Differential genotoxicity of Polygoni Multiflori in rat and human: insights from Ames test and S9 metabolic activation system.

The Ames test is used worldwide to initially screen the mutagenic potential of new chemicals. In the standard Ames test, S. typhimurium strains (TA100, TA98, TA1535, and TA1537) and Escherichia coli (WP2uvrA) are treated with substances with/without cytochrome P450s (CYPs)-induced rat S9 fractions for identifying mutagens and pro-mutagens. However, many substances show completely different toxicity patterns depending on whether the liver S9 fraction belongs to rats or humans. The natural product Polygoni Multiflori Radix (PMR) can also show bacterial reverse mutation, followed by the rat or human liver S9 fraction. While PMR elicits reverse mutations in the TA1537 strain in rat liver S9 but not in human liver S9, this mechanism has not been verified yet. To explain this, the differences in metabolic enzymes compositions commonly observed between rats and humans have been implicated. This study aimed to explore the key factors that cause differences in the genotoxicity of PMR between rat and human liver S9 metabolic enzymes. The results of next-generation sequencing (NGS) analysis showed that both rat and human metabolic enzymes caused similar mutations in TA1537. However, when the metabolic enzymes in each S9 fraction were analyzed using ion mobility tandem mass spectrometry (IM-MS), rat- and human-specific enzymes were identified among the cytochrome (CYP) family, especially aryl hydrocarbon receptor (AHR)-related CYPs. These findings suggest that CYP1A1 isoforms contribute to the mechanism of PMR in the Ames test. Therefore, an in vitro Ames test might be more reliable in predicting genotoxicity for both rodents and humans. This will also help overcome the limitations of laboratory animal-based toxicity evaluations, which provide unreliable results due to interspecies differences between humans and rodents.

Novel insights into regulators and functional modulators of adipogenesis.

Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.

Bee (Apis mellifera L. 1758) wax restores adipogenesis and lipid accumulation of 3T3-L1 cells in cancer-associated cachexia condition.

Cachexia is associated with various diseases, such as heart disease, infectious disease, and cancer. In particular, cancer-associated cachexia (CAC) accounts for more than 20% of mortality in cancer patients worldwide. Adipose tissue in CAC is characterized by adipocyte atrophy, mainly due to excessively increased lipolysis and impairment of adipogenesis. CAC is well known for the loss of skeletal muscle mass and/or fat mass. CAC induces severe metabolic alterations, including protein, lipid, and carbohydrate metabolism. The objectives of this study were to evaluate the effects of bee wax (Apis mellifera L. 1758) (BW) extract on adipogenesis, lipolysis, and mitochondrial oxygen consumption through white adipocytes, 3T3-L1. To achieve this study, cancer-associated cachexia condition was established by incubation of 3T3-L1 with colon cancer cell line CT26 cultured media. BW extract recovered the reduced adipogenesis under cachectic conditions in CT26 media. Treatment of BW showed increasing lipid accumulation as well as adipogenic gene expression and its target gene during adipogenesis. The administration of BW to adipocytes could decrease lipolysis. Also, BW could significantly downregulated the mitochondrial fatty acid oxidation-related genes, oxygen consumption rate, and extracellular acidification rate. Our results suggest that BW could improve metabolic disorders such as CAC through the activation of adipogenesis and inhibition of lipolysis in adipocytes, although we need further validation in vivo CAC model to check the effects of BW extract. Therefore, BW extract supplements could be useful as an alternative medicine to reverse energy imbalances.

Multilevel Conductance States of Vapor-Transport-Deposited Sb2S3 Memristors Achieved via Electrical and Optical Modulation.

The pursuit of advanced brain-inspired electronic devices and memory technologies has led to explore novel materials by processing multimodal and multilevel tailored conductive properties as the next generation of semiconductor platforms, due to von Neumann architecture limits. Among such materials, antimony sulfide (Sb2S3) thin films exhibit outstanding optical and electronic properties, and therefore, they are ideal for applications such as thin-film solar cells and nonvolatile memory systems. This study investigates the conduction modulation and memory functionalities of Sb2S3 thin films deposited via the vapor transport deposition technique. Experimental results indicate that the Ag/Sb2S3/Pt device possesses properties suitable for memory applications, including low operational voltages, robust endurance, and reliable switching behavior. Further, the reproducibility and stability of these properties across different device batches validate the reliability of these devices for practical implementation. Moreover, Sb2S3-based memristors exhibit artificial neuroplasticity with prolonged stability, promising considerable advancements in neuromorphic computing. Leveraging the photosensitivity of Sb2S3 enables the Ag/Sb2S3/Pt device to exhibit significant low operating potential and conductivity modulation under optical stimulation for memory applications. This research highlights the potential applications of Sb2S3 in future memory devices and optoelectronics and in shaping electronics with versatility.

Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated ß-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Gonadal efficacy of Thymus quinquecostatus Celakovski: Regulation of testosterone levels in aging mouse models.

Late-onset hypogonadism (LOH) is an age-related disease in men characterized by decreased testosterone levels with symptoms such as decreased libido, erectile dysfunction, and depression. Thymus quinquecostatus Celakovski (TQC) is a plant used as a volatile oil in traditional medicine, and its bioactive compounds have anti-inflammatory potential. Based on this knowledge, the present study aimed to investigate the effects of TQC extract (TE) on LOH in TM3 Leydig cells and in an in vivo aging mouse model. The aqueous extract of T. quinquecostatus Celakovski (12.5, 25, and 50 µg/mL concentrations) was used to measure parameters such as cell viability, testosterone level, body weight, and gene expression, via in vivo studies. Interestingly, TE increased testosterone levels in TM3 cells in a dose-dependent manner without affecting cell viability. Furthermore, TE significantly increased the expression of genes involved in the cytochrome P450 family (Cyp11a1, Cyp17a1, Cyp19a1, and Srd5a2), which regulate testosterone biosynthesis. In aging mouse models, TE increased testosterone levels without affecting body weight and testicular tissue weight tissue of an aging animal group. In addition, the high-dose TE-treated group (50 mg/kg) showed significantly increased expression of the cytochrome p450 enzymes, similar to the in vitro results. Furthermore, HPLC-MS analysis confirmed the presence of caffeic acid and rosmarinic acid as bioactive compounds in TE. Thus, the results obtained in the present study confirmed that TQC and its bioactive compounds can be used for LOH treatment to enhance testosterone production.

α-Klotho levels in girls with central precocious puberty: potential as a diagnostic and monitoring marker.

Background: Recent studies suggest a link between the Klotho protein, sex hormones, and insulin-like growth factor-1 (IGF-1), indicating that α-Klotho levels may rise during puberty, including in central precocious puberty (CPP) cases. This study aimed to explore α-Klotho levels in girls with CPP to assess its potential as a diagnostic and monitoring tool for this condition. Methods: In total, 139 girls, comprising 82 patients diagnosed with CPP and 57 healthy prepubertal controls, were enrolled in this study. From March 2020 to May 2023, we assessed both α-Klotho levels and clinical parameters. α-Klotho concentrations were measured using an α-Klotho ELISA kit. For the girls with CPP, we additionally analyzed samples taken 6 months after GnRH agonist treatment. Results: α-Klotho levels were higher in the CPP group compared with the control (CPP group: 2529 ± 999 ng/mL; control group: 1802 ± 675 pg/mL) (P < 0.001), and its level modest decreased after 6 months of GnRH agonist treatment (2147± 789 pg/mL) (P < 0.001). The association between α-Klotho and IGF-1 SDS, follicular stimulating hormone and baseline luteinizing hormone was assessed by partial correlation after adjusting for age, BMI SDS (r= 0.416, p= <0.001; r= 0.261, p= 0.005; r= 0.278, p= 0.002), respectively. Receiver operating characteristic curve analysis identified an α-Klotho cut-off differentiating CPP from controls, with a cut-off of 1914 pg/mL distinguishing girls with CPP from controls with a sensitivity of 69.5% and specificity of 70.2%; the area under the curve was 0.723. Conclusion: The findings of our study are the first step towards deciphering the role of α-Klotho in puberty induction. With additional data and further research, α-Klotho could potentially be utilized as a significant diagnostic and monitoring tool for CPP.

Artificial intelligence-based speckle featurization and localization for ultrasound speckle tracking velocimetry.

