Preparation and characterization of brain-targeted polymeric nanocarriers (Frankincense-PMBN-lactoferrin) and in-vivo evaluation on an Alzheimer's disease-like rat model induced by scopolamine.

Experiments have demonstrated that frankincense may offer protection against scopolamine-induced Alzheimer's disease by mitigating cholinergic dysfunction and inhibiting inflammatory mediators. Nevertheless, its instability and limited water solubility lead to diminished medicinal efficacy. In this study, we utilized PMBN (poly [MPC-co-(BMA)-co-(MEONP)]) as a nanocarrier for targeted brain drug delivery of frankincense, employing lactoferrin as a ligand for precise targeting. Characterization of nanoparticle properties was conducted through FTIR and FESEM analysis, and the in-vitro drug release percentage from the nanoparticles was quantified. To induce Alzheimer's-like dementia in rats, scopolamine was intraperitoneally administered at a dose of 1 mg/kg/day for 14 days. Subsequently, behavioral assessments (Y-maze, passive avoidance test, tail suspension test) were performed, followed by evaluations of acetylcholinesterase (AChE), reduced glutathione (GSH), catalase (CAT), and brain histopathology at the conclusion of the treatment period. The results revealed that the nanoparticles had a size of 106.6 nm and a zeta potential of -3.8 mV. The maximum release of frankincense in the PBS environment from PMBN nanoparticles was 18.2 %, in accordance with the Peppas model. Behavioral tests indicated that targeted drug nanoparticles (F-PMBN-Lf) exhibited the capability to alleviate stress and depression while enhancing short-term memory in scopolamine-induced animals. Additionally, F-PMBN-Lf counteracted the scopolamine-induced elevation of AChE activity and GSH levels. However, it resulted in decreased activity of the antioxidant enzyme CAT compared to the scopolamine group. Histological analysis of brain tissue suggested that F-PMBN-Lf exerted a notable neuroprotective effect, preserving neuronal cells in contrast to the scopolamine-induced group. It appears that the polymer nanoparticles containing this plant extract have introduced a novel neuroprotective approach for the treatment of Alzheimer's disease.

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer's Disease Brain Pathology Exacerbated by Sleep Deprivation.

Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer's disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AßP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AßP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier.

Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson's Disease.

Parkinson's disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AßP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AßP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AßP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AßP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD.

Nanowired Delivery of Curcumin Attenuates Methamphetamine Neurotoxicity and Elevates Levels of Dopamine and Brain-Derived Neurotrophic Factor.

Curcumin is a well-known antioxidant used as traditional medicine in China and India since ages to treat variety of inflammatory ailments as a food supplement. Curcumin has antitumor properties with neuroprotective effects in Alzheimer's disease. Curcumin elevates brain-derived neurotrophic factor (BDNF) and dopamine (DA) levels in the brain indicating its role in substance abuse. Methamphetamine (METH) is one of the most abused substances in the world that induces profound neurotoxicity by inducing breakdown of the blood-brain barrier (BBB), vasogenic edema and cellular injuries. However, influence of curcumin on METH-induced neurotoxicity is still not well investigated. In this investigation, METH neurotoxicity and neuroprotective effects of curcumin nanodelivery were examined in a rat model. METH (20 mg/kg, i.p.) neurotoxicity is evident 4 h after its administration exhibiting breakdown of BBB to Evans blue albumin in the cerebral cortex, hippocampus, cerebellum, thalamus and hypothalamus associated with vasogenic brain edema as seen measured using water content in all these regions. Nissl attaining exhibited profound neuronal injuries in the regions of BBB damage. Normal curcumin (50 mg/kg, i.v.) 30 min after METH administration was able to reduce BBB breakdown and brain edema partially in some of the above brain regions. However, TiO2 nanowired delivery of curcumin (25 mg/kg, i.v.) significantly attenuated brain edema, neuronal injuries and the BBB leakage in all the brain areas. BDNF level showed a significant higher level in METH-treated rats as compared to saline-treated METH group. Significantly enhanced DA levels in METH-treated rats were also observed with nanowired delivery of curcumin. Normal curcumin was able to slightly elevate DA and BDNF levels in the selected brain regions. Taken together, our observations are the first to show that nanodelivery of curcumin induces superior neuroprotection in METH neurotoxicity probable by enhancing BDNF and DA levels in the brain, not reported earlier.

Glycolysis-based drug delivery nanosystems for therapeutic use in tumors and applications.

