Awake Craniotomy for a Frontal Astrocytoma: A Case Report.

Awake craniotomy is a surgical procedure that has been gaining significance over the past decades. Neuronavigation is an intraoperative technology that locates tumors and monitors the brain cortex during awake craniotomy. The presence of cerebral low-grade gliomas in the frontal lobe creates a risk of affecting vital centers of the brain cortex during surgery. We present a clinical case of a 42-year-old male patient who entered the neurosurgery clinic with a clinical manifestation of headache for two months. MRI showed evidence of the recurrence of a left frontal glioma. Differential diagnoses of frontal gliomas include metastases, abscesses, and cysts. The pathophysiologic background of the disease is the mutation of neuroglial cells, which leads to an abnormal and uncontrollable proliferation. Under sleep-awake anesthesia, operative treatment was performed through left frontal awake craniotomy under neuronavigation. As a result, a total excision was achieved. Motor functions of the right limbs and speech have been preserved. The patient was mobilized on the day after the intervention. Surgery-related complications were not observed. The patient had relief from the symptoms and was discharged on the fifth day. Awake craniotomy combined with neuronavigation was the most efficient and the least harmful method for the excision of the tumor. For low-grade gliomas localized in the frontal area of the encephalon, awake craniotomy is the only secure option for surgery.

Chronic Cerebellar Meningoencephalitis in Adulthood: A Report of a Rare Case.

The development of meningoencephalitis is a result of an inflammation of the meninges and the brain, which can cause neurological sequelae. Cerebellar meningoencephalitis in adult patients is extremely rare and requires special diagnostic approaches. The aim of this report is to present a rare case of meningoencephalitis and evaluate the diagnostic and therapeutic techniques. We present a 45-year-old male patient who has entered the neurosurgery clinic with a severe headache lasting for a month. Neurological status determines intracranial hypertension. Magnetic resonance tomography (MRT) showed evidence of hyperintense lesions with homogenous enhancement in the right hemisphere of the cerebellum. The patient underwent a suboccipital paramedian craniotomy to excise the lesions and for the pathohistological examination of the biopsy material. Biopsy examination found sections expressing an infection process causing chronic meningoencephalitis in the right hemisphere of the cerebellum. The patient was treated postoperatively with cephalothin 2 g every 12 hours for 14 days. Follow-up examinations proved a relief of the symptoms. Meningoencephalitis of the cerebellum and the meninges is a complication that may occur in adulthood, and surgical excision, biopsy examination, and antibiotic therapy are promising methods for managing the disease.

Double Trouble: A Case Report on the Surgical Management of Dual Intracranial Metastases.

Intracranial metastasis disease (IMD) has proven to be a frequent secondary occurrence, usually for primary cancers such as lung, breast, and melanoma, which have a high possibility of metastasizing to the brain. Due to the reasons listed above, treatment and early diagnosis are incredibly challenging. In the past decade, medicine has developed much better imaging solutions and radiological and surgical approaches, increasing the postoperative survival prognosis and achieving more time-efficient results. It is still exceptionally difficult to be able to prevent what type of metastasis a patient might develop other than by using the tumor type or subtype. We present a case of a 51-year-old female patient entering the Neurosurgical Clinic at the University Hospital "St. Ivan Rilski" for operative treatment of a second metastatic lesion located on the left parietal lobe in January 2024. She had previously had an operative resection of an initial lesion located on the left temporal lobe in December 2023. Her medical history began in 2015 when her first diagnosis was a breast carcinoma, followed by operative treatment and radio-, chemo-, and targeted therapy. In 2020, due to metastases located in the bones, she had to undergo another treatment with chemotherapy as well as have a total hysterectomy done as a result of another metastasis. The patient did not provide any family history, nor did she confirm any past or current allergies to foods, drugs, etc. Under general inhalation anesthesia, the patient was placed in a park bench position to the right and had a Mayfield head holder applied. Through a left parietal craniotomy and neuronavigation, a tumor formation was revealed with the characteristic of a secondary lesion. A gross total resection was achieved through a microsurgical technique. Postoperatively, there were no further complications observed in the patient, and she was discharged on day five from the hospital with relief of her symptoms.

