A novel tumor microenvironment-related gene signature with immune features for prognosis of lung squamous cell carcinoma.

PURPOSE: Lung squamous cell carcinoma (LUSC) is an aggressive subset of non-small-cell lung cancer (NSCLC). The tumor microenvironment (TME) plays an important role in the development of LUSC. We aim to identify potential therapeutic targets and a TME-related prognostic signature and for LUSC. METHODS: TME-related genes were obtained from TCGA-LUSC dataset. LUSC samples were clustered by the non-negative matrix clustering algorithm (NMF). The prognostic signature was constructed through univariate Cox regression, multivariate Cox regression, and the least absolute shrinkage and selection operator (LASSO) analyses. Gene set enrichment analysis (GSEA) was carried out to explore the enrichment pathways. RESULTS: This study constructed a prognostic signature which contained 12 genes: HHIPL2, PLK4, SLC6A4, LSM1, TSLP, P4HA1, AMH, CLDN5, NRTN, CDH2, PTGIS, and STX1A. Patients were classified into high-risk and low-risk groups according to the median risk score of this signature. Compared with low-risk group patients, patients in high-risk group patients had poorer overall survival, which demonstrated this signature was an independent prognostic factor. Besides, correlation analysis and GSEA results revealed that genes of this signature were correlated with immune cells and drug response. CONCLUSION: Our novel signature based on 12 TME-related genes might be applied as an independent prognostic indicator. Importantly, the signature could be a promising biomarker and accurately predict the prognosis of LUSC patients.

Arabidopsis mRNA decay landscape shaped by XRN 5'-3' exoribonucleases.

5'-3' exoribonucleases (XRNs) play crucial roles in the control of RNA processing, quality, and quantity in eukaryotes. Although genome-wide profiling of RNA decay fragments is now feasible, how XRNs shape the plant mRNA degradome remains elusive. Here, we profiled and analyzed the RNA degradomes of Arabidopsis wild-type and mutant plants with defects in XRN activity. Deficiency of nuclear XRN3 or cytoplasmic XRN4 activity but not nuclear XRN2 activity greatly altered Arabidopsis mRNA decay profiles. Short excised linear introns and cleaved pre-mRNA fragments downstream of polyadenylation sites were polyadenylated and stabilized in the xrn3 mutant, demonstrating the unique function of XRN3 in the removal of cleavage remnants from pre-mRNA processing. Further analysis of stabilized XRN3 substrates confirmed that pre-mRNA 3' end cleavage frequently occurs after adenosine. The most abundant decay intermediates in wild-type plants include not only the primary substrates of XRN4 but also the products of XRN4-mediated cytoplasmic decay. An increase in decay intermediates with 5' ends upstream of a consensus motif in the xrn4 mutant suggests that there is an endonucleolytic cleavage mechanism targeting the 3' untranslated regions of many Arabidopsis mRNAs. However, analysis of decay fragments in the xrn4 mutant indicated that, except for microRNA-directed slicing, endonucleolytic cleavage events in the coding sequence rarely result in major decay intermediates. Together, these findings reveal the major substrates and products of nuclear and cytoplasmic XRNs along Arabidopsis transcripts and provide a basis for precise interpretation of RNA degradome data.

Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

The ecological clusters of soil organisms drive the ecosystem multifunctionality under long-term fertilization.

Long-term fertilization is known to impact the biodiversity and community structures of soil organisms, which are responsible for multiple soil ecosystem functions (multifunctionality). However the relationship between the alterations of soil organisms and ecosystem multifunctionality remains unclear, especially in the case of long-term fertilization. To explore the contribution of soil organismal biodiversity and community structures to ecosystem multifunctionality, we took soil samples from a nearly 25-year field fertilization experiment. Organic matter significantly improved the soil ecosystem multifunctionality. Ecosystem multifunctionality was found to be closely linked to the biodiversity and communities of soil organisms within the major ecological clustering of soil organisms (Module 1) according to the trophic co-occurrence network, rather than the entire community of soil organisms. This indicated that ecological clusters of soil organisms within the network were critical in maintaining soil ecosystem multifunctionality. The application of organic fertilization could enrich specialized soil organisms and increase interactions of soil organisms in the ecological cluster. As a result, our findings emphasize the role of ecological clusters in the soil organismal co-occurrence network in controlling soil multifunctionality after long-term fertilization, presenting a novel perspective on the link between soil biodiversity and ecosystem multifunctionality.

Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

MTR-G is a high-risk allele for lower-extremity arteriosclerotic occlusion.

OBJECTIVE: This study investigated the relationship between the MTRA2576G polymorphism of the key enzyme in homocysteine metabolism and deep vein thrombosis (DVT), chronic venous insufficiency (CVI) and arteriosclerotic occlusion (ASO) of the lower extremities. METHODS: Genomic DNA was extracted from the peripheral blood of patients with lower-extremity vascular diseases, including 125 cases of DVT, 125 cases of CVI and 125 cases of ASO. DNA samples extracted from 197 healthy individuals were used as control samples. PCR-RFLP was used to investigate the polymorphisms of MTR in these subjects. RESULTS: The frequency of the G allele in MTR was 6.8%, 6.1% and 12.8% for the DVT group, CVI group and ASO group, respectively (p = 0.003). The frequency of the GG allele was 13.6%, 12.2% and 22.4% for the DVT group, CVI group and ASO group, respectively (p = 0.014). Only the allele frequency of GG in the ASO group was higher than that in the control group, and the disease risk was also 1.3 times higher than that in the control group (OR = 1.299, 95% CI = 1.025 ∼ 2.575). CONCLUSION: Patients with the G allele in MTR have a high risk for ASO, and the GG allele is a risk gene for ASO.

Phytochemical and Therapeutic Potential of Citrus grandis (L.) Osbeck: A Review.

Citrus grandis or Citrus maxima, widely recognized as Pomelo is widely cultivated in many countries because of their large amounts of functional, nutraceutical and biological activities. In traditional medicine, various parts of this plant including leaf, pulp and peel are used for generations as they are scientifically proven to have therapeutic potentials and safe for human use. The main objective of this study was to review the different therapeutic applications of Citrus grandis and the phytochemicals associated with its medicinal values. In this article different pharmacological properties like antimicrobial, antitumor, antioxidant, anti-inflammatory, anticancer, antiepileptic, stomach tonic, cardiac stimulant, cytotoxic, hepatoprotective, nephroprotective, and anti-diabetic activities of the plant are highlighted. The enrichment of the fruit with flavonoids, polyphenols, coumarins, limonoids, acridone alkaloids, essential oils and vitamins mainly helps in exhibiting the pharmacological activities within the body. The vitamins enriched fruit is rich in nutritional value and also has minerals like calcium, phosphorous, sodium and potassium, which helps in maintaining the proper health and growth of the bones as well as the electrolyte balance of the body. To conclude, various potential therapeutic effects of Citrus grandis have been demonstrated in recent literature. Further studies on various parts of fruit, including pulp, peel, leaf, seed and it essential oil could unveil additional pharmacological activities which can be beneficial to the mankind.

Comparative Study of Damage Detection Methods Based on Long-Gauge FBG for Highway Bridges.

Damage detection of highway bridges is a significant part of structural heath monitoring. Conventional accelerometers or strain gauges utilized for damage detection have many shortcomings, especially their monitoring gauge length being too short, which would result in poor damage detection results. Under this circumstance, long-gauge FBG sensors as a novel optical sensor were developed to measure the macro-strain response of the structure. Based on this sensor, many derived damage detection methods were proposed. These methods exhibit various characteristics and have not been systematically compared. As a result, it is difficult to evaluate the state of the art and also leads to confusion for users to select. Therefore, a strict comparative study on three representative methods using long-gauge FBG was carried out. First, these methods' theoretical backgrounds and formats were reformulated and unified for better comparison. Then, based on validated vehicle-bridge coupling simulation, these methods' performances were tested through a series of parametric studies including various damage scenarios, vehicle types, speeds, road roughness and noise levels. The precision and reliability of three methods have been thoroughly studied and compared.

