A Poly(γ, l-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery

A cisplatin-loaded nanoconjugate, poly(γ, l-glutamic acid)-citric acid-cisplatin [γ-PGA-CA-CDDP], as a tumor-targeted drug delivery system with sustained release capacity was successfully synthesized and characterized, and its antitumor activity was evaluated. The particle size (107?±?6.3?nm) and average molecular weight (66?kDa) were determined by dynamic light scattering (DLS) and gel permeation chromatography (GPC), respectively. The nanoconjugate delivery system released platinum in a sustained manner in PBS at 37?°C with an initial burst release during the first 8?h and 50% cumulative release within 48?h. Both in-vitro and in-vivo studies showed that the toxicity of γ-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of γ-PGA-CA-CDDP nanoconjugate was about 38?mg/kg versus 8?mg/kg for CDDP. No apathy or acute adverse reactions were observed in γ-PGA-CA-CDDP nanoconjugate groups while mice expressed apathy at all dose levels with CDDP treatment. In ICR mice, the area under the curve and total body clearance values for γ-PGA-CA-CDDP nanoconjugate were 9-fold and one-twentieth of the values for CDDP, respectively. With the aid of near-infrared fluorescence (NIRF) imaging system, it was demonstrated that γ-PGA-CA-CDDP nanoconjugate gradually accumulated at the tumor site within 15?min postinjection and exhibited prolonged retention for more than 8?h. In H22-implanted mice, γ-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that γ-PGA-CA-CDDP nanoconjugate with improved stability, reduced toxicity and prolonged in-vivo retention time holds great potential in terms of clinical application to cancer therapy.     

Preparation and in vitro evaluation of vancomycin hydrochloride@polylactic acid-glycolic acid copolymer-chitosan-hyaluronic acid composite sustained-release microspheres北大核心

BACKGROUND: Local antibiotic slow-release system can solve the problems of total toxicity caused by systemic antibiotics and short half-life of short-term local antibiotics. OBJECTIVE: To prepare polylactic acid-glycolic acid copolymer-chitosan-hyaluronic acid composite sustained-release microspheres loaded with vancomycin and evaluate its performance. METHODS: Vancomycin-loaded polylactic acid-glycolic acid copolymer-chitosan-hyaluronic acid composite sustained-release microspheres and unloaded polylactic acid-glycolic acid copolymer-chitosan-hyaluronic acid composite microspheres were prepared by emulsion method. Mass concentrations of vancomycin in the drug-loaded microspheres were 25, 50, and 100 g/L. The drug-loading amount, encapsulation efficiency, and in vitro sustained release properties of the drug-loaded microspheres were detected. The three kinds of drug-loaded microspheres were co-cultured with Staphylococcus aureus bacteria separately, and the antibacterial rate was detected within the corresponding time points. The four kinds of microsphere extracts were co-cultured with MC3T3-E1 cells and MG-63 cells, and the cytotoxicity was detected by CCK-8 method after 1, 3, and 7 days of culture. RESULTS AND CONCLUSION: (1) The encapsulation efficiencies of 25, 50, and 100 g/L drug-loaded microspheres were (79.70±5.11)%, (86.41±3.91)%, and (63.18±1.96)%, and the drug loading was (3.98±0.26)%, (8.64±0.39)%, and (12.63±0.39)%. The encapsulation efficiency of 50 g/L drug-loaded microspheres was higher than that of 100 g/L drug-loaded microspheres (P < 0.05). The drug loading of 100 g/L drug-loaded microspheres was higher than that of the other two groups (P < 0.05). (2) Three kinds of drug-loaded microspheres had no obvious burst release within 24 hours, of which the drug release rate of 50 g/L drug-loaded microspheres at different time points was faster than that of the other two groups. The drug release amount of 100 g/L drug-loaded microspheres at different time points was higher than that of the other two groups, and the drug mass concentration of the three groups was higher than minimum antibacterial concentration of vancomycin at 56 days. (3) All three kinds of drug-loaded microspheres could effectively kill Staphylococcus aureus within a certain period of time. From 14 to 28 days, the relative colony rate of the three kinds of microspheres was lower than 3%, indicating that three kinds of drug-loaded microspheres can continuously and effectively kill Staphylococcus aureus. (4) The 25 and 50 g/L drug-loaded microspheres have no obvious cytotoxicity to MC3T3-E1 cells and MG-63 cells, and 100 g/L drug-loaded microspheres have certain cytotoxicity. (5) The results show that the VA@PLGA-CS-HA microspheres have good sustained-release performance, antibacterial ability and biological tissue compatibility. © 2022, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.     