Diagnostic Problem in a Child With an Isolated Renal Hydatid Cyst: A Case Report.

Cystic hydatid disease is a parasitic disease caused by the larvae of the small tapeworm Echinococcus granulosus. It is still a serious public health problem in endemic regions such as the Mediterranean basin, especially in the Balkans. Usually, the complaints caused by the cysts are non-specific and there are rarely abnormalities in routine laboratory tests. The most common is the involvement of the liver. The frequency of isolated kidney involvement, especially in a child, is uncommon. We describe a rare pediatric case of an isolated renal hydatid cyst presenting with a urinary tract infection-like clinical presentation, leading to misdiagnosis and delayed treatment.

Cerebral Calcifications as a Result of Primary Hyperparathyroidism: A Report of a Rare Case.

Primary hyperparathyroidism (PHPT) is an extremely uncommon cause of cerebral calcification. A male patient, aged 45, was admitted to the neurosurgery clinic with a closed traumatic brain injury, namely a concussion, resulting in symptoms of headache and loss of balance. A CT scan was conducted, which detected bilateral calcifications on the basal ganglia and the tentorium. The blood tests revealed increased levels of serum calcium, phosphate, and parathyroid hormone (PTH), while vitamin D levels were within the normal range. The patient received symptomatic therapy for the cerebral concussion and was referred for further diagnostic procedures. Based on these exams, it was determined that the patient had a parathyroid adenoma, which was responsible for PHPT characterised by increased levels of calcium, phosphate, and PTH. The patient subsequently underwent a successful parathyroidectomy. Half a year following the surgical procedure, the patient remained free of any indications of neurological conditions, and the levels of PTH and calcium in their body were within the expected range. Whenever trying to identify the cause of cerebral calcification, it is important to explore several possible diagnoses. A possible cause that should be taken into account is PHTP.

Symptomatic Cavum Vergae Cyst in a Geriatric Patient: A Report of a Rare Case and Conservative Management Approach.

Cavum vergae (CV) cysts constitute a small proportion of intracranial cysts, and although generally asymptomatic, there are occasional cases where they might exhibit clinical manifestations. We present a clinical case of a 79-year-old female patient who had a clinical manifestation of headache on the occipital side of the head with irradiation to the shoulder girdle as well as numbness, dizziness, visual impairment, sleep disturbances, and tingling in the hands for three months. Vertigo and rightward staggering had been experienced for two weeks. On physical examination, it was discovered that there was smoothed physiological lordosis, restricted and painful movements, and paravertebral muscle rigidity in the cervical region. The patient had bilaterally reduced biceps and triceps reflexes, painful Erb's points, and hypesthesia over the C5 and C6 dermatomes on the right side. The patient had decreased coordination and displayed staggered movement to the right. A CT scan discovered dilated subarachnoid spaces of the convexity and a CV cyst. The patient was prescribed conservative therapy consisting of etoricoxib oral at a dosage of 2 × 60 mg for seven days, tolperisone hydrochloride orally at a dosage of 2 × 150 mg for seven days, pregabalin 75 mg, one pill in the evening for seven days, ozoid (a gel containing ozone) for external application, and vinpocetine 2 × 10 mg orally for two months. Following the conservative treatment, the patient exhibited improvement in her symptoms and no longer had challenges carrying out her daily tasks. Furthermore, six months after the therapy, the patient did not experience any symptoms. Long-term follow-up will be conducted in cases of symptom recurrence or cyst enlargement.

Radical Removal of Low-Differentiation Thymic Squamous Cell Carcinoma: A Rare Clinical Case.

