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Endoplasmic reticulum stress (ER stress) is suggested to promote cardiomyocyte apoptosis and ultimately lead to ischemic injury. Inhibition of ER stress-induced apoptosis may be a therapeutic strategy for MI injury. Astragaloside-IV (AST) from Astragalus membranaceus (Fisch) Bge, was reported to have cardioprotective properties. In this study, we investigated the protective effect of AST on cardiomyocytes against hypoxia injury by regulating ER stress and inhibiting apoptosis. H9c2 cardiomyocytes were divided into three groups, normal group, hypoxia group and AST group. Cell viability was determined by CCK-8 assay. Intracellular reactive oxygen species (ROS) production was detected by DCFH-DA (2,7- dichloro-dihydrofluorescein diacetate) florescent staining. The study showed that AST treatment could significantly increase the cell viability of H9c2 cells exposed to hypoxia. Furthermore, AST could restrain cell apoptosis and decrease the production of ROS. Compared with normal group, the protein levels of Bax, caspase-3, caspase-9, GRP78, p-eIF2α, and CHOP were enhanced in the hypoxia group, whereas the protein level of Bcl-2 was dramatically reduced. Compared with hypoxia group, AST markedly inhibited the phosphorylation of eIF2α and the expression of caspase-3, caspase-9 and CHOP, and promoted the protein expression of Bcl-2. Thus, AST can inhibit the ER stress-mediated apoptosis, partly through the eIF2α/CHOP pathway suppression to inhibit ER stress.

The antitumor drug candidate X-05 is being developed as an innovative anti-lung cancer drug candidate due to its excellent antitumour activity. A Caco-2 cell permeability study and solubility study confirmed that X-05 belonged to BCS class or compounds. Therefore, the main challenge is to develop appropriate preparations for preclinical studies and further clinical phase research. By evaluating the preliminary results of kinetic solubility in biorelevant media and the structural analysis of X-05 and polymers, three polymers PVP K30, PVP VA 64 and HPMCAS, which may have intermolecular interactions with X-05, were chosen to select the optimal carrier for X-05 to prepare amorphous solid dispersions (ASDs). ASD X-05-PVP VA 64 was selected as the optimal polymer by evaluating its kinetic solubility in biorelevant media and solid stability. The physical and chemical properties of ASD X-05-PVP VA 64 remain stable when the drug loading is as high as 50%. The drug-polymer interactions of ASD X-05-PVP VA 64 were studied by ultraviolet spectrophotometry, nuclear magnetic resonance spectrometry, infrared and Raman spectrophotometry, and the results indicated that the intermolecular hydrogen bond interaction between the drug and polymer was the foundation of the solubilization and stabilization of X-05 in PVP VA 64.

Free amino acids constitute the largest portion (40%) of the natural moisturizing factor. Their level might decline and cause dry skin condition. The treatment strategy involves the replenishment of these components to the skin, and, to our knowledge, there are no reports that involve dermal delivery of free amino acids. The purpose of the current study was therefore to prepare and characterize different micro-emulsions, micro-emulsion-based hydrogels, and hydrophilic creams loaded with free amino acids for dermal delivery. Oil-in-water microemulsions were prepared using carefully selected formulation components. Poloxamer^® 407 and carbopol^® 934 were used to prepare the hydrogels. All the formulations were characterized for physico-chemical, permeation and cytotoxicity properties. The results showed that the prepared microemulsions had desired droplet size, size distribution, zeta potential, refractive index, and pH. In the gel preparations, the elastic properties prevailed over the viscous behavior. The hydrogels had non-Newtonian shear-thinning behavior with some thixotropic properties. The free amino acids permeated into the deeper layers of the stratum corneum from the microemulsions, and microemulsion-based hydrogels as compared to conventional hydrophilic cream. The hydrogels were more effective than the microemulsions to deliver the FAAs to the desired site of the skin in a sustained manner. Poloxamer-based hydrogel permeated into deeper skin layers than Carbopol-based hydrogel. Formulations prepared using standard free amino acids and those extracted and purified from oyster mushroom had similar characteristics. All the formulations were stable and safe to be applied topically. In conclusion, microemulsions and microemulsion-based hydrogels can be considered as safe carrier systems for dermal delivery of free amino acids.

