Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders

Cholesteryl esters(CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer's disease(AD).Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain:senile plaques,neurofibrillary tangles,and lipid granule accumulation.Senile plaques,which are aggregates of amyloid-beta(Aβ),and neurofibrillary tangles,which are aggregates of phosphorylated tau,have been regarded as more consistent characteristics of the AD brain compared with lipid granule accumulation and thus have been studied more intensively(Foley,2010).

Pharmaceutical properties of insulin conjugate with glucuronylglucosyl-β-cyclodextrin

In the clinical field,insulin has been used for treatment of diabetes.However,insulin often shows low physicochemical stability,adsorption onto tubes and enzymatic degradation in injection site or blood.Previously,we demonstrated that cyclodextrins(CyDs),especially branchedβ-CyDs,improve the pharmaceutical properties of insulin through complexation with its aromatic residues.However,little has been reported on the insulin conjugate with branchedβ-CyD.In the present study,to improve the pharmaceutical properties of insulin,we newly prepared 6-Ο-α-(4-Ο-α-D-glucuronyl)-D-glucosyl-β-CyD(GUG-β-CyD)conjugate with insulin,and evaluated its thermal or enzymatic stability and adsorption onto glass or polypropylene tube[1].

Feasibility study of cyclodextrins as active pharmaceutical ingredients for the treatment of GM1-gangliosidosis

GM1-gangliosidosis is a rare lysosomal storage disorder characterized clinically by a wide range of variable neurovisceral,ophthalmological and dysmorphic features. Without enough functionalβ-galactosidase, GM1-gangliosides cannot be degraded in lysosomes, and accumulate to toxic levels in many tissues and organs, particularly in the brain. In spite of several approaches for the treatment of GM1-gangliosidosis.

Efficacy of tolvaptan in an infant with syndrome of inappropriate antidiuretic hormone secretion associated with holoprosencephaly:A case report

BACKGROUND Holoprosencephaly(HPE)is a congenital malformation with various degrees of incomplete separation of the cerebral hemispheres due to differentiation disorders of the forebrain.Although HPE with diabetes insipidus due to associated pituitary dysfunction has been reported,HPE with the syndrome of inappropriate antidiuretic hormone secretion(SIADH)is very rare.Tolvaptan,a vasopressin V2 receptor antagonist,is effective in adults with SIADH.However,there is no report of its efficacy in infants with SIADH.The purpose of this report is to demonstrate that tolvaptan is effective for SIADH in infants and that administration of tolvaptan eliminates the need for restriction of water intake and sodium administration.CASE SUMMARY A 2414-g female infant was born at 38 wk by normal vaginal delivery.Facial anomalies and head magnetic resonance imaging indicated semilobar HPE.After birth,she had hyponatremia due to SIADH and was treated using water and sodium restriction.However,she developed an exaggerated response to the fluid restrictions,resulting in large fluctuations in serum sodium levels.Subsequent administration of tolvaptan improved the fluctuations in serum sodium levels without the need for adjustment of water or sodium administration.Serum sodium was maintained within the normal range after discontinuation of tolvaptan at 80 d of life.There were no side effects,such as hypernatremia or liver dysfunction,during the administration of tolvaptan.CONCLUSION This is the first report on the safety and efficacy of tolvaptan in an infant with SIADH associated with HPE.

If not me, then who? Social media, vaccine hesitancy, and ethical responsibility in the face of the Covid-19 pandemic

The Covid-19 pandemic is the most significant public health emergency of the 21st century.However,the infection of social media with fact-less,false,and misleading information concerning Covid-19 has direct and detrimental effects on millions of people’s health and well-being,often with deadly consequences.With the introduction of Covid-19 vaccines,an end to the pandemic is in sight.Yet,the unsubstantiated and damaging claims about the vaccine remain prevalent throughout society.As a result,a large segment of the population is hesitant to be vaccinated.As social media is used to sow false information.It also can be used to temper or eradicate the cascading and self-perpetuating flow of misinformation and misperceptions by disseminating truthful,timely,and action-oriented information.And in doing so,promote the efficacy and safety of the vaccines and highlight the responsibility we get vaccinated for Covid-19.Therefore,it is the ethical and moral obligation of every powerful entity-healthcare providers,pharmaceutical companies,social media platforms,and individual users-to stop the spread of misinformation and promote fact-and evidence-based information throughout the media that they control or participate in.Pathways to overcoming vaccine hesitancy and a return to a sense of normalcy depend on these efforts.