Deep learning-based super-resolution ultrasound (DL-SRU) framework has been successful in improving spatial resolution and measuring the velocity field information of a blood flows by localizing and tracking speckle signals of red blood cells (RBCs) without using any contrast agents. However, DL-SRU can localize only a small part of the speckle signals of blood flow owing to ambiguity problems encountered in the classification of blood flow signals from ultrasound B-mode images and the building up of suitable datasets required for training artificial neural networks, as well as the structural limitations of the neural network itself. An artificial intelligence-based speckle featurization and localization (AI-SFL) framework is proposed in this study. It includes a machine learning-based algorithm for classifying blood flow signals from ultrasound B-mode images, dimensionality reduction for featurizing speckle patterns of the classified blood flow signals by approximating them with quantitative values. A novel and robust neural network (ResSU-net) is trained using the online data generation (ODG) method and the extracted speckle features. The super-resolution performance of the proposed AI-SFL and ODG method is evaluated and compared with the results of previous U-net and conventional data augmentation methods under in silico conditions. The predicted locations of RBCs by the AI-SFL and DL-SRU for speckle patterns of blood flow are applied to a PTV algorithm to measure quantitative velocity fields of the flow. Finally, the feasibility of the proposed AI-SFL framework for measuring real blood flows is verified under in vivo conditions.

Chondroprotective effects of Protaetia brevitarsis seulensis larvae as an edible insect on osteoarthritis in mice.

Osteoarthritis (OA) is a common chronic joint inflammatory disease characterized by progressive destruction of the articular cartilage, bone remodeling, and excessive chronic pain. Most therapeutic approaches do not rescue the progression of OA effectively or provide relief of symptoms. Protaetia brevitarsis seulensis larva (PBSL), which is attracting attention, is an edible insect with very high nutritional value and herbal medicine for the treatment of blood stasis, hepatic disease, and various inflammatory diseases. However, the effect of PBSL on OA has not yet been investigated. This study aimed to demonstrate the effects of PBSL water extract on the progression of OA using monosodium iodoacetate (MIA)-induced mice and SW1353 chondrocytes or murine macrophages. We injected MIA into the intraarticular area of mice following pretreatment with either saline or PBSL (200 mg/kg) for 2 weeks, and then locomotor activity, microcomputed tomography and histopathological analysis, quantitative reverse transcriptase-polymerase chain reaction analysis, and western blot analysis were performed. To determine the molecular effects of PBSL, we used interleukin-1ß (IL-1ß)-induced SW1353 chondrosarcoma or lipopolysaccharide (LPS)-stimulated macrophages. Pretreatment with PBSL diminished the symptoms of OA. Physical activity, articular cartilage damage, and the generation of microfractures were rescued by pretreatment with PBSL in the mouse model. Pretreatment with PBSL suppressed the progress of OA through the regulation of articular cartilage degradation genes and inflammation in both in vivo and in vitro models. Our results demonstrated that PBSL has value as edible insect that can be used in the development of functional foods for OA.

Enhanced Performance of Inverted Perovskite Quantum Dot Light-Emitting Diode Using Electron Suppression Layer and Surface Morphology Control.

The energy level offset at inorganic layer-organic layer interfaces and the mismatch of hole/electron mobilities of the individual layers greatly limit the establishment of balanced charge carrier injection inside the emissive layer of halide perovskite light-emitting diodes (PeQLEDs). In contrast with other types of light-emitting devices, namely OLEDs and QLEDs, various techniques such as inserting an electron suppression layer between the emissive and electron transport layer have been employed as a means of establishing charge carrier injection into their respective emissive layers. Hence, in this study, we report the use of a thin layer of Poly(4-vinylpyridine) (PVPy) (an electron suppression material) placed between the emissive and electron transport layer of a halide PeQLEDs fabricated with an inverted configuration. With ZnO as the electron transport material, devices fabricated with a thin PVPy interlayer between the ZnO ETL and CsPbBr3 -based green QDs emissive layer yielded a 4.5-fold increase in the maximum observed luminance and about a 10-fold increase in external quantum efficiency (EQE) when compared to ones fabricated without PVPy. Furthermore, the concentration and coating process conditions of CsPbBr3 QDs were altered to produce various thicknesses and film properties which resulted in improved EQE values for devices fabricated with QDs thin films of lower surface root-mean-square (RMS) values. These results show that inhibiting the excessive injection of electrons and adjusting QDs layer thickness in perovskite-inverted QLEDs is an effective way to improve device luminescence and efficiency, thereby improving the carrier injection balance.

NFAT1 and NFκB regulates expression of the common γ-chain cytokine receptor in activated T cells.

INTRODUCTION: Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood. OBJECTIVE: This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation. METHODS: The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling. RESULTS: We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis. CONCLUSION: Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies. Video Abstract.

Camellia sinensis (L.) Kuntze Extract Attenuates Ovalbumin-Induced Allergic Asthma by Regulating Airway Inflammation and Mucus Hypersecretion.