The presented case report demonstrates the successful operative treatment of a patient with thymic carcinoma located in the anterior mediastinum, infiltrating the vena cava, and affecting the upper lobe of the left lung. Our multidisciplinary approach, incorporating various operative techniques, proved effective in treating this type of pathology. The Clinic for Thoracic Surgery at UMHAT Kaspela, Plovdiv admitted a 72-year-old female patient due to complaints related to her cardiovascular and respiratory systems. The patient presented with symptoms such as chest pain, shortness of breath, cough with expectoration, and the presence of blood in her sputum. Additionally, the patient exhibited an increased temperature and experienced shortness of breath at rest. Extensive imaging and diagnostic studies were performed, including computed axial tomography of the chest with contrast material, echocardiography, functional breathing tests, and laboratory tests. The clinical board unanimously agreed that operative treatment was necessary, and the techniques used included robot-assisted surgery and median sternotomy. A low-differentiated carcinoma was identified during the surgical intervention and confirmed through patho-anatomical examination (frozen section) and permanent histological preparation. Immunohistochemical examination revealed that the immunophenotype of the tumor corresponds to thymic neuroplastic squamous cell carcinoma (poorly differentiated). The patient had a smooth postoperative period and was discharged in a satisfactory general condition.

Natural and Synthetic Polymers for Biomedical and Environmental Applications.

Natural and synthetic polymers are a versatile platform for developing biomaterials in the biomedical and environmental fields. Natural polymers are organic compounds that are found in nature. The most common natural polymers include polysaccharides, such as alginate, hyaluronic acid, and starch, proteins, e.g., collagen, silk, and fibrin, and bacterial polyesters. Natural polymers have already been applied in numerous sectors, such as carriers for drug delivery, tissue engineering, stem cell morphogenesis, wound healing, regenerative medicine, food packaging, etc. Various synthetic polymers, including poly(lactic acid), poly(acrylic acid), poly(vinyl alcohol), polyethylene glycol, etc., are biocompatible and biodegradable; therefore, they are studied and applied in controlled drug release systems, nano-carriers, tissue engineering, dispersion of bacterial biofilms, gene delivery systems, bio-ink in 3D-printing, textiles in medicine, agriculture, heavy metals removal, and food packaging. In the following review, recent advancements in polymer chemistry, which enable the imparting of specific biomedical functions of polymers, will be discussed in detail, including antiviral, anticancer, and antimicrobial activities. This work contains the authors' experimental contributions to biomedical and environmental polymer applications. This review is a vast overview of natural and synthetic polymers used in biomedical and environmental fields, polymer synthesis, and isolation methods, critically assessessing their advantages, limitations, and prospects.

pH-responsive niosome-based nanocarriers of antineoplastic agents.

Differences in pH between the tumour interstitium and healthy tissues can be used to induce conformational changes in the nanocarrier structure, thereby triggering drug release at the desired site. In the present study, novel pH-responsive nanocarriers were developed by modifying conventional niosomes with hexadecyl-poly(acrylic acid)n copolymers (HD-PAAn). Niosomal vesicles were prepared by the thin film hydration method using Span 60, Span 60/Tween 60 and cholesterol as main constituents, and HD-PAA modifiers of different concentrations (0.5, 1, 2.5, 5 mol%). Next, two model substances, a water-soluble fluorescent dye (calcein) and a hydrophobic agent with pronounced antineoplastic activity (curcumin), were loaded in the aqueous core and hydrophobic membrane of the elaborated niosomes, respectively. Physicochemical properties of blank and loaded nanocarriers such as hydrodynamic diameter (Dh), size distribution, zeta potential, morphology and pH-responsiveness were investigated in detail. The cytotoxicity of niosomal curcumin was evaluated against human malignant cell lines of different origins (MJ, T-24, HUT-78), and the mechanistic aspects of proapoptotic effects were elucidated. The formulation composed of Span 60/Tween 60/cholesterol/2.5% HD-PAA17 exhibited optimal physicochemical characteristics (Dh 302 nm; ζ potential -22.1 mV; high curcumin entrapment 83%), pH-dependent drug release and improved cytotoxic and apoptogenic activity compared to free curcumin.

Anaplastic Transformation of Sphenoid Wing Meningioma With Orbital and Cavernous Sinus Invasion: Unveiling the Aggressive Nature.