Tumor cells are able to use glycolysis to produce energy under hypoxic conditions, and even under aerobic conditions, they rely mainly on glycolysis for energy production, the Warburg effect. Conventional tumor therapeutic drugs are unidirectional, lacking in targeting and have limited therapeutic effect. The development of a large number of nanocarriers and targeted glycolysis for the treatment of tumors has been extensively investigated in order to improve the therapeutic efficacy. This paper reviews the research progress of nanocarriers based on targeting key glycolytic enzymes and related transporters, and combines nanocarrier systems with other therapeutic approaches to provide a new strategy for targeted glycolytic treatment of tumors, providing a theoretical reference for achieving efficient targeted treatment of tumors.

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-ß1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

Gold Nanoparticles Functionalized with Au-Se-Bonded Peptides Used as Gatekeepers for the Off-Target Release of Resveratrol in the Treatment of Triple-Negative Breast Cancer.

Resveratrol has been garnering considerable attention as a promising chemopreventive and chemotherapeutic drug against metastatic tumors such as triple-negative breast cancer (TNBC). However, the potential in vivo application of resveratrol has been highly limited due to its poor solubility, rapid conjugation, low bioavailability, and bioactivity. In this study, a silica mesoporous nanoparticle (MSN)-based drug delivery system (DDS), named Au-Se@MSN, is developed to deliver the loaded resveratrol, endowing it with properties of targeted delivery, excellent bioavailability, and antioxidation of resveratrol. In Au-Se@MSN(RES), gold nanoparticles functionalized with selenol-modified uPA-specific peptides act as gatekeepers to avoid the interference of glutathione in the bloodstream and realize negligible premature release of resveratrol during delivery. Au-Se@MSN(RES) shows prolonged resveratrol release at the tumor site and endows resveratrol with a remarkable in vitro therapeutic effect. The pharmacological dose of resveratrol treatment on MDA-MB-231 cells was found to result in the generation of a high level of NAD(P)H other than H2O2, indicating reductive stress instead of oxidative stress involved in the resveratrol therapeutic process. In vivo experiments showed that Au-Se@MSN greatly improves the chemotherapeutic effect of resveratrol on mice bearing TNBC tumors, and damage to normal tissues and cells is negligible. Overall, Au-Se@MSN is a potential tool for further studies on the anticancer mechanism and clinical applications of resveratrol.

Polymer drug conjugates containing memantine, tacrine and cinnamic acid: promising nanotherapeutics for the treatment of Alzheimer's disease.

AIM: To prepare polymer-drug conjugates containing a combination of memantine, tacrine, and E)-N-(3-aminopropyl)cinnamide, promising therapeutics for the treatment of neurodegenerative disorders. METHODS: The conjugates were characterised by 1HNMR, particle size analysis, SEM, LC-MS, TEM/EDX, and XRD, followed by in vitro anti-acetylcholinesterase and drug release studies. RESULTS: 1H NMR analysis revealed successful drug conjugation with drug mass percentages in the range of 1.3-6.0% w/w. The drug release from the conjugates was sustained for 10 h in the range of 20-36%. The conjugates' capability to inhibit acetylcholinesterase (AChE) activity was significant with IC50 values in the range of 13-44.4 µm which was more effective than tacrine (IC50 =1698.8 µm). The docking studies further confirmed that the conjugation of the drugs into the polymer improved their anti-acetylcholinesterase activity. CONCLUSION: The drug release profile, particle sizes, and in vitro studies revealed that the conjugates are promising therapeutics for treating neurodegenerative disorders.

Hyaluronic Acid-Guided Cerasome Nano-Agents for Simultaneous Imaging and Treatment of Advanced Atherosclerosis.

Early noninvasive screening and regression therapy for vulnerable atherosclerotic plaques remain challenging. In this study, it is aimed to develop a new approach for the active targeting of atherosclerotic plaques with nano-agents to aid imaging and treatment. Biocompatible hyaluronic acid (HA)-guided cerasomes are generated to selectively target CD44-positive cells within the plaque in in vitro studies and in vivo testing in Apoe-/- mice. Rosuvastatin (RST) is encapsulated in the HA-guided cerasome nano-formulation to produce HA-CC-RST, which results in significant plaque regression as compared to treatment with the free drug. Moreover, gadodiamide-loaded HA-CC enhances magnetic resonance images of vulnerable plaques, thereby attaining the goal of improved simultaneous treatment and imaging. Transcriptomic analysis confirms plaque regression with HA-CC-RST treatment, which potentially benefits from the anti-inflammatory effect of RST. In summary, a safe and efficient nano-formulation for the targeted delivery of active agents to atherosclerotic plaques is developed and may be applicable to other diagnostic and therapeutic agents for atherosclerosis treatment.