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production.

Drug delivery by sonosensitive liposome and microbubble with acoustic-lens attached ultrasound: an in vivo feasibility study in a murine melanoma model.

Conventional chemotherapy methods have adverse off-target effects and low therapeutic efficiencies of drug release in target tumors. In this study, we proposed a combination therapy of doxorubicin (DOX)-loaded ultrasound (US)-sensitive liposomal nanocarriers (IMP301), microbubbles (MBs) under focused US exposure using convex acoustic lens-attached US (LENS) to tumor treatment. The therapeutic effects of each treatment in a murine melanoma model were evaluated using contrast-enhanced US (CEUS) and micro-computed tomography (micro-CT) imaging, bioluminescence and confocal microscopy imaging, and liquid chromatography-mass spectroscopy (LC/MS) analysis. Tumor-bearing mice were randomly assigned to one of the following groups: (1) G1: IMP301 only (n = 9); (2) G2: IMP301 + LENS (n = 9); (3) G3: IMP301 + MB + LENS (n = 9); (4) G4: DOXIL only (n = 9); and (5) G5: IMP301 without DOXIL group as a control group (n = 4). Ten days after tumor injection, tumor-bearing mice were treated according to each treatment strategy on 10th, 12th, and 14th days from the day of tumor injection. The CEUS images of the tumors in the murine melanoma model clearly showed increased echo signal intensity from MBs as resonant US scattering. The relative tumor volume of the G2 and G3 groups on the micro-CT imaging showed inhibited tumor growth than the reference baseline of the G5 group. DOX signals on bioluminescence and confocal microscopy imaging were mainly located at the tumor sites. LC/MS showed prominently higher intratumoral DOX concentration in the G3 group than in other treated groups. Therefore, this study effectively demonstrates the feasibility of the synergistic combination of IMP301, MBs, and LENS-application for tumor-targeted treatment. Thus, this study can enable efficient tumor-targeted treatment by combining therapy such as IMP301 + MBs + LENS-application.

A novel convex acoustic lens-attached ultrasound drug delivery system and its testing in a murine melanoma subcutaneous model.

Target-specific drug release is indispensable to improve chemotherapeutic efficacy as it enhances drug uptake and penetration into tumors. Sono-responsive drug-loaded nano-/micro-particles are a promising solution for achieving target specificity by exposing them to ultrasound near tumors. However, the complicated synthetic processes and limited ultrasound (US) exposure conditions, such as limited control of ultrasound focal depth and acoustic power, prevent the practical application of this approach in clinical practice. Here, we propose a convex acoustic lens-attached US (CALUS) as a simple, economic, and efficient alternative of focused US for drug delivery system (DDS) application. The CALUS was characterized both numerically and experimentally using a hydrophone. In vitro, microbubbles (MBs) inside microfluidic channels were destroyed using the CALUS with various acoustic parameters (acoustic pressure [P], pulse repetition frequency [PRF], and duty cycle) and flow velocity. In vivo, tumor inhibition was evaluated using melanoma-bearing mice by characterizing tumor growth rate, animal weight, and intratumoral drug concentration with/without CALUS DDS. US beams were measured to be efficiently converged by CALUS, which was consistent with our simulation results. The acoustic parameters were optimized through the CALUS-induced MB destruction test (P = 2.34 MPa, PRF = 100 kHz, and duty cycle = 9%); this optimal parameter combination successfully induced MB destruction inside the microfluidic channel with an average flow velocity of up to 9.6 cm/s. The CALUS also enhanced the therapeutic effects of an antitumor drug (doxorubicin) in vivo in a murine melanoma model. The combination of the doxorubicin and the CALUS inhibited tumor growth by âˆ¼ 55% more than doxorubicin alone, clearly indicating synergistic antitumor efficacy. Our tumor growth inhibition performance was better than other methods based on drug carriers, even without a time-consuming and complicated chemical synthesis process. This result suggests that our novel, simple, economic, and efficient target-specific DDS may offer a transition from preclinical research to clinical trials and a potential treatment approach for patient-centered healthcare.

Sonothrombolysis with an acoustic net-assisted boiling histotripsy: A proof-of-concept study.

