Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: a scientometric study to an in-depth review.

Aberrant neurogenesis is a major factor in psychiatric and neurological disorders that have significantly attracted the attention of neuroscientists. Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. First, it is important to understand the different processes of neurogenesis, and whether their dysfunction promotes etiology as well as the development of many psychiatric and neurological disorders; then investigate mechanisms by which curcumin affects neurogenesis as an active participant in pathophysiological events. Based on scientometric studies and additional extensive research, we explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.

Enhanced antidepressant effects of BDNF-quercetin alginate nanogels for depression therapy.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) with neuronic development and function is a promising therapeutic agent for treating depressive disorder, according to the neurotrophin hypothesis. However, the delivery of BDNF into the brain is not easy as these large protein molecules cannot efficiently cross the blood-brain barrier (BBB) and easily suffer oxidative damage in vivo. Therefore, the quercetin-based alginate nanogels (quercetin nanogels) loaded with BDNF have been developed, which could efficiently bypass the BBB via the nose-to-brain pathway and protect BDNF from oxidative damage, providing an effective route for the therapy of depressive disorders by intranasal delivery. RESULTS: Quercetin nanogels exhibited uniform size distribution, excellent biocompatibility, and potent antioxidant and anti-inflammatory activities. Quercetin nanogels in the thermosensitive gel achieved sustained and controlled release of BDNF with non-Fick's diffusion, exhibited rapid brain distribution, and achieved nearly 50-fold enhanced bioavailability compared to oral quercetin. Quercetin nanogels as a therapeutic drug delivery carrier exerted antidepressant effects on reserpine-induced rats, effectively delivered BDNF to reverse despair behavior in stress-induced mice, and exhibited antidepressant effects on chronic mild unpredictable stimulation (CUMS) rats. These antidepressant effects of BDNF-Quercetin nanogels for CUMS rats are associated with the regulation of the glutamatergic system, PI3K-Akt, and BDNF-TrkB signaling pathway. CONCLUSIONS: In this study, we provide a promising strategy for brain delivery of BDNF for treating depressive disorders, effectively achieved through combining quercetin nanogels and intranasal administration.

A novel inhalable quercetin-alginate nanogel as a promising therapy for acute lung injury.

BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.

Systematic identification of the interventional mechanism of Qingfei Xiaoyan Wan (QFXYW) in treatment of the cytokine storm in acute lung injury using transcriptomics-based system pharmacological analyses.

CONTEXT: Acute lung injury (ALI) is a complex, severe inflammation disease with high mortality, and there is no specific and effective treatment for ALI. Qingfei Xiaoyan Wan (QFXYW) has been widely used to treat lung-related diseases for centuries. OBJECTIVE: This study evaluates the potential effects and elucidates the therapeutic mechanism of QFXYW against LPS induced ALI in mice. MATERIALS AND METHODS: BALB/c Mice in each group were first orally administered medicines (0.9% saline solution for the control group, 0.5 mg/kg Dexamethasone, or 1.3, 2.6, 5.2 g/kg QFXYW), after 4 h, the groups were injected LPS (1.0 mg/kg) to induce ALI, then the same medicines were administered repeatedly. The transcriptomics-based system pharmacological analyses were applied to screen the hub genes, RT-PCR, ELISA, and protein array assay was applied to verify the predicted hub genes and key pathways. RESULTS: QFXYW significantly decreased the number of leukocytes from (6.34 ± 0.51) × 105/mL to (4.01 ± 0.11) × 105/mL, accompanied by the neutrophil from (1.41 ± 0.19) × 105/mL to (0.77 ± 0.10) × 105/mL in bronchoalveolar lavage fluid (BALF). Based on Degree of node connection (Degree) and BottleNeck (BN), important parameters of network topology, the protein-protein interaction (PPI) network screened hub genes, including IL-6, TNF-α, CCL2, TLR2, CXCL1, and MMP-9. The results of RT-PCR, ELISA, and protein chip assay revealed that QFXYW could effectively inhibit ALI via multiple key targets and the cytokine-cytokine signalling pathway. CONCLUSIONS: This study showed that QFXYW decreased the number of leukocytes and neutrophils by attenuating inflammatory response, which provides an important basis for the use of QFXYW in the treatment of ALI.

Antioxidant Activities of Quercetin and Its Complexes for Medicinal Application.

Quercetin is a bioactive compound that is widely used in botanical medicine and traditional Chinese medicine due to its potent antioxidant activity. In recent years, antioxidant activities of quercetin have been studied extensively, including its effects on glutathione (GSH), enzymatic activity, signal transduction pathways, and reactive oxygen species (ROS) caused by environmental and toxicological factors. Chemical studies on quercetin have mainly focused on the antioxidant activity of its metal ion complexes and complex ions. In this review, we highlight the recent advances in the antioxidant activities, chemical research, and medicinal application of quercetin.

The anti-inflammatory activities of ethanol extract from Dan-Lou prescription in vivo and in vitro.

