Taste Bud Wiring

Here is an interesting basic science paper about how the taste bud sensors are “wired” to detect the basic taste sensations.  Abstract:

In mammals, taste buds typically contain 50-100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami. Notably, mature taste cells have life spans of only 5-20 days and, consequently, are constantly replenished by differentiation of taste stem cells. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A). We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells

Plant Extract Against Colon Cancer?

Anti-cancer benefits of a plant extract, mediated through inhibition of Wnt signaling. This may be useful for developing preventive or therapeutic approaches to colon cancer.  Abstract:

OBJECTIVE:

To investigate the effect of the ethanol extract of Scutellaria barbata D. Don (EESB) on colorectal cancer (CRC) growth and Wnt/β-catenin signaling pathway in vivo and in vitro.

METHODS:

In vivo experiment, CRC xenograft mouse model was constructed with injection of HT-29 cells. Following xenograft implantation, twenty mice were randomly divided into EESB-treated group (n=10) and control group (n=10) by a random number table, and were given with intra-gastric administration of 2 g/kg EESB or saline, 5 days a week for 16 days, respectively. At the end of experiment, tumors were removed and weighed by electronic scales. The proliferation biomarker Ki-67 of tumor was evaluated by immunohistochemistry (IHC) assay. In vitro study, HT-29 cells were treated with 0, 0.5, 1.5, 2.5 mg/mL EESB for 24 h. At the end of the treatment, the viability and survival of HT-29 cells were determined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and colony formation assay, respectively. The mRNA expression of c-Myc, Survivin and adenomatous polyposis coli (APC) was examined by reverse transcription-polymerase chain reaction (RT-PCR) both in tumor tissues of CRC xenograft mice and HT-29 cells. Protein expression of c-Myc, Survivin, APC, and β-catenin as well as β-catenin phosphorylation level were evaluated by IHC assay or Western blotting.

RESULTS:

EESB significantly reduced tumor weight in CRC xenografts mice, compared with the control group (P<0.05). IHC assay showed that EESB significantly inhibited protein expression of Ki-67 in tumor tissues (P<0.05). MTT assay showed that EESB significantly reduced HT-29 cell viability in a dose-dependent manner (P<0.05). Colony formation assay showed that EESB dose-dependently decreased the survival of HT-29 cells (P<0.05). In addition, RT-PCR assay showed that EESB decreased the mRNA expression of c-Myc and Survivin and increased APC expression, both in tumor tissues of CRC xenograft mice and HT-29 cells (P<0.05). IHC assay or Western blotting showed that EESB decreased protein expression of β-catenin, c-Myc and Survivin, as well as increased APC expression and β-catenin phosphorylation in tumor tissues or HT-29 cells (P<0.05).

CONCLUSIONS:

EESB significantly reduced tumor growth in CRC xenografts mice, and inhibited the viability and survival of HT-29 cells. EESB could suppress the activation of the Wnt/β-catenin pathway, which might be one of the mechanisms whereby Scutellaria barbata D. Don exerts its anticancer activity.

Inflammation Memory

By The original uploader was Samir at English Wikipedia - Transferred from en.wikipedia to Commons., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2107303

Here is an interesting study that suggests a form of “inflammation memory” exists.  Therefore, in epithelial stem cells that have already been exposed to acute inflammation there is a molecular “memory” of the event, which enables a more rapid response for subsequent inflammatory exposures.   While this has some benefits in dealing with the immediate need for a response to certain stimuli, this increased sensitivity may contribute to autoimmune diseases and cancer.  From the preventive and therapeutic angle, it is therefore important to study.  Abstract:

The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.

Do you need to let go

Today I am sick, sitting in a chair next to the window and looking at the remaining tree leaves. They are all golden-brown and moving with the wind. Soon there will be only naked branches to look at.

I am also listening to Enya:

Enya's music is like a stream that purifies, flows through you and allows you to let go, let go of worries, pain, and pettiness.