Evaluation of Auranofin Loading within Ferritin Nanocages.

Auranofin (AF), a gold(I) compound that is currently used for the treatment of rheumatoid arthritis and is in clinical trials for its promising anticancer activity, was encapsulated within the human H-chain and the horse spleen ferritin nanocages using the alkaline disassembly/reassembly protocol. The aim of the work was to highlight possible differences in their drug loading capacity and efficacy. The drug-loaded ferritins were characterized via UV-vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy to assess AF encapsulation and to define the exact amount of gold atoms trapped in the Ft cavity. The crystal structures allowed us to define the nature of AF interaction with both ferritins and to identify the gold binding sites. Moreover, the biological characterization let us to obtain preliminary information on the cytotoxic effect of AF when bound to the human H-chain.

Turmeric-derived nanovesicles as novel nanobiologics for targeted therapy of ulcerative colitis.

Rationale: Ulcerative colitis (UC), a typical kind of inflammatory bowel disease (IBD), is an idiopathic chronic intestinal inflammation. Conventional therapeutic strategies mainly focus on the rebalance of pro-inflammation and anti-inflammation cytokines, whereas targeting damaged intestinal barriers, imbalanced intestinal microbiota and dysregulated mucosal immune responses in UC remain a big challenge. The objective of this study was to develop turmeric-derived nanovesicles (TNVs) for alleviation of colitis and explore the underlying mechanisms. Methods: TNVs were isolated and purified through differential centrifugation. The targeted ability was evaluated on the dextran sulfate sodium (DSS)-induced mouse model by IVIS imaging system. The anti-inflammation efficacy was studied in lipopolysaccharide (LPS)-induced macrophages and DSS-induced acute and chronic colitic mouse model. In addition, the influence of TNVs on the intestinal microbiota was investigated via 16S rRNA microbiome sequence and the condition of macrophage polarization after TNVs treatment was analyzed by flow cytometry. Results: TNVs were isolated and characterized as nano-size spheroids. The IVIS imaging experiment indicated that orally administrated TNVs could accumulate in the inflamed colon sites and exhibited superior anti-inflammatory activity both in vitro and in vivo. The 16S rRNA sequencing suggested the important role of TNVs in the regulation of gut microbiota. Further, TNVs could promote the transformation of M1 phenotype to M2 macrophages and restore the damaged intestinal epithelium barrier to exert the anti-colitis efficacy. Conclusion: Collectively, oral administration of TNVs exhibited excellent anti-inflammatory efficacy through restoring the damaged intestinal barrier, regulating the gut microbiota and reshaping the macrophage phenotype. This study sheds light on the application of natural exosome-like nanovesicles for the treatment of UC.

The Effect of Microcirculation Disturbance of Peribiliary Vascular Plexus on Hepatic Bile Duct Epithelial Cells in Rats Undergoing Liver Transplantation and Postoperative Rejection Reduction by Nanocarrier Mediation.

This study was to investigate the effect of microcirculation disturbance of PVP on HBD epithelial cells in rats undergoing liver transplantation and to explore the postoperative rejection reduction by nanocarriers mediation. For this aim, adult male rats weighing 210-250 g, were fed cleanly and were subjected to liver transplantation. 3 days after the surgery, the rats were randomly divided into three groups based on different intervention factors: group A (HAL), group B (HAMI combined with HAL), and group C (control). The three groups of rats were divided into three subgroups according to the duration of the University of Wisconsin (UW) solution (UW time) used to preserve the donor organs for transplantation, which were 2h, 8h, and 16h, respectively. In addition, the RNA sequence of rat class-II transactivator (CIITA) the rat was searched, and the target interference sequence was designed concerning the RNA. Results showed that the carrier nanoparticles were spherical without obvious oxygen vacancies, the distribution was relatively tight and concentrated, and the main particle size was 50-140 nm. As the mass ratio of HGPAE to DNA increased, the mobility speed of the nanocarrier/shRNA plasmid complex decreased due to the decrease in surface charge. When the mass ratio reached 90:1, the mobility of the complex was completely blocked, suggesting that the DNA was completely compounded. The counts of PCNA, CK-19, F-VIII-Ag, VEGFA, VEGFB, and VEGFC in the 3 groups all showed a downward trend with the increase of UW time; the count in group B was lower than that of groups A and C. In the PCNA count statistics, there was no obvious difference between group A and group B at UW8h, but there were differences in contrast to group C (p<0.05). It was concluded that the blood supply of the microcirculation of the PVP was extremely important for the transplanted liver tissue. When the blood vessels around the HBD of the rat were completely ischemic, the HBD epithelial cells became the most important target of damage, and the proliferation and changes of the HBD epithelial cells can be directly observed. In addition, the nanocarrier-mediated genes were applied to discuss postoperative rejection. The expression of class-II MHC-II gene in nanocarrier CIITA-shRNA was inhibited, which interfered with the recipient's immune recognition of the graft, thereby reducing the intensity of the rejection reaction and relieving the rejection reaction.