Primary tumors in the central nervous system, known as meningiomas, are frequently found and constitute a substantial proportion of tumor cases. Although generally benign, there are occasional cases where they might exhibit malignant characteristics. Anaplastic meningioma is a rare subtype of malignant meningiomas, representing only a small proportion of cases. We present the case of a 70-year-old female patient who presented to the Neurosurgery Clinic of University Hospital "Saint George" with clinical manifestations of monocular vision and blurry vision in the right eye for three months. On physical examination, unilateral ptosis and mydriasis were noted in the left eye. MRI revealed an extra-axial mass located supratentorial in the left temporopolar region affecting the wing of the left sphenoidal bone, invading the cavernous sinus, suppressing the left and right optic nerves, and involving the left orbit. Operative treatment was performed through a left pterional craniotomy and resection of the tumor mass by microsurgical technique. The subdural, epidural, and intraorbital mass were resected. Total removal of the tumor was not achievable and subtotal resection was performed. Pathology results showed that the tumor mass was anaplastic meningioma. Surgery-related complications were not observed. Postoperatively, the patient was mobilized on the day after intervention and the control CT scan showed no ischemic or hemorrhagic events. The patient experienced relief in her symptoms and was discharged on the fifth day. The patient underwent radiation therapy, resulting in the complete removal of the left tumor in the cavernous sinus. After six months, no tumor recurrence was found, and a long-term follow-up is planned to monitor for possible recurrence.

Epidemiological Study of Traumatic Brain and Spinal Injuries in a Pediatric Population: A One-Year Analysis of Prevalence, Causes and Trends.

Background Traumatic brain injury (TBI) and spinal cord injury (SCI) are leading causes of morbidity and mortality in pediatric patients. However, the epidemiology of pediatric brain and spine injuries in Bulgaria is poorly documented. This study aims to analyze and identify the prevalence, causes, and trends of traumatic brain and spinal cord injuries in pediatric patients during the period of 1st June 2022 to 30th June 2023. Methods A retrospective study was conducted on the medical records of patients under 18 years of age who visited the emergency department of University Multiprofile Hospital for Active Treatment (UMHAT) Burgas, Bulgaria between 1st June 2022 and 30th June 2023. The incidence and etiology were stratified by age, gender, and anamnesis. Data processing and analysis were performed with the statistical package IBM SPSS v. 26.0 (IBM Corp., Armonk, NY, USA), and graphical analysis with MS Office Excel 2016 (Microsoft, Redmond, WA, USA). Means ± standard deviation and 95% confidence interval were calculated. All p-values less than 0.05 were considered indicative of statistical significance. Results Data for patients aged <18 years, admitted to the emergency department (ED) of UMHAT Burgas, Bulgaria from 1st June 2022 to 30th June 2023 were analyzed (n=38504). Of these patients, 32% were children (n=13857). One hundred thirty-four (0.3%) of the pediatric patients were hospitalized in the neurosurgical ward, and 4653 (10.7%) were hospitalized in other wards. Of the analyzed patients, 89 are boys (66.4%), 45 are girls (33.6%) (male-female ratio 2:1) and the mean age of the patients with a head trauma was 8.07 years old. The average number of patients by diagnosis is 13.4±35.37. The largest percent are patients with brain concussion (85.07%, n=114), followed by contusion of the nerve roots in the lumbar region or late contusion wound of the head (with 2.99% each, n=4); hydrocephalus or skull fracture (with 2.24% each, n=3); contusion of the nerve roots in the thoracic region (1.49%, n=2); and fracture at Th9 vertebrae, fracture at C2 vertebrae, brain trauma or brain tumor (with 0.75% each, n=1). The average number of patients by anamnesis is 13.2±17.99. The largest percent are patients who fall from their own height (44.78%, n=60); followed by falls from height (20.90%, n=28); car accident (7.46%, n=10); injured by fight, fall from a bicycle or incident during a football game (with 5.97% each, n=8); fall from electric scooter (4.48%, n=6); hit in the closet (2.99%, n=4); and finally from bike accident or hit by a rock (with 0.75% each, n=1). From 134 hospitalized patients in neurosurgery, 114 (85.07%) did not require surgical treatment and were treated with conservative treatment and 20 (14.93%) were treated surgically.  Conclusion In conclusion, this study highlights a significant burden of pediatric traumatic brain and spinal injuries in Bulgaria. The majority of cases were managed conservatively, emphasizing the need for preventive measures.