This study aimed to determine the efficacy of zinc acetate hydrate (ZAH) for hypozincemia in elderly hospitalized patients with an accumulated exposure of < 1000 mg of ZAH and to explore the factors affecting the therapeutic efficacy of ZAH. Seventy-four patients (mean age, 82 years) were enrolled in this study. All patients (n = 74) had low serum zinc levels (< 80 μg/dL), and the mean serum zinc concentration before ZAH administration was 53.6±10.7 μg/dL. The median serum zinc level (μg/dL) elevated per tablet (25 mg) of ZAH was 1.26 μg/dL, and the patients were divided into two groups, the slightly increased (< 1.26) and significantly increased (≥ 1.26) groups, based on the median cutoff value for the median increase in serum zinc level. A significant difference was found between the slightly increased (0.63±0.35 μg/dL, n = 36) and significantly increased (2.37±0.95 μg/dL, n = 38) groups (p < 0.0001, Wilcoxon rank-sum test). Logistic regression analysis with the accumulated exposure dose of ZAH, sex, and body weight as multivariate variables showed a significant difference in the accumulated exposure dose (total number of tablets per 25 mg: odds ratio, 1.119; 95% confidence interval, 1.052???1.203; p = 0.0009). There was no effect of underlying disease or of diet or zinc-containing intravenous or enteral nutrition on serum zinc levels. These results suggest that at an accumulated exposure of < 1000 mg of ZAH, serum zinc levels tend to increase with smaller accumulated doses. Therefore, serum zinc concentrations should be measured at the accumulated exposure to 500-1000 mg after ZAH initiation for the treatment of zinc deficiency in elderly hospitalized patients.

To achieve appropriate blood pressure control in the treatment of hypertension in Japan, this study examined the relationship between office blood pressure and actual antihypertensive drug use in general hospitals following the promulgation of the guidelines for hypertension (JSH2019). This study focused on blood pressure levels and drug use in outpatients on antihypertensive treatment from June to July 2020. The subjects were 2,537 patients classified into four groups based on their medical history, patients with: hypertension only; hypertension and cardiovascular disease; hypertension and dyslipidaemia; and hypertension and diabetes mellitus. The results showed a significant difference in systolic blood pressure (SBP) between patients with hypertension only and those with hypertension and cardiovascular disease (138.3±17.9 mmHg vs 135.6±19.9 mmHg, p<0.05). Regarding actual drug use, it was found that diuretics were prescribed more frequently in patients with hypertension and cardiovascular disease than in those with hypertension alone (15.5% vs 37.9%, p<0.05), even though the number of drugs for hypertension did not differ significantly. In addition, the dose of diuretics was greater only in patients with cardiovascular disease. These results show the actual drug use and blood pressure for each comorbidity. Furthermore, they suggest that the results of antihypertensive treatment may differ by changing the combination and dosage of antihypertensive drugs without changing the number of antihypertensive drugs used. The study also shows the problem of using less diuretics depending on the risk the patient has, and solving the problem may lead to achieving further antihypertensive goals.

We developed a drug delivery system for atherosclerotic lesions using immuno-liposomes. We focused on enhancing the delivery efficiency of the liposomes to macrophages in atherosclerotic lesions by antibody modification of lectinlike oxidized low-density lipoproteins (LDL) receptor 1 (LOX-1). The cellular accumulation of the liposomes in foam cells induced by oxidized LDL (oxLDL) in Raw264 mouse macrophages was evaluated. The cellular accumulation of LOX-1 antibody modified liposomes in oxLDL-induced foam cells and untreated Raw264 cells was significantly higher compared with that of unmodified liposomes. The liposomes were also administered intravenously to Apoe^shl mice as an atherosclerosis model. Frozen sections were prepared from the mouse aortas and observed by confocal laser microscopy. The distribution of LOX-1 antibody modified liposomes in the atherosclerotic regions of Apoe^shl mice was significantly greater compared with that of unmodified liposomes. The results suggest that LOX-1 antibody modified liposomes can target foam cells in atherosclerotic lesions, providing a potential route for delivering various drugs with pharmacological effects or detecting atherosclerotic foci for the diagnosis of atherosclerosis.

Medieval European medicine relied on monasteries where ancient medical works were transcribed. Trade routes to the East and the influence of Arab medicine, which supplemented the knowledge of Greco-Roman physicians, enabled the foundation and development of the Salerno Medical School, whose most famous work is Flos medicinae: Regimen sanitatis Salernitanum. This medical textbook, written in verse and drawn up on the basis of ancient sources and empirical experiences of Salerno physicians, contains rules on how to preserve health, on diseases and the use of medicinal plants for medicinal purposes. The work was originally written in Latin, and was translated into Croatian by Franciscan Father Emerik Pavi^c' (1768). It was the first medical book in the Croatian language. This paper provides an insight into the importance of Regimen sanitatis Salernitanum in medieval medicine and its influence on European medical literature through many translations, commentaries and analyses. In this context, ten recipes from the Croatian translation of Flos medicinae were researched and analysed which contain medicinal plants most of which grow in Croatia, and which were in use at that time: fig, fennel, anise, mallow, peppermint, sage, rue, nettle, celandine and willow. Most of the listed herbal drugs are used in contemporary phytotherapy and some of them have the potential for further research. The paper also deals with the particularities of the Croatian translation of this medical textbook, which can be used for further multidisciplinary research involving medicinal and pharmaceutical historians, botanists and philologists.

The activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiac damage during diabetes. In the present study, we investigated the role of pioglitazone, dapagliflozin and their combination on RAS components in streptozotocin-induced diabetic cardiomyopathy in Wistar rats. Blood glucose, serum lipids, and ACE (angiotensin-converting enzyme), ACE2 levels were determined. mRNA levels of Myh6 (myosins heavy chain), Myh7, Ace, Ace2, Nppa, Nppb (natriuretic peptide A, B) and Ppars (peroxisome proliferator activating receptors) genes in the heart were determined by real-time PCR (polymerase chain reaction). Protein expression of ACE and ACE2 was assessed by western blotting. After six weeks pioglitazone suppressed Ace mRNA and protein levels (p<0.05) and modified the Ace/Ace2 ratio (p<0.05) in the cardiac tissue of diabetic rats. Pioglitazone significantly decreased serum lipids (p<0.05) but did not significantly influence blood glucose and ACE serum levels of diabetic animals. Dapagliflozin had a significant glucose-lowering action (p<0.05) however, it had no impact on the Ace/Ace2 ratio. The combination of both compounds markedly improved blood glucose (p<0.05) as well as the Myh6/Myh7 ratio (p<0.05) but had no further impact on the Ace to Ace2 balance in cardiac tissue compared to pioglitazone monotherapy. We found that pioglitazone improves the cardiac Ace/ Ace2 ratio in diabetic rats suggesting a potential cardioprotective effect. This effect is independent of its antidiabetic and metabolic effects.

The aim of this study was to evaluate the anti-allergic potentials of dactolisib, a dual PI3K/mTOR kinase inhibitor, on two important events for allergy: sensitization and the onset of anaphylactic symptoms. After sensitization with the antigen ovalbumin (OVA), five successive oral administrations of dactolisib effectively decreased serum anti-OVA antibody-an indicator of sensitization-levels in mice. In parallel with the antibody levels in their serum, anaphylactic rectal temperature decrease induced by the re-administration of OVA to dactolisib-treated mice was strongly diminished compared to that in vehicle-treated mice. The inhibitor also inhibited ex vivo splenic B cell activation indicated by the increase of phosphorylation of Akt, CD69 expression levels, and proliferation upon anti-B cell receptor antibody treatment, suggesting that suppressive effects of the inhibitor on B cell activation plays a role in its ability to decrease sensitization in vivo. We concurrently observed the anti-anaphylactic ability of dactolisib in vivoand in vitro. A single oral administration of the inhibitor attenuated the anaphylactic rectal temperature decrease induced in a mouse model of passive systemic anaphylaxis. In in vitro mast cell models, pretreatment with the drug inhibited the degranulation response and cytokine production in RBL2H3 cells triggered by IgE and antigens, without affecting cell viability. These results suggest that dactolisib, as well as other PI3K/mTOR inhibitors, might be a good candidate for anti-allergic drugs that exhibit both anti-sensitizing and anti-anaphylactic effects.

The professor of pharmacy, Johann Georg Noel Dragendorff (1836-1898) is primarily known in the history of pharmacy as a pharmacognosist and forensic chemist, so far he has been less described as a toxicologist. He worked for 30 years (1864-1894) at the University of Dorpat (Tartu) in Estonia, and had been invited from Germany, developing here one of the pharmaceutical research centers in all of Europe. Dr. Dragendorff supervised 90 theses of Master of Pharmacy and 87 theses of Doctor of Medicine in Tartu/Dorpat. Dragendorff's supervised master's theses reveal his particular interest in phytochemistry. Of the 87 doctoral dissertations supervised by Dragendorff, are related to forensic chemistry (26 works), and toxicology with pharmacology (21). This work introduces Dragendorff as a toxicologist, discusses the theses supervised by him and his textbooks. Dragendorff's development as a toxicologist was logical considering his extensive scientific activities and the drugs characteristic of the 19 th century. These, especially alkaloids and mercury preparations, are introduced in more detail in this study.