Chitosan-gelatin-hyaluronic acid scaffolds used for skin substitute

Skin is composed of both a dermal layer—consisting primarily of fibroblasts,and matrix macromolecules ( ECM)— and an epidermal layer— composing of epider-mal cells containing keratin filaments undergoing progressive differentiation from abasal proliferating layer to a surface consisting of terminally differentiated,epider-mal cellsthatprotectthe skin from the environment.Typically,the ECM are highlyhydrated macromolecular networks composed of various kinds of glycoproteins suchas collagen…     

Is aspartic acid a regulator of hematopoiesis?

Ekaterinburg Branch of the All-Union Kurgan Restorative Traumatology and Orthopedics Research Center. Presented by Academician of the Russian Academy of Medical Sciences E. D. Gol'dberg.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 114, No. 9, pp. 293–294, September, 1992.     

Host-guest interaction of β-cyclodextrin with isomeric ursolic acid and oleanolic acid: physicochemical characterization and molecular modeling study

Ursolic acid (UA) and oleanolic acid (OA) are insoluble drugs. The objective of this study was to encapsulate them into β-cyclodextrin (β-CD) and compare the solubility and intermolecular force of β-CD with the two isomeric triterpenic acids. The host-guest interaction was explored in liquid and solid state by ultraviolet-visible absorption, 1 H NMR, phase solubility analysis, and differential scanning calorimetry, X-ray powder diffractometry, and molecular modeling studies. Both experimental and theoretical studies revealed that β-CD formed 1: 1 water soluble inclusion complexes and the complexation process was naturally favorable. In addition, the overall results suggested that ring E with a carboxyl group of the drug was encapsulated into the hydrophobic CD nanocavity. Therefore, a clear different inclusion behavior was observed, and UA exhibited better affinity to β-CD compared with OA in various media due to little steric interference, which was beneficial to form stable inclusion complex with β-CD and increase its water solubility effectively.     

Further studies on the antinociceptive effects ofΔ acid

The antinociceptive effects of (THC-7-oic) acid have been investigated further with particular regard to the influence of certain experimental parameters in the hot plate test. These included the degree of the thermal stimulus, the nature of the vehicle and a possible role for copper in the response. A temperature effect similar to that seen with nonsteroidalantiinflammatory drugs (NSAIDs) was observed, 55° produced observable antinociception, however, at a surface temperature of 58°C no drug effect was seen. Non-aqeous vehicles such as peanut oil increased the potency of THC-7-oic acid. Finally, the substitution of purified water for tap water reduced,the drug response which could be partially restored by adding copper to the purified drinking water. An increase in the inhibitory effect when copper was added was also seenin vitro in a cell culture model where the acid reduced prostaglandin synthesis induced by THC. Our findings suggest that THC-7-oic acid probably acts by mechanisms similar to the NSAIDs and that the above mentioned experimental conditions can greatly influence the outcome of studies with this agent.     

Regulated acid–base transport in the collecting duct

The renal collecting system serves the fine-tuning of renal acid–base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H⁺-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid–base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H⁺-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H⁺-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid–base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid–base homeostasis.     

The glio-toxic mechanism of α-aminoadipic acid on cultured astrocytes

The mechanism of action of the glutamate analogue -aminoadipic (A A A) acid was investigated in terms of its toxicity to cultured astrocytes. A A A was more toxic to type 1 astrocytes than type 2 astrocytes. Also the higher toxicity of the L-isomer as compared to the D-isomer was seen on type 1 astrocytes but not type 2. The toxicity of A A A can be reduced by co-culture of type 1 astrocytes with microglia. This inhibition may be due to glutamate release by microglia. No such effect is seen for type 2 astrocytes. The major uptake route for A A A by type 1 astrocytes is through the sodium dependent glutamate port. Both isomers of A A A are toxic to dividing astrocytes. The D-isomer appears to be toxic only for mitotic cells. The mechanism of this toxicity is protein synthesis dependent. It is suggested that A A A is toxic to mitotic astrocytes by interference with protein synthesis needed for cell division. D-A A A as opposed to L-A A A may prove a valuable tool for investigation of astrocyte proliferation in development and disease.     