Comprehensive in-vivo secondary structure of SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms

SARS-CoV-2 is the positive-sense RNA virus that causes COVID-19, a disease that has triggered a major human health and economic crisis. The genome of SARS-CoV-2 is unique among viral RNAs in its vast potential to form stable RNA structures and yet, as much as 97% of its 30 kilobases have not been structurally explored in the context of a viral infection. Our limited knowledge of SARS-CoV-2 genomic architecture is a fundamental limitation to both our mechanistic understanding of coronavirus life cycle and the development of COVID-19 RNA-based therapeutics. Here, we apply a novel long amplicon strategy to determine for the first time the secondary structure of the SARS-CoV-2 RNA genome probed in infected cells. In addition to the conserved structural motifs at the viral termini, we report new structural features like a conformationally flexible programmed ribosomal frameshifting pseudoknot, and a host of novel RNA structures, each of which highlights the importance of studying viral structures in their native genomic context. Our in-depth structural analysis reveals extensive networks of well-folded RNA structures throughout Orf1ab and reveals new aspects of SARS-CoV-2 genome architecture that distinguish it from other single-stranded, positive-sense RNA viruses. Evolutionary analysis of RNA structures in SARS-CoV-2 shows that several features of its genomic structure are conserved across beta coronaviruses and we pinpoint individual regions of well-folded RNA structure that merit downstream functional analysis. The native, complete secondary structure of SAR-CoV-2 presented here is a roadmap that will facilitate focused studies on mechanisms of replication, translation and packaging, and guide the identification of new RNA drug targets against COVID-19.

Single-cell longitudinal analysis of SARS-CoV-2 infection in human bronchial epithelial cells

SARS-CoV-2, the causative agent of COVID-19, has tragically burdened individuals and institutions around the world. There are currently no approved drugs or vaccines for the treatment or prevention of COVID-19. Enhanced understanding of SARS-CoV-2 infection and pathogenesis is critical for the development of therapeutics. To reveal insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2 we performed single-cell RNA sequencing of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface cultures over a time-course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target of infection, which we confirmed by electron microscopy. Over the course of infection, cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III IFNs and IL6 but not IL1. This results in expression of interferon-stimulated genes in both infected and bystander cells. We observe similar gene expression changes from a COVID-19 patient ex vivo. In addition, we developed a new computational method termed CONditional DENSity Embedding (CONDENSE) to characterize and compare temporal gene dynamics in response to infection, which revealed genes relating to endothelin, angiogenesis, interferon, and inflammation-causing signaling pathways. In this study, we conducted an in-depth analysis of SARS-CoV-2 infection in HBECs and a COVID-19 patient and revealed genes, cell types, and cell state changes associated with infection.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

RIG-I: a multifunctional protein beyond a pattern recognition receptor

It was widely known that retinoic acid inducible gene I (RIG-I) functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent studies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting STAT1 activation by competitively binding STAT1 against its negative regulator SHP1 or inhibiting AKT-mTOR signaling pathway by directly interacting with Src respectively. These new findings suggest that RIG-I plays more diverse roles in various cellular life activities, such as cell proliferation and differentiation, than previously known. Taken together, the function of RIG-I exceeds far beyond that of a pattern recognition receptor.

Formulation design, absorption mechanism and bioavailability of nanoemulsions for enhancing oral absorption of raloxifene / 药学学报