In Situ Gelling Hydroxypropyl Cellulose Formulation Comprising Cannabidiol-Loaded Block Copolymer Micelles for Sustained Drug Delivery.

Cannabidiol (CBD) is a natural terpenophenolic compound with known pharmacological activities, but the poor solubility of CBD in water limits its widespread use in medicine and pharmacy. Polymeric (nano)carriers demonstrated high potential for enhancing the solubility and therapeutic activity of lipophilic drugs such as CBD. Here, we report the elaboration of a novel hydroxypropyl cellulose (HPC)-based in situ gelling formulation for controlled delivery of CBD. In the first stage, nanosized polymeric micelles from poly(ethylene oxide)-block-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone) (PEO-b-P(CyCL-co-CL) diblock copolymers) were used to increase the solubility of CBD in water. Different copolymers were assessed, and the carrier with the highest encapsulation efficiency (EE) and drug loading capacity (DLC) was selected for further elaboration of nanocomposite in situ gel formulations. Next, the sol-to-gel transition behavior of HPC as a function of K2SO4 concentration in the aqueous solution was investigated by microcalorimetry and dynamic oscillatory rheology, and the optimal formulation capable of forming a physical gel under physiological conditions was determined. Finally, injectable nanocomposite hydrogels comprising cannabidiol were fabricated, and their drug release profile and cytotoxicity against human tumor cell lines were evaluated. The in situ gels exhibited prolonged drug release over 12 h, controlled by gel erosion, and the cytotoxicity of formulated cannabidiol was comparable with that of a free drug.

Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol.

The present study describes the development of novel block copolymer nanocarriers of the phytocannabinoid cannabidiol (CBD), designed to enhance the solubility of the drug in water while achieving high encapsulation efficiency and prolonged drug release. Firstly, a well-defined amphiphilic block copolymer consisting of two outer hydrophilic polyglycidol (PG) blocks and a middle hydrophobic block of poly(ε-caprolactone) bearing pendant cinnamyl moieties (P(CyCL-co-CL)) were synthesized by the click coupling reaction of PG-monoalkyne and P(CyCL-co-CL)-diazide functional macroreagents. A non-modified polyglycidol/poly(ε-caprolactone) amphiphilic block copolymer was obtained as a referent system. Micellar carriers based on the two block copolymers were formed via the solvent evaporation method and loaded with CBD following two different protocols-loading during micelle formation and loading into preformed micelles. The key parameters/characteristics of blank and CBD-loaded micelles such as size, size distribution, zeta potential, molar mass, critical micelle concentration, morphology, and encapsulation efficiency were determined by using dynamic and static multiangle and electrophoretic light scattering, transmission electron microscopy, and atomic force microscopy. Embedding CBD into the micellar carriers affected their hydrodynamic radii to some extent, while the spherical morphology of particles was not changed. The nanoformulation based on the copolymer bearing cinnamyl moieties possessed significantly higher encapsulation efficiency and a slower rate of drug release than the non-modified copolymer. The comparative assessment of the antiproliferative effect of micellar CBD vs. the free drug against the acute myeloid leukemia-derived HL-60 cell line and Sezary Syndrome HUT-78 demonstrated that the newly developed systems have pronounced antitumor activity.

Incorporation of Resveratrol in Polymeric Nanogel for Improvement of Its Protective Effects on Cellular and Microsomal Oxidative Stress Models.