Pro-and anti-epileptic roles of microglia

Microglia are brain-resident immune cells that contribute to the maintenance of brain homeostasis.In the epileptic brain, microglia show various activation phenotypes depending on the stage of epileptogenesis.Therefore, it remains unclear whether microglial activation acts in a pro-epileptic or anti-epileptic manner.In mesial temporal lobe epilepsy, one of the most common form of epilepsies, microglia exhibit at least two distinct morphologies, amoeboid shape and ramified shape.Amoeboid microglia are often found in sclerotic area, whereas ramified microglia are mainly found in non-sclerotic area;however, it remains unclear whether these structurally distinct microglia share separate roles in the epileptic brain.Here, we review the roles of the two distinct microglial phenotypes, focusing on their pro-and anti-epileptic roles in terms of inflammatory response, regulation of neurogenesis and microglia-neuron interaction.

Prevention of esophageal strictures after endoscopic submucosal dissection

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have recently been accepted as less invasive methods for treating patients with early esophageal cancers such as squamous cell carcinoma and dysplasia of Barrett’s esophagus. However, the large defects in the esophageal mucosa often cause severe esophageal strictures, which dramatically reduce the patient’s quality of life. Although preventive endoscopic balloon dilatation can reduce dysphagia and the frequency of dilatation, other approaches are necessary to prevent esophageal strictures after ESD. This review describes several strategies for preventing esophageal strictures after ESD, with a particular focus on anti-inflammatory and tissue engineering approaches. The local injection of triamcinolone acetonide and other systemic steroid therapies are frequently used to prevent esophageal strictures after ESD. Tissue engineering approaches for preventing esophageal strictures have recently been applied in basic research studies. Scaffolds with temporary stents have been applied in five cases, and this technique has been shown to be safe and is anticipated to prevent esophageal strictures. Fabricated autologous oral mucosal epithelial cell sheets to cover the defective mucosa similarly to how commercially available skin products fabricated from epidermal cells are used for skin defects or in cases of intractable ulcers. Fabricated autologous oral-mucosal-epithelial cell sheets have already been shown to be safe.

Induced biosyntheses of a novel butyrophenone and two aromatic polyketides in the plant pathogen Stagonospora nodorum

Fungal aromatic compounds comprise an important and structurally diverse group of secondary metabolites.Several genome sequencing projects revealed many putative biosynthetic gene clusters of fungal aromatic compounds,but many of these genes seem to be silent under typical laboratory culture conditions.To gain access to this untapped reservoir of natural products,we utilized chemical epigenetic modifiers to induce the expression of dormant biosynthetic genes.As a result,the concomitant supplementation of the histone deacetylase inhibitors suberoylanilide hydroxamic acid(500mM)and nicotinamide(50mM)to the culture medium of a fungal pathogen,Stagonospora nodorum,resulted in the isolation of three aromatic compounds(1-3),including a novel natural butyrophenone,(+)-4'-methoxy-(2S)-methylbutyrophenone(1),and two known polyketides,alternariol(2)and(-)-(3R)-mellein methyl ether(3).

Chemical Composition of the Essential Oil of Mastic Gum and their Antibacterial Activity Against Drug-Resistant Helicobacter pylori

Mastic gum is derived from the tree named Pistacia lentiscus that is grown only in Island Hios of Greek.Since Mastic was first reported to kill Helicobacter pylori(H.pylori)in 1998,there has been no further study to elucidate which component of mastic specifically shows the antimicrobial activity against H.pylori.In this study,we examined which component of mastic gum was responsible for anti-H.pylori activity.We prepared the essential oil of mastic gum and identified 20 constituents by GC–MS analysis.Ten standard components were assayed for anti-H.pylori activity,and it clarified that a-terpineol and(E)-methyl isoeugenol showed the anti-H.pylori activity against four different H.pylori strains that were established from patients with gastritis,gastric ulcer and gastric cancer.These components could be useful to overcome the drug-resistance H.pylori growth in stomach.

Stronger inhibition of gastric acid secretion by lafutidine, a novel H_2 receptor antagonist, than by the proton pump inhibitor lansoprazole

AIM: To compare the antisecretory activity and plasma drug concentrations of a single oral dose of 10 mg lafutidine, a novel H2 receptor antagonist, with those of the proton pump inhibitor lansoprazole (LPZ) 30 mg. METHODS: Ten volunteers without H pylori infection participated in this crossover study comparing lafutidine 10 mg with LPZ 30 mg. Intragastric pH was monitored for 6 h in all participants, and blood samples were collected from four randomly selected individuals after single-dose administration of each drug. RESULTS: The median intragastric pH was significantly higher in individuals who received lafutidine 10 mg than in those who received LPZ 30 mg 2, 3, 4, 5, and 6 h after administration. Maximal plasma drug concentration was reached more promptly with lafutidine 10 mg than with LPZ 30 mg. CONCLUSION: In H pylori-negative individuals, gastric acid secretion is more markedly inhibited by lafutidinethan by LPZ.