Oral formulations of nanoemulsions (NE) were systematically designed, and then their effects on oral absorption of raloxifene (RAL), including their absorption mechanisms were investigated. RAL solubility in water and various excipients of NE and oil-water partition coefficient[P(O/W)] of RAL were examined. Next the optimal compatibility between emulsifiers and oils in NE were ascertained by emulsification ability. Proportions of each component and optimal RAL-NE were fully confirmed by a pseudo-ternary phase diagram and drug loading, respectively. RAL-NE quality was evaluated by particle size, zeta potential, morphology, entrapment efficiency and stability in simulated gastrointestinal fluid. A MDCK cell model was used to study the in vitro transport mechanism of RAL-NE. Oral bioavailability of RAL-NE was eventually performed in SD rats. RAL can be classified as BCSⅡ based on the solubility and P(O/W). The best formulation of RAL-NE was composed of linoleic acid (LOA):isopropyl palmitate (IPP):cremophor RH40 (RH40):alcohol as 1.67:3.33:3:2. Drug loading in pre-nanoemulsion was 15 mg·g-1 andentrapment efficiency of RAL in NE was (79.4 ±0.4)%. The particle size, zeta potential and drug content of RAL-NE were maintained in the simulated gastrointestinal fluid. The in vitro transport mechanism of RAL-NE in MDCK cells was mainly clathrin-mediated endocytosis. The oral bioavailability of RAL in RAL-NE relative to RAL-suspension was 171.9%. The best formulation of RAL-NE studied systematically was confirmed to significantly improve the RAL absorption by in vitro and in vivo evaluations (P < 0.05). This paper provides references for oral NE research and development.

Association between Nutritional Status, Food Insecurity and Frailty among Elderly with Low Income / Jurnal Sains Kesihatan Malaysia

Aging is associated with increased risk of frailty and malnutrition. However, food insecurity has rarely been highlighted in the elderly population, especially among the low income group. Thus, a cross-sectional study was conducted to determine the association between nutritional status, food insecurity and frailty among elderly in low income residences in Klang Valley. A total of 72 elderly individuals aged 60 years and above was selected (mean age 66 ± 6 years) through convenient sampling. Participants were interviewed to obtain information on socio-demographic, health status, food insecurity and cognitive status. Anthropometrics parameters and frailty assessments was measured using standard criteria. Results showed that 75.0% of the participants had abdominal obesity. Nearly half of the participants were overweight (41.7%), followed by normal (43.0%) and underweight (15.3%). With respect to food insecurity, most of them reported that they had enough food (93.1%). There were significant correlation (p < 0.05) between food insecurity with height (r = -0.263, p = 0.026). Most of the participants were pre-frail (58.3%), frail (27.8%) and followed by non-frail (13.9%). Calcium intake is inversely associated with frailty (t = -2.62, p = 0.011). In conclusion, food insecurity was not a problem, however, half of the subjects were overweight and pre-frail. Three out four subjects had abdominal obesity. There is a need to investigate further the pathogenesis of fat frail in this low income elderly population and formulate effective intervention strategies.

DNA marker-assisted selection of medicinal plants (Ⅰ) .Breeding research of disease-resistant cultivars of Panax notoginseng / 中国中药杂志

The study is aimed to estimate the diversity of arbuscular mycorrhizal fungi (AMF) in the main producing areas of Salvia miltiorrhiza.Diversity of AMF was surveyed directly on spores isolated from the field soil, collected from 20 sites of 8 provinces. Identification of the AMF was made by observation of spore morphology. At least 27 recognized AMF species were identified in samples from field soil, belonging to seven genera of AMF-Acaulospora, Glomus, Funneliformis, Ambispora, Rhizophagus, Pacispora, and Claroideoglomus. Acaulospora and Glomus were the dominant genera, respectively including nine and eight species. A. laevis (90%), R.manihotis (80%), A. brieticulata (75%), A. tuberculata (70%) were the dominant species.Colonization rate was determined,colonization was easily found, but the colonization intensities were low, the colonization rate remained at 10.92%-25.93%. The similarity between provinces is generally low, and the similarity coefficients were from 0.20 to 0.57.

[Therapeutic bloodletting at Jing-well points combine hypothermia attenuated acute cerebral edema after traumatic brain injury in rats].

