Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression.

Pharmacological vitamin C (VC) is a potential natural compound for cancer treatment. However, the mechanism underlying its antitumor effects remains unclear. In this study, we found that pharmacological VC significantly inhibits the mTOR (including mTORC1 and mTORC2) pathway activation and promotes GSK3-FBXW7-mediated Rictor ubiquitination and degradation by increasing the cellular ROS. Moreover, we identified that HMOX1 is a checkpoint for pharmacological-VC-mediated mTOR inactivation, and the deletion of FBXW7 or HMOX1 suppresses the regulation of pharmacological VC on mTOR activation, cell size, cell viability, and autophagy. More importantly, it was observed that the inhibition of mTOR by pharmacological VC supplementation in vivo produces positive therapeutic responses in tumor growth, while HMOX1 deficiency rescues the inhibitory effect of pharmacological VC on tumor growth. These results demonstrate that VC influences cellular activities and tumor growth by inhibiting the mTOR pathway through Rictor and HMOX1, which may have therapeutic potential for cancer treatment.

Effect of Vitamin D Deficiency and Supplementation in Lactation and Early Life on Allergic Airway Inflammation and the Expression of Autophagy-Related Genes in an Ovalbumin Mouse Model.

BACKGROUND AND OBJECTIVE: Vitamin D is involved in various physiological and pathological processes, including inflammation and autophagy. We aimed to investigate the effects of dietary vitamin D deficiency or supplementation initiated in lactation and early life on inflammation and autophagy in an ovalbumin (OVA) mouse model. METHODS: Female BALB/c were fed with vitamin D-deficient, sufficient or supplemented diets throughout lactation and their offspring followed the same diet after weaning. Offspring were then sensitized and challenged with OVA, airway resistance (RL) was measured, and their serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected. Alveolar macrophages (AMs) were isolated from lung tissue and cultured with different concentrations of 1,25(OH)2D3. The expressions of autophagy-related (ATG) proteins including light-chain 3 (LC3), Beclin-1, and ATG5, and NF-κB p65 in lung tissue and AMs were measured. RESULTS: OVA sensitization and challenge induced dramatic allergic airway inflammation and higher RL in the vitamin D-deficient group compared with vitamin D-sufficient or the supplemented group. The expression of ATGs including LC3, Beclin-1, and ATG5, and NF-κB p65 in lung tissue in the vitamin D-deficient OVA-mediated group was increased compared with vitamin D-supplemented OVA-mediated group. There was correlation between the expression of LC3 mRNA and inflammatory cell numbers and cytokines in BALF. In vitro, 1,25(OH)2D3 also regulated the expression of LC3, Beclin-1, ATG5, and NF-κB p65 mRNA in AMs in a time- and dose-dependent manner. CONCLUSION: Deficiency of vitamin D in early life may aggravate allergic airway inflammation, and maintaining sufficient vitamin D during early life is necessary for lung health. Vitamin D may modulate autophagy in lungs of OVA sensitized/challenged mice, thus playing a protective role in OVA-induced allergic airway inflammation.

Aloperine improves osteoporosis in ovariectomized mice by inhibiting RANKL-induced NF-κB, ERK and JNK approaches.

Presently, postmenopausal osteoporosis mainly caused by excessive activation of in vivo osteoclasts has become a global public health burden. Natural compounds have gradually become the potential drugs for the treatment of postmenopausal osteoporosis. Aloperine is a new alkaloid extracted from the leaves and seeds of sophora bean. The current studies have proved that aloperine has many biological activities, including anti-inflammatory, antiviral and anticancer activities. This study shows that aloperine can inhibit activity and formation of osteoclast mediated by RANKL in a dose-dependent manner without affecting the activity of bone marrow macrophages (BMM). In addition, it is found that aloperine can inhibit the expression of osteoclast specific marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), matrix metallopeptidase 9 (MMP9), cathepsin K (Ctsk), V-ATPase d2 and calcitonin receptor. The in vitro experiment of aloperine proved that aloperine can inhibit the degradation of IκBα and the phosphorylation of P65, ERK and JNK. Additionally, aloperine improves bone loss in ovariectomized (OVX) mice by inhibiting osteoclast activity. This project proved that aloperine can affect the formation of osteoclasts by inhibiting RANKL signaling channel, and it is indicated that aloperine has the potential to be developed as a new drug for the prevention and treatment of postmenopausal osteoporosis.

Traditional Chinese medicine symptom normalization approach leveraging hierarchical semantic information and text matching with attention mechanism.