Effect of Peptide Drug Liraglutide Nano-Formulation Combined with Sodium-Glucose Cotransporter-2 Inhibitor on Blood Lipids in Patients with Type 2 Diabetes.

With the aging of our population and the increase in the number of obese people, diabetes has become a common disease. At present, drug treatment is mainly used for diabetes. Dyslipidemia is the main cause of diabetes. The regulation of blood lipids in diabetic patients through drugs is the key to treating diabetes. The purpose of this article is to further explore the specific effect and mechanism of peptide drug liraglutide nano-formulation combined with sodium-glucose co-transporter-2(SGCT-2) inhibitor on blood lipids in patients with type 2 diabetes. This article uses 30 people included in our hospital in 2019 2 patients with type 2 diabetes are divided into the group of peptide drug liraglutide nano preparations, the group of SGCT-2 inhibitors and the peptide drug liraglutide nano preparations combined with SGCT-2. In the inhibitor combination medication group, patients were given drug intervention according to the group name with the consent of the patients. After three days, the serum cholesterol, triglyceride, lipoprotein and lipid metabolism levels of all patients were tested. The results showed that under the intervention of peptide drug liraglutide nanoparticles combined with SGCT-2 inhibitor, the cholesterol level of patients with type 2 diabetes decreased from (368.2 ± 8.3) mmol / L to (1978.4 ± 4.7) mmol/L, triglyceride level decreased from (653.7 ± 12.5) mg/dL to (426.8 ± 9.6) mg/dl, and lipid metabolism level increased by 25.6%. Therefore, it can be seen that the peptide drug liraglutide nano preparation combined with SGCT-2 inhibitor has a certain therapeutic effect on type 2 diabetes.

Analysis of Inhibitory Effect of the Double-layer Nano-infusion on Vascular Restenosis in Animal Models of Coronary Atherosclerosis.

This study aimed to investigate the effect of double-layer nano-infusion on restenosis in animal models of coronary atherosclerosis (CAD). For this purpose, forty Apolipoprotein E (APOE) gene mice (ApoE -/ -) were fed with 1.25% cholesterol, 10% fat, and 88.75% standard diet to establish CAD models. They were classified into the control group with paclitaxel nanoparticles (PTX-NPs) and the observation group with balloon infusion of PTX combined with vascular endothelial growth factor (VEGF) double-layer nanoparticles (V-P-NPs). The vascular endothelial healing and the occurrence of vascular restenosis were assessed. Results showed no significant differences in the particle size, distribution, and Zeta-potential between PTX-NPs and V-P-NPs (P>0.05). According to the transmission electron microscope (TEM), the nanoparticles had good dispersity, and the structure of the inner and outer layers of V-P-NPs was obvious. There were insignificant differences between the entrapment efficiency of PTX in PTX-PNS and the PTX and VEGF in V-P-NPs (94.32%, 95.66%, 97.89%) and drug-loading rate (28.91%, 30.12%, 29.91%) (P>0.05). The vascular endothelial healing degree of the observation group was better than that of the control group under optical coherence tomography (OCT). The restenosis, including the stenosis (6.91±7.59)%, proliferation (0.12±0.02), and the maximum intima thickness (0.07±0.09)mm of the observation group was decreased compared with the control group ((24.01±12.78)%, (0.28±0.01), (0.19±0.08)mm) (P<0.05). Then the double-layer nano-infusion therapy was conducive to healing vascular endothelial tissue and could effectively inhibit vascular restenosis, with clinical adoption value.

The Intervention of Nano-targeted Drugs & Angioplastryin Treatment and Prevention of Vascular Restenosis and its Influence on Monocyte Chemotactic Protein-1 in Lower Extremity Angiopathy.