Poly(γ-glutamic acid), coagulation? Anticoagulation?

Poly(γ-glutamic acid) (γ-PGA) powder was usually used as hemostatic agent because of its excellent physical properties of water-absorption and water-locking. However, if γ-PGA absorbs enough water, how about its blood compatibility? Here, the other side of the coin was investigated. The anticoagulant properties of γ-PGA were characterized by in vitro coagulation tests, hemolytic assay, platelet adhesion, and platelet activation. Moreover, cytotoxicity experiments of γ-PGA were also carried out by MTT assay. Results indicated that the sufficient water-absorbed γ-PGA has good anticoagulant property and non-cytotoxicity. It means γ-PGA has good anticoagulant property, non-cytotoxicity. If γ-PGA has absorbed enough water, it can be used as an anticoagulation biomaterial. With double effects (coagulation and anticoagulation), the γ-PGA with desirable bioproperties can be readily tailored to cater to various biomedical applications.     

Immunobiological specificity of antibodies against glutamate and γ-aminobutyric acid

Experiments on C57Bl/6 mice showed that chronic epileptization of the brain (pharmacological pentylenetetrazole kindling) is accompanied by induction of autoantibodies against glutamate and GABA. Immunohistochemical similarity of antibodies against glutamate and GABA was demonstrated. Study on the model of pentylenetetrazoleinduced acute generalized epileptiform activity showed high immunobiological specificity of intraperitoneally injected antibodies against GABA and glutamate: antiepileptic effect of antiglutamate antibodies and proepileptic effect of antibodies against GABA. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 5, pp. 572–575, May, 2007     

Inhibition of the fibrinolytic and fibrinogenolytic activity of plasminogen activators in vitro by the antidotes ϵ-aminocaproic acid,tranexamic acid and aprotinin

The effects of the potential antifibrinolytic antidotes EACA, AMCA and aprotinin on the pharmacological activity of SK, u-PAs, APSAC and t-PA (alteplase) were compared in vitro. Both the initiation of human plasma clot lysis and ongoing clot lysis in the presence of SK and APSAC were effectively inhibited by concentrations of EACA (1 mM) and aprotinin (50 KIU/ml) equivalent to those found at steady state conditions during the standard therapeutic regimens. The actions of tcu-PA and scu-PA were also inhibited, at least initially, although some fibrinolytic activity appeared on extended incubation with tcu-PA. EACA (1 mM) was only moderately inhibitory to t-PA, and aprotinin (50 KIU/ml) was not an effective antidote. Ongoing fibrinogenolysis was generally less readily inhibited than fibrinolysis. A higher concentration of EACA (12 mM, equivalent to the initial peak level achieved therapeutically) effectively inhibited fibrinolytic activity for all thrombolytic agents but the higher concentration of aprotinin (500 KIU/ml) failed to inhibit t-PA completely. Inhibition by AMCA, at concentrations equivalent to those used therapeutically, was similar to the maximum effect achieved by EACA.In conclusion, aprotinin and EACA/AMCA represent useful antidotes for those rare occasions when it is necessary to terminate the action of SK, APSAC and u-PA—even when plasma levels of thrombolytic agent are high, as after the standard administration of APSAC as a short injection. Concentrations of aprotinin and EACA/AMCA achievable by current dosage regimens are relatively less able to inhibit t-PA.     

Reproducibility of prefrontal γ-aminobutyric acid measurements with J-edited spectroscopy

γ‐Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA‐ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J‐edited, single‐voxel spectroscopy method of measurement of GABA + macromolecules (GABA + ) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra‐class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in‐house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABA + /creatine, GABA + /H₂O, GABA + , creatine, partially co‐edited glutamate + glutamine (Glx)/creatine, partially co‐edited Glx and N‐acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA + /creatine, GABA + , creatine, partially co‐edited Glx and NAA/creatine to be 0.88 ± 0.21 (standard deviation), 1.52 ± 0.32, 1.77 ± 0.4, 2.69 ± 0.74 and 0.70 ± 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations. Published in 2011 by John Wiley & Sons, Ltd.