these findings by showing the opposite results from the knockdown of LLGL2 in E2-treated BPH-1 cells. Collectively, our results suggest that LLGL2 is closely involved in the proliferation of prostate cells by regulating autophagosome formation. These results provide a better understanding of the mechanism involved in the effect of LLGL2 on prostate cell proliferation. LLGL2 might serve as a potential target in the diagnosis and/or treatment of human BPH.

New insights into the role of marine plastic-gels in microplastic transfer from water to the atmosphere via bubble bursting.

The pervasiveness of microplastics (MPs) in global oceans is raising concerns about their adverse impacts on ecosystems. The mechanistic understanding of MP transport is critical for evaluating its fate, flux, and ecological risks specifically. Currently, bubble bursting is believed to represent an important route for MP transfer from sea surfaces to the atmosphere. However, the detailed mechanisms of the complex physico-chemical interactions between MPs, water composition, and gel particles in the air-sea interface remain unknown. Our results suggested three steps for MP transfer between air-sea phases: (1) MPs incorporating into gel aggregates in the water column; (2) further accumulation of plastic-gel aggregate in the surface layer phase; finally (3) ejection of aggregates from the sea when bubbles of trapped air rise to the surface and burst. The water composition (e.g., high salinity, gel concentration and viscosity) can modulate plastic-gel aggregation and subsequent transport from water to the atmosphere. The possible mechanism may be closely tied to the formation of plastic-gel via cation-linking bridges, thereby enhancing plastic-gel ejection into air. Collectively, this work offers unique insights into the role of marine plastic-gels in determining MP fate and transport, especially at air-sea interfaces. The data also provide a better understanding of the corresponding mechanism that may explain the fates of missing plastics in the ocean.

The extract of Celtis choseniana Nakai alleviates testosterone-induced benign prostatic hyperplasia through inhibiting 5α reductase type 2 and the Akt/NF-κB/AR pathway.

Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.

Autistic-like social deficits in hippocampal MeCP2 knockdown rat models are rescued by ketamine.

Autism or autism spectrum disorder (ASD) is a behavioral syndrome characterized by persistent deficits in social interaction, and repetitive patterns of behavior, interests, or activities. The gene encoding Methyl-CpG binding protein 2 (MeCP2) is one of a few exceptional genes of established causal effect in ASD. Although genetically engineered mice studies may shed light on how MeCP2 loss affects synaptic activity patterns across the whole brain, such studies are not considered practical in ASD patients due to the overall level of impairment, and are technically challenging in mice. For the first time, we show that hippocampal MeCP2 knockdown produces behavioral abnormalities associated with autism-like traits in rats, providing a new strategy to investigate the efficacy of therapeutics in ASD. Ketamine, an N-Methyl-D-aspartate (NMDA) blocker, has been proposed as a possible treatment for autism. Using the MeCP2 knockdown rats in conjunction with a rat model of valproic acid (VPA)-induced ASD, we examined gene expression and ASD behaviors upon ketamine treatment. We report that the core symptoms of autism in MeCP2 knockdown rats with social impairment recovered dramatically following a single treatment with ketamine. [BMB Reports 2022; 55(5): 238-243].

IFIT2-depleted metastatic oral squamous cell carcinoma cells induce muscle atrophy and cancer cachexia in mice.

BACKGROUND: Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is a reported metastasis suppressor in oral squamous cell carcinoma (OSCC). Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2-depleted metastatic OSCC mouse model. METHODS: Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2-depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C-reactive protein (CRP) levels, and survival were assessed. The activation of the IL6/p38 pathway in atrophied muscle was measured. RESULTS: IFIT2-depleted metastatic tumours caused marked body weight loss (-18.2% vs. initial body weight, P < 0.001) and a poor survival rate (P < 0.01). Skeletal muscles were markedly smaller in IFIT2-depleted metastatic tumour-bearing mice (quadriceps: -28.7%, gastrocnemius: -29.4%, and tibialis: -24.3%, all P < 0.001). Tumour-derived circulating granulocyte-macrophage colony-stimulating factor (+772.2-fold, P < 0.05), GROα (+1283.7-fold, P < 0.05), IL6 (+245.8-fold, P < 0.001), IL8 (+616.9-fold, P < 0.001), IL18 (+24-fold, P < 0.05), IP10 (+18.8-fold, P < 0.001), CCL2 (+439.2-fold, P < 0.001), CCL22 (+9.1-fold, P < 0.01) and tumour necrosis factor α (+196.8-fold, P < 0.05) were elevated in IFIT2-depleted metastatic tumour-bearing mice. Murine granulocyte colony-stimulating factor (+61.4-fold, P < 0.001) and IL6 (+110.9-fold, P < 0.01) levels were significantly increased in IFIT2-depleted metastatic tumour-bearing mice. Serum CRP level (+82.1%, P < 0.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (-26.7%, P < 0.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (-81%, P < 0.001) and lean tissue (-21.7%, P < 0.01), which was consistent with the reduced food intake (-19.3%, P < 0.05). Muscle loss was accompanied by a smaller muscle cross-sectional area (-23.3%, P < 0.05). Muscle atrophy of cachectic IFIT2-depleted metastatic tumour-bearing mice (i.v.-shIFIT2 group) was associated with elevated IL6 (+2.7-fold, P < 0.05), phospho-p38 (+2.8-fold, P < 0.05), and atrogin-1 levels (+2.3-fold, P < 0.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium-induced myotube atrophy (+24.6%, P < 0.01). CONCLUSIONS: Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.