Therapeutic potential of prophylactic exercise for intracerebral hemorrhage

Exercise and brain health:Physical activity helps promote and maintain our brain health,including memory and cognitive performance.Research has shown that exercise is a safe behavioral intervention that reduces the risk of hypokinetic diseases,such as hypertension,diabetes,and lipid metabolic disorders.In addition.

Percoll fractionation of adult mouse spermatogonia improvesgerm cell transplantation

Aim: To isolate and transplant germ celis from adult mouse testes for transplantation. Methods: In order to distinguish transplanted celis from endogenous celis of recipients, donor transgenic mice expressing green fluores cent protein (GFP) were used. Germ celis were collected from the donors at 10-12 weeks of age and spermatogonia were concentrated by percoll fractionation and transplanted into recipient seminiferous tubules that had been previ ously treated with busulfan at 5 weeks of age to remove the endogenous spermatogenic celis. Results: Twenty vveeks after the transplantation, a wide spread GFP signal was observed in the recipient seminiferous tubules. The presence of spermatogenesis and spermatozoa was confirmed in sections of 12 out of 14 testes transplanted (86 %). However, when germ celis were transplanted without concentration the success rate was zero (0/9). Conclusion: Germ celis from adult mouse testes can be successfully transplanted into recipient seminiferous tubules if the cell population is rich in spermatogonia and the percoll fractionation is useful in obtaining such a cell population.

A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Transforming growth factor-β(TGF-β)and bone morphogenetic protein(BMP)play important roles in bone metabolism.Smad ubiquitination regulatory factors(Smurfs)regulate TGF-β/BMP signaling via ubiquitination,resulting in degradation of signaling molecules to prevent excessive activation of TGF-β/BMP signaling.Though Smurf2 has been shown to negatively regulate TGF-β/Smad signaling,its involvement in BMP/Smad signaling in bone metabolism has not been thoroughly investigated.In the present study,we sought to evaluate the role of Smurf2 in BMP/Smad signaling in bone metabolism.Absorbable collagen sponges containing 3μg of recombinant human BMP2(rhBMP2)were implanted in the dorsal muscle pouches of wild type(WT)and Smurf2−/−mice.The rhBMP2-induced ectopic bone in Smurf2−/−mice showed greater bone mass,higher mineral apposition and bone formation rates,and greater osteoblast numbers than the ectopic bone in WT mice.In WT mice,the ectopic bone consisted of a thin discontinuous outer cortical shell and scant inner trabecular bone.In contrast,in Smurf2−/−mice,the induced bone consisted of a thick,continuous outer cortical shell and abundant inner trabecular bone.Additionally,rhBMP2-stimulated bone marrow stromal cells(BMSCs)from Smurf2−/−mice showed increased osteogenic differentiation.Smurf2 induced the ubiquitination of Smad1/5.BMP/Smad signaling was enhanced in Smurf2−/−BMSCs stimulated with rhBMP2,and the inhibition of BMP/Smad signaling suppressed osteogenic differentiation of these BMSCs.These findings demonstrate that Smurf2 negatively regulates BMP/Smad signaling,thereby identifying a new regulatory mechanism in bone metabolism.

Early effects of Lansoprazole orally disintegrating tablets on intragastric pH in CYP2C19 extensive metabolizers

AIM: To compare rabeprazole (RPZ; 10 mg) with Lansoprazole orally disintegrating tablets (LPZ; 30 mg OD) in terms of antisecretory activity and blood drug concentration after a single dose. METHODS: Eight H pylori-negative cytochrome P450 (CYP) 2C19 extensive metabolizers were assigned to receive a single oral dose of RPZ 10 mg or LPZ 30 mg OD. Twelve hour intragastric pH monitoring was perform- ed on the day of treatment. Blood samples were also collected after the administration of each drug. RESULTS: LPZ 30 mg OD induced a significantly earlier rise in blood drug concentration than RPZ 10 mg; consequently, LPZ 30 mg OD induced a significantly earlier rise in median pH in the third and fourth hours of the study. CONCLUSION: In H pylori-negative CYP2C19 extensive metabolizers, LPZ 30 mg OD induced a significantly faster inhibition of gastric acid secretion than RPZ 10 mg.

Epigenetic modifier-induced biosynthesis of novel fusaric acid derivatives in endophytic fungi from Datura stramonium L.