BACKGROUND: Although, Dan-Lou prescription (DLP) is used for antagonizing check discomfort and heartache, the pharmacological mechanism has not been clearly illustrated. Our present study aimed to design inflammatory models induced by LPS in vivo and in vitro to investigate the anti-inflammation of DLP ethanol extract (EEDL) and the potential mechanisms. METHODS: EEDL was prepared and then analyzed by high performance liquid chromatography (HPLC). Further, the anti-inflammatory effects of EEDL in vivo was evaluated by measuring inflammation-associated factors includingcytokines, chemokines and acute phase proteins in lipopolysaccharide (LPS)-induced mice serum and liver. The anti-inflammatory mechanism exploration of EEDL was performed in LPS-stimulated RAW 264.7 cells. Different effects of EEDL on nitric oxide (NO) and prostaglandin (PG)E2 secretion were investigated by Griess reagent method and enzyme-linked immunosorbent assay (ELISA) respectively. Then the mRNA and protein expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were measured by real-time reverse-transcription polymerase chain reaction (RT-PCR), ELISA and Western blot. Other chemokines and acute phase proteins were determined by proteome profile array. Finally, the ELISA based transcription factor assay was applied to measure the DNA-binding activity of nuclear transcription factor (NF)-κB p65. RESULTS: Eight compounds from EEDL have been identified as gallic acid, salvianic acid, puerarin, daidzin, paeoniflorin, salvianolic acid B, cryptotanshinone, and tanshinone IIA, with amounts of 0.26, 9.84, 10.41, 2.55, 9.44, 3.82, 0.24 and 0.3 mg/kg, respectively. In vivo, EEDL administration antagonized the up-regulation of more than 17 kinds of cytokines, chemokines and acute phase proteins in LPS-treated mice serum, and inhibited LPS-induced IL-6 mRNA and protein expression in mice liver tissue. In vitro, LPS-induced NO and PGE2 over-productions were decreased by EEDL treatment. The mRNA and protein expression of iNOS, COX-2 and IL-6 were similarly inhibited by EEDL treatment, which might be attributed to decrease the DNA-binding activity of NF-κB p65. CONCLUSION: EEDL was valid for anti-inflammation and the potential molecular mechanisms might be due to the inhibition of of LPS-induced iNOS/NO, COX-2/PGE2 and cytokines expression by antagonizing the activation of NF-κB p65.

[Advance in modern studies on compatibility of Coptidis Rhizoma and Evodiae Fructus].

In traditional clinical application, Coptidis Rhizome and Evodiae Fructus have been combined to treat various stomach heat and cold syndromes, gastritis, gastric ulcer and the like. With the application of modem instruments and the development of molecular pharmacologic theory, their chemical constituents and pharmacological effects have been sufficiently studied. In this paper, literatures from Pubmed were adopted, with particular emphasis on findings of international counterparts and studies on compatibility of main chemical components in Coptidis Rhizoma and Evodiae Fructus, in order to elaborate on the scientific comparability of Coptidis Rhizoma and Evodiae Fructus through chemical analysis, and pharmacological and biopharmaceutics studies and introduce the future development trend of the studies.

Mucoadhesive microparticles for gastroretentive delivery: preparation, biodistribution and targeting evaluation.

The aim of this research was to prepare and characterize alginate-chitosan mucoadhesive microparticles containing puerarin. The microparticles were prepared by an emulsification-internal gelatin method using a combination of chitosan and Ca2+ as cationic components and alginate as anions. Surface morphology, particle size, drug loading, encapsulation efficiency and swelling ratio, in vitro drug released, in vitro evaluation of mucoadhesiveness and Fluorescence imaging of the gastrointestinal tract were determined. After optimization of the formulation, the encapsulation efficiency was dramatically increased from 70.3% to 99.2%, and a highly swelling ratio was achieved with a change in particle size from 50.3 ± 11.2 µm to 124.7 ± 25.6 µm. In ethanol induced gastric ulcers, administration of puerarin mucoadhesive microparticles at doses of 150 mg/kg, 300 mg/kg, 450 mg/kg and 600 mg/kg body weight prior to ethanol ingestion significantly protected the stomach ulceration. Consequently, significant changes were observed in inflammatory cytokines, such as prostaglandin E2 (PGE2), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), and interleukin1ß (IL-1ß), in stomach tissues compared with the ethanol control group. In conclusion, core-shell type pH-sensitive mucoadhesive microparticles loaded with puerarin could enhance puerarin bioavailability and have the potential to alleviate ethanol-mediated gastric ulcers.

Comparative studies of paeoniflorin and albiflorin from Paeonia lactiflora on anti-inflammatory activities.