Cordycepin prevents and ameliorates experimental autoimmune encephalomyelitis by inhibiting leukocyte infiltration and reducing neuroinflammation.

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease characterized by multifocal perivascular infiltration of immune cells in the central nervous system (CNS). Cordycepin (3'-deoxyadenosine), an adenosine analogue initially extracted from the fungus Cordyceps militarisa, is one of the candidates that has multiple actions. We investigated that cordycepin attenuated the activation of LPS-induced mouse bone marrow-derived dendritic cells (BMDCs) and human monocyte-derived dendritic cells (MoDCs) through the inhibition of the AKT, ERK, NFκB, and ROS pathways and impaired the migration of BMDCs through the downregulation of adhesion molecules and chemokine receptors in vitro. In experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with cordycepin decreased the expression of trafficking factors in the CNS, inhibited the secretion of inflammatory cytokines (IFN-γ, IL-6, TNF-α, and IL-17), and attenuated disease symptoms. A chemokine array indicated that cordycepin treatment reversed the high levels of CCL6, PARRES2, IL-16, CXCL10, and CCL12 in the brain and spinal cord of EAE mice, consistent with the RNA-seq data. Moreover, cordycepin suppressed the release of neuroinflammatory cytokines by activated microglial cells, macrophages, Th17 cells, Tc1 cells, and Th1 cells in vitro. Furthermore, cordycepin treatment exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that cordycepin treatment may not only prevent the occurrence of MS by inhibiting DC activation and migration but also potentially ameliorates the progression of MS by reducing neuroinflammation, which may provide insights into the development of new approaches for the treatment of MS.

Stauntonia hexaphylla Extract Ameliorates Androgenic Alopecia by Inhibiting Androgen Signaling in Testosterone-induced Alopecia Mice.

Background: Stauntonia hexaphylla has been a traditional folk remedy for alleviating fever and providing anti-inflammatory properties. Androgenetic alopecia (AGA) is the most common form mediated by the presence of the dihydrotestosterone (DHT). Objectives: In this study, we evaluated the effects of an extract of S. hexaphylla on AGA models and its mechanisms of action. Methods: We studied S. hexaphylla extract to evaluate 5α-reductase and androgen receptor (AR) levels, apoptosis, and cell proliferation in vitro and in vivo. In addition, paracrine factors for androgenic alopecia, such as transforming growth factor beta-1 (TGF-ß1) and dickkopf-a (DKK-1), were examined. Apoptosis was investigated, and the evaluation of proliferation was examined with cytokeratin 14 (CK-14) and proliferating cell nuclear antigen (PCNA). Results: In human follicular dermal papilla cells, the 5α-reductase and AR were decreased following S. hexaphylla treatment, which reduced the Bax/Bcl-2 ratio. Histologically, the dermal thickness and follicle number were higher in the S. hexaphylla groups compared with the AGA group. In addition, the DHT concentration, 5α-reductase, and AR were decreased, thereby downregulating TGF-ß1 and DKK-1 expression and upregulating cyclin D in S. hexaphylla groups. The numbers of keratinocyte-positive and PCNA-positive cells were increased compared to those in the AGA group. Conclusions: The present study demonstrated that the S. hexaphylla extract ameliorated AGA by inhibiting 5α-reductase and androgen signaling, reducing AGA paracrine factors that induce keratinocyte (KC) proliferation, and inhibition apoptosis and catagen prematuration.

Anti-Melanogenic Activity of Calocedrus formosana Wood Essential Oil and Its Chemical Composition Analysis.

Calocedrus formosana (Cupressaceae) is one of the five precious woods of Taiwan. In this study, we investigated the anti-melanogenic activity of C. formosana wood essential oil (CFEO) and its bioactive components in vitro. Initially, CFEO exhibited strong mushroom tyrosinase activity in the cell-free mushroom tyrosinase assay system with an IC50 value of 2.72 µg/mL. Next, treatment with CFEO significantly as well as dose-dependently reduced a combination of α-melanocyte-stimulating hormone and forskolin (α-MSH-FSK)-induced melanin synthesis in B16-F10 cells. Indeed, 80 µg/mL CFEO completely inhibited melanin production, which is similar to that of control cells. Further studies revealed that treatment with CFEO significantly inhibited melanogenesis regulatory proteins, including TRP-1, TRP-2, and MITF, whereas tyrosinase was unaffected by either α-MSH-FSK or CFEO. In addition, the composition of the CFEO was characterized. The major components of CFEO were α-terpineol (23.47%), shonanic acid (10.45%), terpinen-4-ol (12.23%), thymol (5.3%), piperitone (3.44%), berbenone (2.81%), thujic acid (1.65%), and chaminic acid (0.13%). Among them, shonanic acid (1), thujic acid (2), and chaminic acid (3) were uncommon constitutes in essential oils, which could be the index compounds of CFEO, and the structure of these compounds were confirmed by spectral analysis. Furthermore, we found that thymol is an active ingredient responsible for CFEO's anti-melanogenic activity. Based on these results, we suggest that CFEO or thymol could be a potential candidate for the development of skin whitening products for cosmetic purposes.