OBJECTIVE: To investigate the influence of therapeutic bloodletting at Jing-well points and hypothermia on acute cerebral edema after traumatic brain injury (TBI) in rats. METHODS: Seventy-five SD rats were randomly divided into sham-operation group (Sham), TBI group (TBI), bloodletting group (BL), mild-induced hypothermia group (MIH), and bloodletting plus MIH group (BL + MIH) (n = 15). The model of TBI was established by electric controlled cortical impactor (eCCI). The rats of BL group were bloodletting at Jing-well points immediately after injury, twice daily. While the MIH group was settled on a hypothermia blanket promptly after TBI for 6 hours, so that the temperature dropped to 32 degrees. Each of measurement was performed after 48 hours. Magnetic resonance imaging (MRI) was used to evaluate the dynamic impairment of cerebral edema after TBI (n = 3). In addition, mNSS score, measurements of wet and dry brain weight, and Evans Blue assay were performed to investigate the neurologic deficit, cerebral water content (n = 8), and blood-brain barrier permeability (BBB), (n = 4), respectively. RESULTS: MRI analysis showed that the cerebral edema, hematoma and midline shifting of rats in TBI group was more serious than other treatment group. Meanwhile compared with TBI group, the mNSS scores of every treatment group were meaningfully lower (all P < 0.05). Furthermore, treatment with BL+ MIH group was superior to the separated BL and MIH group (all P < 0.01). In addition, brain water content of each intervention group reduced to varying degrees (all P < 0.05), especially that of MIH group and BL + MIH group (P <0.01). BBB permeability of each treatment group was also significantly improved (all P < 0.01), and the improvement in MIH group and BL + MIH group was much better than the BL alone group (P < 0.05, P < 0.01). CONCLUSION: Our major finding is that bloodletting at Jing-well points and MIH can reduce cerebral edema and BBB dysfunction and exert neuroprotective effects after TBI. The results suggest that the combination of BL and MIH is more effective than other treatment being used alone.

[Attenuated total reflection-fourier transform infrared spectroscopic study of dried shark fin products].

Sixty-four pieces of shark fin dried products (including real, fake and artificial shark fin products) and real products coated with gelatin were rapidly and nondestructively analyzed by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The characteristic of IR spectrograms among the above four kinds of samples were systematically studied and comparied, the results showed that the spectrograms of the same kind of samples were repeatable, and different kinds of shark fin products presented significant differences in the spectrograms, which mainly manifested as the specific absorption peaks of amido bonds in protein (1650, 1544 cm(-1)) and skeletal vibration in polysaccharide (1050 cm(-1)). The spectrograms of real shark fins were characterized by the strong absorption peaks of protein characteristic amide I and II absorbent (1650, 1544 cm(-1)) and relatively weak C--O--C vibration absorbent (1050 cm(-1)) owing to the high content of protein and relatively low level of polysaccharide. For fake shark fin products that were molded form by mixing together with the offcut of shark, collagen and other substances, the introduction of non-protein materials leaded to the weaker amido bonds absorbent than real products along with a 30 cm(-1) blue shift of amide I absorbent. Opposite to the real sample, the relatively strong absorption peak of polysaccharide (approximately 1047 cm(-1)) and barely existed amide absorbent were the key features of the spectrogram of artificial samples, which was synthersized by polysaccharide like sodium alginate. Real samples coated with gelatin, the peak strength of protein and polysaccharide were decreased simultaneously when the data collection was taken at the surface of sample, while the spectrogram presented no significant difference to real samples when the data was collected in the section. The results above indicated that by analyzing the characteristic of IR spectrograms and the value range of Apro/Apol collected by ATR-FTIR method could perform the undamaged and rapid identification for shark fins.

Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity.

Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg, 15.3 µmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.

Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells.

Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation.

Continentalic acid from Aralia continentalis shows activity against methicillin-resistant Staphylococcus aureus.

In a continuing search for compounds with antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), a chloroform extract of roots of Aralia continentalis was found to contain continentalic acid (CA, C(20)H(30)O(2)), a diterpenic acid. This compound exhibited potent activity against standard methicillin-susceptible Staphylococcus aureus (MSSA) as well as clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). It was determined that continentalic acid had minimum inhibitory concentrations (MICs) of approximately 8-16 microg/mL against S. aureus, including the MSSA and MRSA standard strains. Therefore, the results obtained in this study suggest that continentalic acid might have potential as an adjunct in the treatment of antibiotic-resistant bacteria.