Wool Underwear For Lower Back Pain

Public Domain, https://commons.wikimedia.org/w/index.php?curid=16818

Lower back pain is a common complaint; here we see a study suggesting that the use of wool underwear leads to "significant improvements in pain intensity, disability, and lower back flexibility." Temperature-related mechanism? Abstract:

The aim was to assess the effect of wool underwear use in patients with chronic non specific low back pain. The study employed two-group, experimental design. A total of 48 patients with chronic non specific low back pain were selected for the study. They were distributed into two groups: a control group and a treatment group. The 24 patients in each group were randomly selected and the compositions of the two groups. The patients in the treatment group wore woolen underwear during the experimental period of 2 month. All patients were assessed at the beginning the trial (pre-test) and the end of 8th (post-test) week. Data were collected using the visual analogue pain scale, Oswestry Disability Index and Schober test measurements. Patients in the treatment group reported significant improvements in their conditions including a reduction in pain levels and Oswestry Disability Index, and Schober test measurements increased (p<0.001). Patients with chronic non-specific low back pain who wore wool underwear experienced significant improvements in pain intensity, disability, and lower back flexibility.

Caveat emptor.  

Potential Stem Cell Therapeutic Engineering

This paper discusses some advances in genetic engineering of cells, which may be of use “to develop innovative stem cell-based therapeutics.”  The link between basic science and therapeutic advances remains strong.  Abstract:

Precise and efficient manipulation of genes is crucial for understanding the molecular mechanisms that govern human hematopoiesis and for developing novel therapies for diseases of the blood and immune system. Current methods do not enable precise engineering of complex genotypes that can be easily tracked in a mixed population of cells. We describe a method to multiplex homologous recombination (HR) in human hematopoietic stem and progenitor cells and primary human T cells by combining rAAV6 donor delivery and the CRISPR/Cas9 system delivered as ribonucleoproteins (RNPs). In addition, the use of reporter genes allows FACS-purification and tracking of cells that have had multiple alleles or loci modified by HR. We believe this method will enable broad applications not only to the study of human hematopoietic gene function and networks, but also to perform sophisticated synthetic biology to develop innovative engineered stem cell-based therapeutics.

Spinal Muscular Atrophy Gene Therapy Clinical Trial

By Kashmiri, based on earlier work by Domaina - Own work based on Autosomal dominant - en.svg and Autorecessive.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19018894

Spinal muscular atrophy is an extremely serious neurological disease of childhood that is inherited in an autosomal recessive manner.  There has recently been an encouraging gene therapy clinical trial for this disease.  Families of children with this disorder need to be made aware of these findings.  Note: "...a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts."  Abstract:

BACKGROUND:

Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

METHODS:

Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts).

RESULTS:

As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.

CONCLUSIONS:

In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

The New Blood Pressure Guidelines

The blood pressure guidelines for “high blood pressure” have been lowered once again. As America get fatter and fatter, it’s interesting that the cutoffs for things like blood pressure and cholesterol levels get lower and lower, and drug sales go higher and higher.

New guidelines lower the threshold for high blood pressure, adding 30 million Americans to those who have the condition, which now plagues nearly half of U.S. adults.

High pressure, which for decades has been a top reading of at least 140 or a bottom one of 90, drops to 130 over 80 in advice announced Monday by a dozen medical groups.

I’m skeptical of these new blood pressure standards.  If the ultimate outcome – regardless of what people are saying now – is really going to be an emphasis on losing weight, exercise, and good diets, then fine.  But I believe that the real ultimate outcome is going to be putting half of America, or more, on blood pressure medication, just like we’ll have half on statins, and a big percentage on attention deficit disorder medication, all leading to fat profits for pharmaceutical companies.

So, yes, get your blood pressure to healthy levels. But the specter of folks with 30+ BMIs taking blood pressure medications and statins seems to be self-defeating.