Traditional Chinese medicine (TCM) symptom normalization is difficult because the challenges of the symptoms having different literal descriptions, one-to-many symptom descriptions and different symptoms sharing a similar literal description. We propose a novel two-step approach utilizing hierarchical semantic information that represents the functional characteristics of symptoms and develop a text matching model that integrates hierarchical semantic information with an attention mechanism to solve these problems. In this study, we constructed a symptom normalization dataset and a TCM normalization symptom dictionary containing normalization symptom words, and assigned symptoms into 24 classes of functional characteristics. First, we built a multi-label text classifier to isolate the hierarchical semantic information from each symptom description and count the corresponding normalization symptoms and filter the candidate set. Then we designed a text matching model of mixed multi-granularity language features with an attention mechanism that utilizes the hierarchical semantic information to calculate the matching score between the symptom description and the normalization symptom words. We compared our approach with other baselines on real-world data. Our approach gives the best performance with a Hit@ 1, 3, and 10 of 0.821, 0.953, and 0.993, respectively, and a MeanRank of 1.596, thus outperforming significantly regarding the symptom normalization task. We developed an approach for the TCM symptom normalization task and demonstrated its superior performance compared with other baselines, indicating the promise of this research direction.

Folic Acid-Functionalized Metal-Organic Framework Nanoparticles as Drug Carriers Improved Bufalin Antitumor Activity Against Breast Cancer.

Bufalin (Buf), an active ingredient of the traditional Chinese medicine Chansu, is known to have anticancer effects for breast cancer. However, its poor solubility, high toxicity, and extensive side effects limit its use. Metal-organic frameworks (MOFs) are a class of promising drug delivery systems known for their high porosity. Here, we designed and constructed pH-sensitive and redox-responsive folic acid-modified MOFs as drug carriers of Buf (FA-MOF/Buf). Moreover, the anticancer activity of nanomedicines was also explored in vitro and in vivo. Compared to free Buf, the FA-MOF/Buf nanoparticles demonstrated improved water solubility and stability, higher intracellular uptake, and enhanced cytotoxicity in breast cancer cells in vitro. Furthermore, it displayed improved accumulation in the tumor site, enhanced anticancer activity, and reduced side effects in vivo. Our results demonstrated that FA-MOF could be developed as a potential delivery system for Buf to improve its antitumor activity for breast cancer treatment.

EDTA-Modified 17ß-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis.

Hormone therapy (HT) is one of the most effective treatments for osteoporosis. However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT. Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability. Methods: Herein, a 17ß-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy. EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis. We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging. Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis. Results: The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo. The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h. EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property. The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus. The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group. Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group. Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.

Structural Optimization of Caffeoyl Salicylate Scaffold as NO Production Inhibitors.

Chlorogenic acid (CGA) has been considered as one of important active components in a number of medicinal herbs. Recently our group demonstrated that caffeoyl salicylate scaffold derived from CGA can be employed for the development of novel anti-inflammatory agents. The most active compound D104 can be a very promising starting point for the further structural optimization. A series of novel caffeoyl salicylate analogs were designed, synthesized, and evaluated by preliminary biological evaluation. The obtained results showed that the two compounds B12 and B13 can not only inhibit production of nitric oxide (NO) in RAW264.7 cells induced by lipopolysaccharides (LPS) effectively, but also have high safety in in vitro cytotoxic test, which could be comparable with D104. Molecular docking study on the peroxisome proliferator-activated receptor γ (PPARγ) protein revealed that compounds B12 and B13 can follow the same binding mode with D104, and the carboxyl group of caffeoyl salicylate scaffold might play a key role in the interaction with protein target, which implied the carboxyl group should be retained in the further optimization.

Design, synthesis, and anti-inflammatory activity of caffeoyl salicylate analogs as NO production inhibitors.

Chlorogenic acid (CGA) has been reported to exhibit potent anti-inflammatory activity. However, the development of anti-inflammatory agent based on CGA has not been investigated. In this paper, a series of caffeoyl salicylate compounds derived from CGA were designed, synthesized, and evaluated by LPS-induced nitric oxide synthase inhibition and QRT-PCR technique. Most compounds showed modest activity to inhibit production of nitric oxide (NO) in RAW 264.7 cells induced by lipopolysaccharides (LPS). Among these compounds, QRT-PCR and western blotting results indicated that compounds 6b, 6c, 6f, 6g and D104 that possess 5-member ring or 6-member ring caused a significant inhibition against expression of the iNOS2 in LPS-induced macrophages. In addition, cytotoxic assay displayed most derivatives have good safety in vitro. This new promising scaffold could be further exploited for the development of anti-inflammatory agent in the future.