Nanogels are attractive drug delivery systems that provide high loading capacity for drug molecules, improve their stability, and increase cellular uptake. Natural antioxidants, especially polyphenols such as resveratrol, are distinguished by low aqueous solubility, which hinders therapeutic activity. Thus, in the present study, resveratrol was incorporated into nanogel particles, aiming to improve its protective effects in vitro. The nanogel was prepared from natural substances via esterification of citric acid and pentane-1,2,5-triol. High encapsulation efficiency (94.5%) was achieved by applying the solvent evaporation method. Dynamic light scattering, atomic force microscopy, and transmission electron microscopy revealed that the resveratrol-loaded nanogel particles were spherical in shape with nanoscopic dimensions (220 nm). In vitro release tests showed that a complete release of resveratrol was achieved for 24 h, whereas at the same time the non-encapsulated drug was poorly dissolved. The protective effect of the encapsulated resveratrol against oxidative stress in fibroblast and neuroblastoma cells was significantly stronger compared to the non-encapsulated drug. Similarly, the protection in a model of iron/ascorbic acid-induced lipid peroxidation on rat liver and brain microsomes was higher with the encapsulated resveratrol. In conclusion, embedding resveratrol in this newly developed nanogel improved its biopharmaceutical properties and protective effects in oxidative stress models.

Micellar Form of a Ferrocene-Containing Camphor Sulfonamide with Improved Aqueous Solubility and Tumor Curing Potential.

The discovery of new anticancer drugs with а higher, more specific activity and diminished side effects than the conventional chemotherapeutic agents is a tremendous challenge to contemporary medical research and development. To achieve a pronounced efficacy, the design of antitumor agents can combine various biologically active subunits in one molecule, which can affect different regulatory pathways in cancer cells. We recently demonstrated that a newly synthesized organometallic compound, a ferrocene-containing camphor sulfonamide (DK164), possesses promising antiproliferative activity against breast and lung cancer cells. However, it still encounters the problem of solubility in biological fluids. In this work, we describe a novel micellar form of DK164 with significantly improved solubility in aqueous medium. DK164 was embedded in biodegradable micelles based on a poly(ethylene oxide)-b-poly(α-cinnamyl-ε-caprolactone-co-ε-caprolactone)-b-poly(ethylene oxide) triblock copolymer (PEO113-b-P(CyCL3-co-CL46)-b-PEO113), and the physicochemical parameters (size, size distribution, zeta potential, encapsulation efficiency) and biological activity of the obtained system were studied. We used cytotoxicity assays and flow cytometry to determine the type of cell death, as well as immunocytochemistry to assess the influence of the encapsulated drug on the dynamics of cellular key proteins (p53 and NFkB) and the process of autophagy. According to our results, the micellar form of the organometallic ferrocene derivate (DK164-NP) exhibited several advantages compared to the free substance, such as higher metabolic stability, better cellular uptake, improved bioavailability, and long-term activity, maintaining nearly the same biological activity and anticancer properties of the drug.

Multidisciplinary Management of Invasive Basal Cell Carcinoma With Intracranial Invasion: A Rare Case Report.

The most prevalent kind of skin cancer is basal cell carcinoma (BCC). BCC invasion of the brain occurs quite rarely. Reconstruction approaches along with surgical excision are the gold standard for treating BCC. In this case, we describe a 75-year-old female patient with highly invasive BCC of the head with subdural invasion. The patient underwent surgery in 2022 in another neurosurgery clinic due to BCC of the head, frequent infection of the skin, and involvement of bone structures by the tumor. The patient presented in 2023 to the neurosurgery clinic at Saint Marina University Hospital with cephalgia, right-side hemiparesis, and a 10 x 10 cm skin defect. On a CT scan, we discovered an invasion of the parietal bones of the skull with an extension to the left subdural space. A craniectomy was performed under general anesthesia, along with hard resection to clear the margins of the BCC that had penetrated the cranial bone. Following the resection of the BCC, reconstruction of the skin defect was performed by a plastic surgeon. Consequently, a satisfactory cosmetic outcome was achieved. Postoperative complications were not observed. The patient was followed up for six months.