Whilst sonothrombolysis is a promising and noninvasive ultrasound technique for treating blood clots, bleeding caused by thrombolytic agents used for dissolving clots and potential obstruction of blood flow by detached clots (i.e., embolus) are the major limitations of the current approach. In the present study, a new sonothrombolysis method is proposed for treating embolus without the use of thrombolytic drugs. Our proposed method involves (a) generating a spatially localised acoustic radiation force in a blood vessel against the blood flow to trap moving blood clots (i.e., generation of an acoustic net), (b) producing acoustic cavitation to mechanically destroy the trapped embolus, and (c) acoustically monitoring the trapping and mechanical fractionation processes. Three different ultrasound transducers with different purposes were employed in the proposed method: (1) 1-MHz dual focused ultrasound (dFUS) transducers for capturing moving blood clots, (2) a 2-MHz High Intensity Focused Ultrasound (HIFU) source for fractionating blood clots and (3) a passive acoustic emission detector with broad bandwidth (10 kHz to 20 MHz) for receiving and analysing acoustic waves scattered from a trapped embolus and acoustic cavitation. To demonstrate the feasibility of the proposed method, in vitro experiments with an optically transparent blood vessel-mimicking phantom filled with a blood mimicking fluid and a blood clot (1.2 to 5 mm in diameter) were performed with varying the dFUS and HIFU exposure conditions under various flow conditions (from 1.77 to 6.19 cm/s). A high-speed camera was used to observe the production of acoustic fields, acoustic cavitation formation and blood clot fragmentation within a blood vessel by the proposed method. Numerical simulations of acoustic and temperature fields generated under a given exposure condition were also conducted to further interpret experimental results on the proposed sonothrombolysis. Our results clearly showed that fringe pattern-like acoustic pressure fields (fringe width of 1 mm) produced in a blood vessel by the dFUS captured an embolus (1.2 to 5 mm in diameter) at the flow velocity up to 6.19 cm/s. This was likely to be due to the greater magnitude of the dFUS-induced acoustic radiation force exerted on an embolus in the opposite direction to the flow in a blood vessel than that of the drag force produced by the flow. The acoustically trapped embolus was then mechanically destructed into small pieces of debris (18 to 60 µm sized residual fragments) by the HIFU-induced strong cavitation without damaging the blood vessel walls. We also observed that acoustic emissions emitted from a blood clot captured by the dFUS and cavitation produced by the HIFU were clearly distinguished in the frequency domain. Taken together, these results can suggest that our proposed sonothrombolysis method could be used as a promising tool for treating thrombosis and embolism through capturing and destroying blood clots effectively.

Understanding the relationship between cancer associated cachexia and hypoxia-inducible factor-1.

Cancer-associated cachexia (CAC) is a multifactorial disorder characterized by an unrestricted loss of body weight as a result of muscle and adipose tissue atrophy. Cachexia is influenced by several factors, including decreased metabolic activity and food intake, an imbalance between energy uptake and expenditure, excessive catabolism, and inflammation. Cachexia is highly associated with all types of cancers responsible for more than half of cancer-related mortalities worldwide. In healthy individuals, adipose tissue significantly regulates energy balance and glucose homeostasis. However, in metastatic cancer patients, CAC occurs mainly because of an imbalance between muscle protein synthesis and degradation which are organized by certain extracellular ligands and associated signaling pathways. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1α) accumulated and translocated to the nucleus and activate numerous genes involved in cell survival, invasion, angiogenesis, metastasis, metabolic reprogramming, and cancer stemness. On the other hand, the ubiquitination proteasome pathway is inhibited during low O2 levels which promote muscle wasting in cancer patients. Therefore, understanding the mechanism of the HIF-1 pathway and its metabolic adaptation to biomolecules is important for developing a novel therapeutic method for cancer and cachexia therapy. Even though many HIF inhibitors are already in a clinical trial, their mechanism of action remains unknown. With this background, this review summarizes the basic concepts of cachexia, the role of inflammatory cytokines, pathways connected with cachexia with special reference to the HIF-1 pathway and its regulation, metabolic changes, and inhibitors of HIFs.

Unlocking Prognostic Genes and Multi-Targeted Therapeutic Bioactives from Herbal Medicines to Combat Cancer-Associated Cachexia: A Transcriptomics and Network Pharmacology Approach.