Elucidation of the Mechanisms of Long-Distance mRNA Movement in a Nicotiana benthamiana/Tomato Heterograft System.

Recent heterograft analyses showed that large-scale messenger RNA (mRNA) movement takes place in the phloem, but the number of mobile transcripts reported varies widely. However, our knowledge of the mechanisms underlying large-scale mRNA movement remains limited. In this study, using a Nicotiana benthamiana/tomato (Solanum lycopersicum) heterograft system and a transgenic approach involving potato (Solanum tuberosum), we found that: (1) the overall mRNA abundance in the leaf is not a good indicator of transcript mobility to the root; (2) increasing the expression levels of nonmobile mRNAs in the companion cells does not promote their mobility; (3) mobile mRNAs undergo degradation during their movement; and (4) some mRNAs arriving in roots move back to shoots. These results indicate that mRNA movement has both regulated and unregulated components. The cellular origins of mobile mRNAs may differ between herbaceous and woody species. Taken together, these findings suggest that the long-distance movement of mRNAs is a complex process and that elucidating the physiological roles associated with this movement is challenging but remains an important task for future research.

EM23, A Natural Sesquiterpene Lactone from Elephantopus mollis, Induces Apoptosis in Human Myeloid Leukemia Cells through Thioredoxin- and Reactive Oxygen Species-Mediated Signaling Pathways.

Elephantopus mollis (EM) is a traditional herbal medicine with multiple pharmacological activities. However, the efficacy of EM in treating human leukemia is currently unknown. In the current study, we report that EM23, a natural sesquiterpene lactone isolated from EM, inhibits the proliferation of human chronic myeloid leukemia (CML) K562 cells and acute myeloid leukemia (AML) HL-60 cells by inducing apoptosis. Translocation of membrane-associated phospholipid phosphatidylserines, changes in cell morphology, activation of caspases, and cleavage of PARP were concomitant with this inhibition. The involvement of the mitochondrial pathway in EM23-mediated apoptosis was suggested by observed disruptions in mitochondrial membrane potential. Mechanistic studies indicated that EM23 caused a marked increase in the level of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine, a ROS scavenger, almost fully reversed EM23-mediated apoptosis. In EM23-treated cells, the expression levels of thioredoxin (Trx) and thioredoxinreductase (TrxR), two components of the Trx system involved in maintaining cellular redox homeostasis, were significantly down-regulated. Concomitantly, Trx regulated the activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream regulatory targets, the p38, JNK, and ERK MAPKs. EM23-mediated activation of ASK1/MAPKs was significantly inhibited in the presence of NAC. Furthermore, tumor necrosis factor alpha (TNF-α)-mediated activation of nuclear factor-κB (NF-κB) was suppressed by EM23, as suggested by the observed blockage of p65 nuclear translocation, phosphorylation, and reversion of IκBα degradation following EM23 treatment. Taken together, these results provide important insights into the anticancer activities of the EM component EM23 against human CML K562 cells and AML HL-60 cells.

Phenolic Compounds from the Flowers of Bombax malabaricum and Their Antioxidant and Antiviral Activities.

Three new phenolic compounds 1-3 and twenty known ones 4-23 were isolated from the flowers of Bombax malabaricum. Their chemical structures were elucidated by spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, 1D- and 2D-NMR) and chemical reactions. The antioxidant capacities of the isolated compounds were tested using FRAP and DPPH radical-scavenging assays, and compounds 4, 6, 8, 12, as well as the new compound 2, exhibited stronger antioxidant activities than ascorbic acid. Furthermore, all of compounds were tested for their antiviral activities against RSV by the CPE reduction assay and plaque reduction assay. Compounds 4, 10, 12 possess in vitro antiviral activities, and compound 10 exhibits potent anti-RSV effects, comparable to the positive control ribavirin.

Effect of xanthone derivatives on animal models of depression.