Аn Unusual Case of an Epidural Lesion of the Lumbar Spine: Tumor or Hematoma?

Spinal epidural hematoma is a rare clinical entity with an incidence of approximately one per 1,000,000 patients per year. Spinal epidural hematoma is a lesion that can cause spinal cord compression or cauda equina syndrome. We report a clinical case of Ð° 69-year-old male patient who presented to the Neurosurgery Clinic of the General Hospital for Active Treatment "Dobrich" with pain and weakness in both legs for two months after falling in the bathroom. MRI revealed an L2-L3 fracture and a formation in the L2-L3 epidural space, which was compressing the nerve roots. An operative treatment was performed under general anesthesia and, intraoperatively, it was discovered that the formation was a hematoma. Aspiration of the hematoma and decompression of the spinal canal were performed. An L2-L3 stabilization with pedicle screws was done due to total laminectomy and potential instability. Postoperatively, the patient was mobilized on the day after intervention, and no surgery-related complications were observed. The patient experienced relief from his symptoms and was discharged on the fifth day. Six months post-surgery, the patient started to experience pain in his left leg. Radiography showed coxarthrosis on the left hip joint and the patient was referred to the orthopedics for further treatment.

Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.

Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

Redox-Responsive Crosslinked Mixed Micelles for Controllable Release of Caffeic Acid Phenethyl Ester.

We report the elaboration of redox-responsive functional micellar nanocarriers designed for triggered release of caffeic acid phenethyl ester (CAPE) in cancer therapy. Three-layered micelles, comprising a poly(ε-caprolactone) (PCL) core, a middle poly(acrylic acid)/poly(ethylene oxide) (PAA/PEO) layer and a PEO outer corona, were prepared by co-assembly of PEO113-b-PCL35-b-PEO113 and PAA13-b-PCL35-b-PAA13 amphiphilic triblock copolymers in aqueous media. The preformed micelles were loaded with CAPE via hydrophobic interactions between the drug molecules and PCL core, and subsequently crosslinked by reaction of carboxyl groups from PAA and a disulfide crosslinking agent. The reaction of crosslinking took place in the middle layer of the nanocarriers without changing the encapsulation efficiency (EE~90%) of the system. The crosslinked polymeric micelles (CPMs) exhibited superior structural stability and did not release CAPE in phosphate buffer (pH 7.4). However, in weak acidic media and in the presence of 10 mM reducing agent (dithiothreitol, DTT), the payload was released at a high rate from CPMs due to the breakup of disulfide linkages. The physicochemical properties of the nanocarriers were investigated by dynamic and electrophoretic light scattering (DLS and ELS) and atomic force microscopy (AFM). The rapid release of CAPE under intracellular-like conditions and the lack of premature drug release in media resembling the blood stream (neutral pH) make the developed CPMs a promising candidate for controllable drug release in the microenvironment of tumors.

Polysaccharide Cryogels Containing ß-Cyclodextrin for the Delivery of Cannabidiol.

Cannabidiol (CBD) has attracted increasing interest due to its therapeutic potential for treating numerous diseases. However, CBD is very lipophilic and has very unfavorable pharmacokinetics and low bioavailability. Efforts are focused on developing drug delivery systems for enhanced solubilization and therapeutic activity of CBD. Here, we report the preparation of original super-macroporous cryogels from 2-hydroxyethyl cellulose (HEC) and ß-cyclodextrin (ß-CD) designed for the topical delivery of CBD. The cryogels were synthesized by photochemical crosslinking in a frozen aqueous system, purified, and then loaded with CBD. The effect of HEC/ß-CD mass ratio (100:0; 50:50; 40:60 and 20:80) in the reaction mixture on the reaction efficiency, physico-mechanical properties of cryogels, drug release profile, and antineoplastic potential were evaluated in detail. The cryogels showed a bi-phasic release behavior: initial burst release in the first 3 hours followed by slower drug release which can be beneficial in the treatment of cutaneous neoplastic diseases.