It was to make use of the nano-targeted drugs and angioplastry to treat and prevent the vascular restenosis and analyze its influence on monocyte chemotactic protein 1 (MCP-1) of lower extremity angiopathy (LEA) patients since the patients with diabetic lower extremity angiopathy may be easily infected with vascular restenosis. In this article, the dexamethasone nano drugs were firstly prepared. After that, its related physical and chemical properties were tested, then, dexamethasone nano drugs were applied in treating patients with diabetic lower extremity angiopathy. The results showed that the prepared dexamethasone nanoparticles' encapsulation rate attained 99.2%. The laser light scattering experiment manifested that the particle size of the nanoparticles ranged from 200 to 300nm, and the average particle size was 258nm. The MCP-1 of the control group, conventional group, and observation group were 33.28±1.93 µg/mL, 78.27±9.73 µg/mL, and 75.29±8.99 µg/mL, respectively. The MCP-1 values of the conventional and observation groups were higher than that of the control group, and there was a notable difference (P<0.05). After interventional treatment, the MCP-1 level of the conventional group was 57.82±5.82 µg/mL, and that of the observation group was 41.93±6.92 µg/mL. The MCP-1 level of the group which received the treatment of nano-targeted drugs and angioplastry was superior to that of the conventional group which received the traditional operation, and there was a notable difference (P<0.05). In conclusion, MCP-1 is one of the major causes of lower extremity angiopathy. The nano-targeted drugs and angioplastry can raise the expression level of MCP-1 in patients with lower extremity angiopathy. The experimental results had a high application value and the nano-targeted drugs & angioplastry can be promoted clinically.

The Mechanism of Action of Nanomaterials Loaded with Clarithromycin after Sinusitis Surgery under the Guidance of Dynamic Enhanced Scanning.

This study was to explore the mechanism of action of nanomaterial-loaded clarithromycin (CLA) after sinusitis surgery. Under the guidance of dynamic enhanced scanning (DES). 120 patients with sinusitis admitted to the First Affiliated Hospital of China Medical University from July 2019 to March 2020 were selected and divided into a control group and an observation group according to the random number table method, with 60 cases in each group. Then, the CLA-containing nano-polylactic acid material was prepared, observed with the scanning electron microscope (SEM), and its drug release ability was tested. All patients underwent endoscopic sinus surgery under general anesthesia. After the surgery was completed, patients in the control group were given only CLA capsules, and patients in the observation group were given freshly prepared nanomaterial-loaded CLA, and both groups of patients were continuously observed for two weeks. After that, the patients were examined using the dynamic enhancement computed tomography (CT). The clinical efficacy, serum interleukin-4 (IL-4), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α) levels of the two groups of patients were observed. The secretions of the patients' sinuses were performed with microbial bacterial culture, and the results were observed and recorded. Results showed that the characterization and analysis of the nano drug-carrying preparation suggested that the polylactic acid nanomembrane showed linear fiber morphology, relatively dense distribution, not greatly different fiber diameter, and small porosity. Characterization under a field of view (FOV) of 500 um showed that the fiber surface was smooth and rich in content. The release of CLA showed a gradual and steady upward trend. On the 25th day, nearly 50% of the dose had been released, and it had reached more than 90% of the total release on the 55th day. According to the statistics on the clinical efficacy of patients, it was found that the number of cured and effective patients in the observation group was higher than that of the control group, while the number of ineffective cases was much lower than that of the control group. The dynamic enhanced CT examination results of the patients in the control group after treatment showed that the soft tissue mass on the posterior right side of the nasopharynx was reduced, but the pharyngeal suture still existed; while those in the observation group showed that the plain scan density was uniform, and the mastoid air cells were clear on both sides. The number of cases with Staphylococcus aureus (S. aureus), Staphylococcus saprophyticus (S. saprophyticus), and Pasteurella multocida infections in the observation group were observably lower than those of the control group (P< 0.05), and it was the same case for the levels of serum IL-4, IL-8, and TNF-α. Conclusion: after dynamic enhanced CT scanning, it can be found that the nanomaterial-loaded CLA increased the utilization rate of the drug, showing good clinical efficacy, and effectively improved the clinical symptoms of patients, achieving the therapeutic effect.

Patient-driven discovery of CCN1 to rescue cutaneous wound healing in diabetes via the intracellular EIF3A/CCN1/ATG7 signaling by nanoparticle-enabled delivery.