BACKGROUND: Extracts of the plant Hypericum perforatum L. have been traditionally used in folk medicine for the treatment of depressive disorders. Xanthone, a component of Hypericum perforatum L., has been shown to be effective in animal models of depression. OBJECTIVE: We investigated if 2 xanthone derivatives (1101 and 1105) were as effective as venlafaxine, which is a serotonin-norepinephrine reuptake inhibitor and was used as a positive control, in animal models of depression. METHODS: A series of derivatives from xanthone were designed and synthesized. After preliminary experiments, 2 xanthone derivatives (1101 and 1105) were considered to be effective in our mouse depression model. To further determine their effects on depression, classical behavioral despair animal models (forced swim and tail suspension tests) were used to assess the efficacies of these derivatives, whereas venlafaxine hydrochloride was used as a positive control. Oral acute toxicity studies were used to determine if the derivatives were toxic in mice. RESULTS: The oral acute toxicity studies of 2 xanthone derivatives (1101 and 1105) did not show any toxic effect until the dose at 1000 mg/kg body weight, and xanthone derivatives 1101 and 1105 resulted in a significant decrease of the immobility period (in seconds) compared with the untreated control group during the forced swim test with rats (dose = 12 mg/kg; P < 0.05) and mice (dose = 25 mg/kg; P < 0.001). At lower doses, derivatives 1101 and 1105 also decreased the immobility period of rats and mice during the forced swim test but significant differences were only found in mice compared with the untreated control group (P < 0.05). No difference was found between the groups treated with xanthone derivatives and the positive control group during the swimming period in both mice (dose = 25 mg/kg) and rats (dose = 12 mg/kg) (P > 0.05). In the tail suspension test, derivatives 1101 and 1105 produced marked effects with regard to the motion of mice (P < 0.01 or 0.001, respectively) and the derivatives were also noted to have some effects on rats at a dose of 12 mg/kg (P < 0.05). Compared with the positive venlafaxine control group, no differences were found between those treated with either derivative 1101 or derivative 1105 and venlafaxine (P > 0.05). CONCLUSIONS: Within certain dose ranges, xanthone derivatives 1101 and 1105 have similar effects to venlafaxine hydrochloride in the treatment of depression as suggested by behavioral despair animal models using rats and mice.

[Effect of Dendrobium officinale granule on long-term-alcohol-induced hypertension rats].

OBJECTIVE: To observe the effect of Dendrobium officinale granule (DOG) on symptoms, blood pressure and serum biochemical indexes of long-term-alcohol-induced hypertension rats. METHOD: The alcohol-induced hypertension rat model was established by feeding alcohol drink to normal rats (the alcohol volume fraction increases from 5% to 22%). Since the 4th week, DOG was administered for 32 weeks, once everyday. During the experiment, body weight, kinematic parameters (locomotor activities, grip strength, duration of vertigo) and blood pressures (systolic blood pressure, diastolic blood pressure and mean blood pressure) were detected regularly. On the 28th and 32nd weeks, blood samples were collected to determine serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), uric acid (UA), creatinine (Cr), cholesterol (CH) and triglycerides (TG). RESULT: (1) Sign: The DOG-administered group showed reduction in the duration of vertigo and increase in appetite, body weight, locomotor activities and grip strength. (2) Blood pressure: The DOG-administered group showed significant decrease in blood pressure since the 8th week. (3) Biochemical indexes: The DOG-administered group showed notable decrease in serum ALT, AST, ALP, Cr, UA, TG level, but without significant change in TC level. CONCLUSION: The long-term administration of DOG can relieve alcohol-induced hypertension, while alleviating general signs, liver and kidney injuries and abnormal blood fat biochemical indexes.

The XIA's No. 1 sleeping Prescription for the treatment of insomnia of the deficiency type: a clinical observation of 60 cases.

OBJECTIVE: To evaluate the therapeutic effects and safety of the XIA's No.1 Sleeping Prescription for the treatment of insomnia of the deficiency type. METHODS: 120 cases conformed to the diagnostic criteria of the Chinese Classification of Mental Disorders-Version 3 (CCMD-3) and were diagnosed as having insomnia of the deficiency type were divided randomly into a treatment group and a control group, 60 cases in each group. The treatment group was treated with the XIA's No. 1 Sleeping Prescription, while the control group was given estazolam (1 mg) for 6 weeks. The Athens Insomnia Scale (AIS) was used to evaluate the clinical therapeutic effects, while the treatment emergent symptom scale (TESS) was used to evaluate adverse reactions. RESULTS: The total effective rate of the treatment group (80%) was higher than that of the control group (70%), but with no significant difference (P > 0.05). The effective rate for long-term insomnia was 77.8% in the treatment group and 52.4% in the control group, with a significant difference between the two groups (P < 0.05). The adverse reactions shown in the treatment group were obviously fewer and milder than those in the control group. CONCLUSION: The XIA's No. 1 Sleeping Prescription is effective for insomnia of the deficiency type and with no obvious toxic side effects.