Apigenin's Anti-Cancer Properties

The dietary factor apigenin has anti-cancer properties, affecting important cell signaling pathways.  Note this factor is found in many fruits and vegetables, once again showing the importance of those foodstuffs. Also note the comment: “Apigenin appears to have the potential to be developed either as a dietary supplement or as an adjuvant chemotherapeutic agent for cancer therapy.”  Abstract:

Apigenin is a common dietary flavonoid that is abundantly present in many fruits, vegetables and Chinese medicinal herbs and serves multiple physiological functions, such as strong anti-inflammatory, antioxidant, antibacterial and antiviral activities and blood pressure reduction. Therefore, apigenin has been used as a traditional medicine for centuries. Recently, apigenin has been widely investigated for its anti-cancer activities and low toxicity. Apigenin was reported to suppress various human cancers in vitro and in vivo by multiple biological effects, such as triggering cell apoptosis and autophagy, inducing cell cycle arrest, suppressing cell migration and invasion, and stimulating an immune response. In this review, we focus on the most recent advances in the anti-cancer effects of apigenin and their underlying mechanisms, and we summarize the signaling pathways modulated by apigenin, including the PI3K/AKT, MAPK/ERK, JAK/STAT, NF-κB and Wnt/β-catenin pathways. We also discuss combinatorial strategies to enhance the anti-cancer effect of apigenin on various cancers and its use as an adjuvant chemotherapeutic agent to overcome cancer drug resistance or to alleviate other adverse effects of chemotherapy. The functions of apigenin against cancer stem cells are also summarized and discussed. These data demonstrate that apigenin is a promising reagent for cancer therapy. Apigenin appears to have the potential to be developed either as a dietary supplement or as an adjuvant chemotherapeutic agent for cancer therapy.

Natural Products Screening

By Richard Parker - Conus magus 56mmUploaded by JoJan, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=9831177

We are increasingly seeing a convergence between natural products/traditional medicine and basic science/biomedical, which is both discovering new natural product therapeutics, as well as identifying the molecular mechanisms of action of known metabolites.  A number of natural products affect well-known signaling pathways that contribute to disease, elucidating function and paving the way for further discoveries.  Abstract:

Natural products represent an inexhaustible source of novel therapeutic agents. Their complex and constrained three-dimensional structures endow these molecules with exceptional biological properties, thereby giving them a major role in drug discovery programs. However, the search for new bioactive metabolites is hampered by the chemical complexity of the biological matrices in which they are found. The purification of single constituents from such matrices requires such a significant amount of work that should ideally be performed only on molecules of high potential value (i.e. chemical novelty and biological activity). Recent bioinformatics approaches based on state-of the art mass spectrometry metabolite profiling methods are beginning to address the complex task of chemical identification of individual metabolites within complex mixtures. However, in parallel to these developments, methods providing information on the bioactivity potential of natural products prior to their isolation are still lacking and are of key interest to target the isolation of valuable natural products only. In the present investigation, we propose an integrated analysis strategy for bioactive natural products prioritization. Our approach uses massive molecular networks embedding various informational layers (bioactivity and taxonomical data) to highlight potentially bioactive scaffolds within the chemical diversity of crude extracts collections. We exemplify this workflow by targeting the isolation of predicted active and non-active metabolites from two botanical sources (Bocquillonia nervosa and Neoguillauminia cleopatra) against two biological targets (Wnt signaling pathway and chikungunya virus replication). Eventually, the detection and isolation processes of a daphnane diterpene orthoester and four 12-deoxyphorbols inhibiting the Wnt signaling pathway and exhibiting potent antiviral activities against CHIKV virus are detailed. Combined with efficient metabolite annotation tools, this bioactive natural products prioritization pipeline proves to be efficient. Implementation of this approach in drug discovery programs based on natural extract screening should speed up and rationalize the isolation of bioactive natural products.