Diabetic ulcers (DUs), a devastating complication of diabetes, are intractable for limited effective interventions in clinic. Based on the clinical samples and bioinformatic analysis, we found lower level of CCN1 in DU individuals. Considering the accelerated proliferation effect in keratinocytes, we propose the therapeutic role of CCN1 supplementation in DU microenvironment. To address the challenge of rapid degradation of CCN1 in protease-rich diabetic healing condition, we fabricated a nanoformulation of CCN1 (CCN1-NP), which protected CCN1 from degradation and significantly raised CCN1 intracellular delivery efficiency to 6.2-fold. The results showed that the intracellular CCN1 exhibited a greater anti-inflammatory and proliferative/migratory activities once the extracellular signal of CCN1 was blocked in vitro. The nanoformulation unveils a new mechanism that CCN1 delivered into cells interacted with Eukaryotic translation initiation factor 3 subunit A (EIF3A) to downregulate autophagy-related 7 (ATG7). Furthermore, topical application of CCN1-NP had profound curative effects on delayed wound healing in diabetes both in vitro and in vivo. Our results illustrate a novel mechanism of intracellular EIF3A/CCN1/ATG7 axis triggered by nanoformulation and the therapeutic potential of CCN1-NP for DU management.

Synthetic high-density lipoprotein nanoparticles delivering rapamycin for the treatment of age-related macular degeneration.

Synthetic high-density lipoprotein (sHDL) and rapamycin (Rap) have both been shown to be potential treatments for age-related macular degeneration (AMD). The low aqueous solubility of Rap, however, limits its therapeutic utility. Here we used an Apolipoprotein A-I mimetic peptide and phospholipid-based sHDL for the intravitreal delivery of Rap. By incorporation of Rap in sHDL nanoparticles (sHDL-Rap), we achieve 125-fold increase in drug aqueous concentration. When applied in vitro to retinal pigment epithelium cells, sHDL-Rap exhibited the abilities to efflux cholesterol, neutralize endotoxin, and suppress NF-κB activation. As an mTOR inhibitor, Rap induced autophagy and inhibited NF-κB-mediated pro-inflammatory signaling. Additionally, a greater reduction in lipofuscin accumulation and increased anti-inflammatory effects were achieved by sHDL-Rap relative to free drug or sHDL alone. In vivo studies demonstrated that sHDL reached the target retina pigment epithelium (RPE) layer following intravitreal administration in rats. These results suggest that sHDL-Rap holds potential as a treatment for AMD.

Nano drug delivery in intracellular bacterial infection treatments.

The present work aimed to review the potential mechanisms used by macrophages to kill intracellular bacteria, their entrance to the cell, and mechanisms of escape of cellular immunity and applications of various nanoparticles. Since intracellular bacteria such as Mycobacterium and Brucella can survive in host cells and can resist the lethal power of macrophages, they can cause chronic disease or recur in 10-30% of cases in improved patients Nano drug-based therapeutics are promising tools for treating intracellular bacteria and preventing recurrence of the disease caused by these bacteria. In addition, among their unique features, we can mention the small size and the ability of these compounds to purposefully reach the target location.

Metadichol®: A Novel Nanolipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro.

Increasing outbreaks of new pathogenic viruses have promoted the exploration of novel alternatives to time-consuming vaccines. Thus, it is necessary to develop a universal approach to halt the spread of new and unknown viruses as they are discovered. One such promising approach is to target lipid membranes, which are common to all viruses and bacteria. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reaffirmed the importance of interactions between the virus envelope and the host cell plasma membrane as a critical mechanism of infection. Metadichol®, a nanolipid emulsion of long-chain alcohols, has been demonstrated as a strong candidate that inhibits the proliferation of SARS-CoV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce viral infectivity, including that of coronaviruses (such as SARS-CoV-2) by modifying their lipid-dependent attachment mechanism to human host cells. The receptor ACE2 mediates the entry of SARS-CoV-2 into the host cells, whereas the serine protease TMPRSS2 primes the viral S protein. In this study, Metadichol® was found to be 270 times more potent an inhibitor of TMPRSS2 (EC50 = 96 ng/mL) than camostat mesylate (EC50 = 26000 ng/mL). Additionally, it inhibits ACE with an EC50 of 71 ng/mL, but it is a very weak inhibitor of ACE2 at an EC50 of 31 µg/mL. Furthermore, the live viral assay performed in Caco-2 cells revealed that Metadichol® inhibits SARS-CoV-2 replication at an EC90 of 0.16 µg/mL. Moreover, Metadichol® had an EC90 of 0.00037 µM, making it 2081 and 3371 times more potent than remdesivir (EC50 = 0.77 µM) and chloroquine (EC50 = 1.14 µM), respectively.