The treatment of fungi with DNA methyltransferase(DNMT)and/or histone deacetylase(HDAC)inhibitors is a promising way to activate secondary metabolite biosynthetic pathways that are dormant under normal conditions.In this study,we included an HDAC inhibitor,suberoylanilide hydroxamic acid(SBHA),in the culture medium of endophytic fungi isolated from the medicinal plant Datura stramonium L.The production of two compounds was induced in the culture supplemented with SBHA,and their structures were determined to be the fusaric acid derivatives 5-butyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid and 5-(but-9-enyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid.The result confirmed that the use of chemical epigenetic modifiers is an effective technique for promoting the expression of silent biosynthetic pathways to produce unique secondary metabolites.

Signal transducer and activator of transcription 3 regulation by novel binding partners

Signal transducers and activators of transcription(STATs) mediate essential signals for various biological processes,including immune responses,hematopoiesis,and neurogenesis. STAT3,for example,is involved in the pathogenesis of various human diseases,including cancers,autoimmune and inflammatory disorders. STAT3 activation is therefore tightly regulated at multiple levels to prevent these pathological conditions. A number of proteins have been reported to associate with STAT3 and regulate its activity. These STAT3-interacting proteins function to modulate STAT3-mediated signaling at various steps and mediate the crosstalk of STAT3 with other cellular signaling pathways. This article reviews the roles of novel STAT3 binding partners such as DAXX,zipperinteracting protein kinase,Krüppel-associated box-associated protein 1,Y14,PDZ and LIM domain 2 and signal transducing adaptor protein-2,in the regulation of STAT3-mediated signaling.

Local Peripheral Effects of <i>β</i>-Caryophyllene through CB₂Receptors in Neuropathic Pain in Mice

β-Caryophyllene (BCP) is known as a common constitute of the essential oils of numerous food plants and primary component in Cannabis. In this study, we investigated the effect of local intraplantar (i.pl.) injection of BCP on mechanical hypersensitivity induced by partial sciatic nerve ligation (PSNL) in mice. Relative to sham operation controls, mice with the PSNL displayed a maximum level of hyperresponsiveness to von Frey metallic filament on post-operative day 7. PSNL-induced allodynia was seen in the ipsilateral side of nerve ligation, but not in the contralateral side. The i.pl. injection of BCP into the ipsilateral hindpaw to PSNL attenuated mechanical allodynia in a dose-dependent manner. BCP injection into the contralateral hindpaw did not produce anti-allodynic effects, suggesting a local peripheral anti-allodynic effect of BCP. Anti-allodynic effects induced by i.pl. injection of BCP were prevented by pretreatment with the cannabinoid (CB2) receptor antagonist AM630, but not by the CB1 receptor antagonist AM251. These data suggest that i.pl. injection of BCP could produce anti-allodynia by activating peripheral CB2 receptors, but not CB1 receptors in a mouse model of neuropathic pain. Taken together, these results suggest that peripheral CB2 receptors may contribute to the effectiveness of BCP in the treatment of neuropathic pain disorders.

Tonsil-derived stem cells as a new source of adult stem cells

Located near the oropharynx, the tonsils are the primary mucosal immune organ. Tonsil tissue is a promising alternative source for the high-yield isolation of adult stem cells, and recent studies have reported the identification and isolation of tonsil-derived stem cells (T-SCs) from waste surgical tissue following tonsillectomies in relatively young donors (i.e., under 10 years old). As such, TSCs offer several advantages, including superior proliferation and a shorter doubling time compared to bone marrow-derived mesenchymal stem cells (MSCs). T-SCs also exhibit multi-lineage differentiation, including mesodermal, endodermal (e.g., hepatocytes and parathyroid-like cells), and even ectodermal cells (e.g., Schwann cells). To this end, numbers of researchers have evaluated the practical use of T-SCs as an alternative source of autologous or allogenic MSCs. In this review, we summarize the details of T-SC isolation and identification and provide an overview of their application in cell therapy and regenerative medicine.

Improvement of physicochemical stability of highly-concentrated antibodies using cyclodextrin polypseudorotaxane hydrogels

Recently,a large number of antibodies have been utilized as biodrugs,and their subcutaneous formulations are required to allow the self-administration.However,because of the lower administration capacity of subcutaneous formulation than intravenous ones,highly-concentrated antibody formulations(>100 mg/mL)are desired.Regretfully,highly-concentrated antibodies often cause aggregation during the long-term storage and transportation,resulting in the loss of pharmacological activity and induction of immunogenicity.On the other hand,we previously reported the potential use of polypseudorotaxane(PPRX)hydrogels consisting of polyethylene glycol(PEG,MW 20,000)and cyclodextrins(CyDs)as sustained release systems for protein drugs such as insulin and lysozyme.