Cachexia is a devastating fat tissue and muscle wasting syndrome associated with every major chronic illness, including cancer, chronic obstructive pulmonary disease, kidney disease, AIDS, and heart failure. Despite two decades of intense research, cachexia remains under-recognized by oncologists. While numerous drug candidates have been proposed for cachexia treatment, none have achieved clinical success. Only a few drugs are approved by the FDA for cachexia therapy, but a very low success rate is observed among patients. Currently, the identification of drugs from herbal medicines is a frontier research area for many diseases. In this milieu, network pharmacology, transcriptomics, cheminformatics, and molecular docking approaches were used to identify potential bioactive compounds from herbal medicines for the treatment of cancer-related cachexia. The network pharmacology approach is used to select the 32 unique genes from 238 genes involved in cachexia-related pathways, which are targeted by 34 phytocompounds identified from 12 different herbal medicines used for the treatment of muscle wasting in many countries. Gene expression profiling and functional enrichment analysis are applied to decipher the role of unique genes in cancer-associated cachexia pathways. In addition, the pharmacological properties and molecular interactions of the phytocompounds were analyzed to find the target compounds for cachexia therapy. Altogether, combined omics and network pharmacology approaches were used in the current study to untangle the complex prognostic genes involved in cachexia and phytocompounds with anti-cachectic efficacy. However, further functional and experimental validations are required to confirm the efficacy of these phytocompounds as commercial drug candidates for cancer-associated cachexia.

Hematopoietic Effects of Angelica gigas Nakai Extract on Cyclophosphamide-Induced Myelosuppression.

Myelosuppression is a major adverse effect of chemotherapy. With the increasing number of cancer patients worldwide, there is a growing interest in therapeutic approaches that reduce the adverse effects of chemotherapy. Angelica gigas Nakai (AGN) roots have been widely used in oriental medicine to treat blood-related diseases, including cancer. However, the effects of AGN on myelosuppression have not been studied. Here, we investigated the effects of AGN ethanol extract (AGNEX) on cyclophosphamide-induced myelosuppression. AGNEX treatment significantly decreased white blood cell levels while increasing red blood cell and platelet levels in the peripheral blood. It inhibited thymus and spleen atrophy. It also enhanced serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. qRT-PCR results showed that AGNEX decreased the expression of IL-1b and stem cell factor (SCF) in the bone marrow (BM) while increasing the mRNA expression of IL-3 and IL-6 in the spleen. Although AGNEX did not significantly decrease apoptosis and cell cycle arrest in the BM and splenocytes, AGNEX plays a positive role in cyclophosphamide-induced myelosuppression. AGNEX administration increased BM cells in the femur while decreasing apoptotic BM cells. These findings suggest that AGNEX could be used to treat myelosuppression and as a combination therapy in cancer patients.

Evaluation of Marker Compounds and Biological Activity of In Vitro Regenerated and Commercial Rehmannia glutinosa (Gaertn.) DC. Roots Subjected to Steam Processing.

Rehmannia glutinosa (Gaertn.) DC., belonging to the family Scrophulariaceae, has been known since immemorial times as a prominent oriental drug in East Asia that can treat various ailments, such as kidney disorders, anemia, and diabetes. In order to be applied for medical purposes, R. glutinosa is commonly processed using steam to increase its efficacy and biological activity. The increasing demand for R. glutinosa in the traditional medicine industry encouraged many researchers to develop a fast, efficient, and high-quality production system using biotechnological approaches. This study aimed to compare the chemical and biological activities of in vitro regenerated R. glutinosa (PKR) and commercial R. glutinosa (PCR) samples subjected to steam processing. We assessed the effects of steam processing and the differences in R. glutinosa material on 5-Hydroxymethyl-2-furaldehyde (5-HMF) content, total flavonoid and phenolic content, antioxidant activity, nitric oxide (NO) levels, and anti-inflammatory activity. PKR samples showed a significantly higher content of 5-HMF (0.15%) as compared to PCR samples (0.05%). Compared to unprocessed R. glutinosa (UPR) and PCR samples, PKR again showed the highest total phenolic and flavonoid content of 41.578 mg GAE/g and 17.208 mg RUE/g, respectively. Meanwhile, both processed R. glutinosa samples (PKR and PCR) showed a significantly higher DPPH antioxidant activity ((67.095 + 1.005)% and (61.579 + 0.907)%, respectively) than unprocessed R. glutinosa ((31.452 + 1.371)%). In addition, both PKR and PCR samples showed good anti-inflammatory activity by showing similar effects such as the inhibition of NO production and the suppression of inducible nitric oxide synthase (iNOS). Based on these results, PKR fulfilled the Chinese pharmacopeia standards, in terms of the amount of the marker compounds and showed a high level of bioactivity. Therefore, these findings are expected to be useful in verifying the efficacy of herbal medicines and the availability of suitable materials for medicinal use.