
Genetic inactivation or pharmacological inhibition of the β1 adrenergic receptor significantly reduces the formation and volume of cerebral cavernous malformations in a zebrafish model.


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Propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation of ccm2 . Because morpholino silencing of the β1 adrenergic receptor ( adrb1 ) prevents the embryonic CVP lesion, we proposed that adrb1 plays a role in CCM pathogenesis. Here we report that adrb1-/- zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a β1 selective antagonist, yielded a similar reduction in CCM lesion volume. Adrb1-/- zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through β1 receptor antagonism.

### Competing Interest Statement

The authors have declared no competing interest.

Genetic Inactivation of the β1 adrenergic receptor prevents Cerebral Cavernous Malformations in zebrafish

genetic-inactivation-of-the-β1-adrenergic-receptor-prevents-cerebral-cavernous-malformations-in-zebrafish


Genetic Inactivation of the β1 Adrenergic Receptor Prevents Cerebral Cavernous Malformations in Zebrafish


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The evidence on whether the diabetes drug metformin can extend lifespan in non-diabetic individuals is inconclusive, and further research is needed to validate its purported anti-aging benefits.


Metformin is no one-trick pony, but extending lifespan is not one of its tricks

Will Metformin Really Make Sam Altman Live Longer? Let’s Examine The Evidence!

examining-the-evidence-on-metformin-s-purported-anti-aging-effects


Examining the Evidence on Metformin's Purported Anti-Aging Effects



Recent studies have found no evidence of increased cancer risk or high blood levels of benzene, a breakdown product of benzoyl peroxide, from typical everyday use of benzoyl peroxide-containing acne products.


Two new studies found no increased cancer risk and no difference in blood levels of benzene in users and nonusers of BP-containing acne products.

New Benzoyl Peroxide Research: Reassuring

reassuring-studies-find-no-increased-cancer-risk-from-benzoyl-peroxide-acne-treatments


Reassuring Studies Find No Increased Cancer Risk from Benzoyl Peroxide Acne Treatments



A newly discovered compound could provide a novel strategy to save lives of people who have overdosed on synthetic opioids like fentanyl.


A compound that boosts the effects of a therapy for opioid overdoses.

Opioid crisis: compound opens up potential strategy to tackle overdoses

synthetic-opioid-overdoses-a-compound-with-potential-to-revolutionize-overdose-treatment


Synthetic Opioid Overdoses: A Compound with Potential to Revolutionize Overdose Treatment



新しい負のアロステリック調節剤化合物は、オピオイド過剰摂取の解毒剤であるナロキソンと協調的に作用し、オピオイド作用を効果的に阻害する。


A newly discovered negative allosteric modulator of the µ-opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.

A µ-opioid receptor modulator that works cooperatively with naloxone - Nature

オピオイド過剰摂取を予防する新しい薬剤の発見


A novel negative allosteric modulator compound that binds to the inactive conformation of the mu-opioid receptor can work cooperatively with naloxone to potently block opioid agonist signaling and effectively reverse opioid overdose effects in vivo.


discovery-of-a-negative-allosteric-modulator-that-enhances-the-efficacy-of-naloxone-in-reversing-opioid-overdose


Discovery of a Negative Allosteric Modulator that Enhances the Efficacy of Naloxone in Reversing Opioid Overdose



二量体R25CPTH(1-34)は、PTH1受容体を活性化し、骨粗鬆症モデルマウスにおいて骨形成を促進する。


Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of Parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibiting altered activity in PTH1R-mediated cAMP response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a surprising capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo , suggesting a potential new path of therapeutic PTH analog development.

### Competing Interest Statement

The authors have declared no competing interest.

Dimeric R25CPTH(1–34) Activates the Parathyroid Hormone-1 Receptor in vitro and Stimulates Bone Formation in Osteoporotic Female Mice

骨粗鬆症患者に対して-二量体r25cpth-1-34-は-pth1受容体を活性化し-骨形成を促進する


骨粗鬆症患者に対して、二量体R25CPTH(1-34)は PTH1受容体を活性化し、骨形成を促進する



A dimeric form of the R25CPTH(1-34) peptide, a variant of parathyroid hormone, can activate the PTH1 receptor and stimulate bone formation in osteoporotic mouse models, suggesting its potential as a novel therapeutic for osteoporosis.


dimeric-r25cpth-1-34-peptide-activates-the-parathyroid-hormone-1-receptor-and-stimulates-bone-formation-in-osteoporotic-mice


Dimeric R25CPTH(1-34) Peptide Activates the Parathyroid Hormone-1 Receptor and Stimulates Bone Formation in Osteoporotic Mice



Weakly basic small molecule drugs exhibit slow intracellular diffusion and accumulation in lysosomes, which can reduce their cellular activity and efficacy.


For drugs to be active they have to reach their targets. Within cells this requires free diffusion, distribution, and availability. Here, we explored the intracellular diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP). While all proteins diffused freely, we found a strong correlation between p K a and the intracellular diffusion and distribution of small molecule drugs. Weakly basic, small-molecule drugs displayed lower fractional recovery after photobleaching and 10-to-20-fold slower diffusion rates in cells than in aqueous solutions. As, more than half of pharmaceutical drugs are weakly basic, they, are protonated at pH 7.4, resulting in their sequestration in the cell cytoplasm. Protonation, facilitates the formation of membrane impermeable ionic form of the weak base small molecules. This results in ion trapping, further reducing diffusion rates of weakly basic small molecule drugs under macromolecular crowding conditions where other nonspecific interactions become more relevant and dominant. Our imaging studies showed that acidic organelles, particularly the lysosome, captured these molecules. Surprisingly, blocking lysosomal import only slightly increased diffusion rates and fractional recovery. Conversely, blocking protonation by N- acetylated analogues, greatly enhanced their diffusion and fractional recovery after FRAP. Based on these results, N -acetylation of small molecule drugs may improve the intracellular availability and distribution of weakly basic, small molecule drugs.

### Competing Interest Statement

The authors have declared no competing interest.

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration

slow-intracellular-diffusion-and-lysosomal-sequestration-of-weakly-basic-small-molecule-drugs


Slow Intracellular Diffusion and Lysosomal Sequestration of Weakly Basic Small Molecule Drugs



Clinicians have reported cases of pancreatitis, including a fatal case, in patients taking the diabetes and weight loss medication tirzepatide. Healthcare providers should be aware of this potential side effect and closely monitor patients for signs of pancreatitis when prescribing this medication.


Researchers reported a case of pancreatitis in two patients taking tirzepatide. The risk for pancreatitis is expected to rise with increased prescriptions of these agents.

Researchers Describe Cases of Pancreatitis With Tirzepatide

fatal-pancreatitis-cases-reported-in-patients-taking-tirzepatide-a-diabetes-and-weight-loss-medication


Fatal Pancreatitis Cases Reported in Patients Taking Tirzepatide, a Diabetes and Weight Loss Medication