CONTEXT: Paeonia lactiflora Pall. (Ranunculaceae) has been used for more than 1000 years in traditional Chinese medicine for the treatment of gynecological problems, cramp, pain, giddiness, and congestion. Paeoniflorin, monoterpene glycosides isolated from P. lactiflora, possesses a variety of pharmacological activities. However, the pharmacological activity of the pharmacological activity of albiflorin, another main monoterpene glycoside, has not been well studied. OBJECTIVES: The present study investigated the anti-inflammatory activities of paeoniflorin and albiflorin using models of lipopolysaccharides (LPS) induced RAW 264.7 cells. MATERIALS AND METHODS: Production of nitric oxide (NO) was measured by the Griess colorimetric method. In addition, prostaglandin E2 (PGE2), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) synthesis were analyzed using an enzyme-linked immunosorbent assay (ELISA). The protein expression of cyclooxygenase-2 (COX-2) was detected by a cell-based ELISA. The gene expression levels of inducible nitric oxide synthase (iNOS), COX-2, TNF-α, and IL-6 were detected by quantitative real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). RESULTS: Compared with the LPS-induced group, the inhibition rates of NO, PGE2, TNF-α, and IL-6 production were 17.61, 27.56, 20.57, and 29.01% by paeoniflorin and 17.35, 12.94, 15.29, and 10.78% by albiflorin. The IC50 values of paeoniflorin and albiflorin on NO production were 2.2 × 10(-4 )mol/L and 1.3 × 10(-2 )mol/L, respectively. The protein expression of COX-2 was reduced by 50.98% with paeoniflorin and 17.21% with albiflorin. The inhibition rates of gene expression of iNOS, COX-2, IL-6, and TNF-α were 35.65, 38.08, 19.72, and 45.19% by paeoniflorin and 58.36, 47.64, 50.70, and 12.43% by albiflorin, respectively. CONCLUSION: These results show that albiflorin has similar anti-inflammatory effects to paeoniflorin, which provides new evidence that albiflorin can serve as a new chemical marker for the quality control of Paeoniae Radix and the Chinese Pharmacopoeia can be updated.

Advances and future perspectives of intranasal drug delivery: A scientometric review.

Intranasal drug delivery is as a noninvasive and efficient approach extensively utilized for treating the local, central nervous system, and systemic diseases. Despite numerous reviews delving into the application of intranasal drug delivery across biomedical fields, a comprehensive analysis of advancements and future perspectives remains elusive. This review elucidates the research progress of intranasal drug delivery through a scientometric analysis. It scrutinizes several challenges to bolster research in this domain, encompassing a thorough exploration of entry and elimination mechanisms specific to intranasal delivery, the identification of drugs compatible with the nasal cavity, the selection of dosage forms to surmount limited drug-loading capacity and poor solubility, and the identification of diseases amenable to the intranasal delivery strategy. Overall, this review furnishes a perspective aimed at galvanizing future research and development concerning intranasal drug delivery.

Pulmonary administration of tetrandrine loaded Zinc-Alginate nanogels attenuates pulmonary fibrosis in rats.

Pulmonary fibrosis is a chronic and progressive disease, current systemic administration is not fully effective with many side effects, such as gastrointestinal and liver injury. The pulmonary delivery system for pulmonary fibrosis may contribute to maximize therapeutic benefit. Natural compounds might have prominence as potential drug candidates, but the low bioavailabilities affect their clinical use. Tetrandrine is a natural alkaloid with good anti-inflammatory, antifibrogenetic and antioxidant effects, and it is used as a clinical therapeutic drug for the treatment of silicosis in China. In the present study, we explore a new strategy of pulmonary delivery system to improve low solubility and pesticide effect of tetrandrine. Tetrandrine was loaded into alginate nanogels by reverse microemulsion method. The release behavior of tetrandrine reached zero-order kinetics release and the maximum free radical clearance rates reached up to 90%. The pulmonary fibrosis rats were treated with tetrandrine nanogels by using ultrasonic atomizing inhalation. Tetrandrine nanogels decreased the development and progression of fibrosis by reducing inflammation response and bating the deposition of extra cellular matrix. In conclusion, ultrasonic atomizing inhalation of tetrandrine nanogels provided a new therapeutic strategy for pulmonary fibrosis.

A self-healing hydrogel wound dressing based on oxidized Bletilla striata polysaccharide and cationic gelatin for skin trauma treatment.

Skin trauma presents significant treatment challenges in clinical settings. Hydrogels made from naturally-derived polysaccharide have demonstrated great potential in wound healing. Here, a novel in-situ crosslinked self-healing hydrogel was prepared using oxidized Bletilla striata polysaccharide (BSP) and cationic gelatin via a Schiff-base reaction without the need for any chemical crosslinkers. Similar to the natural extracellular matrix, the BSP-gelatin hydrogel (BG-gel) exhibited typical viscoelastic characteristics. The rheological properties, mechanical behavior, porous structure, and degradation performance of BG-gel could be adjusted by changing the aldehyde group content of BSP. Importantly, the hydrogel showed superior hemostatic performance in mouse tail amputation and rat liver incision models. It significantly facilitated wound healing by promoting hair follicles regeneration, blood vessels repair, collagen deposition, and inducing skin tissue remodeling via increased CD31 expression in a full-thickness skin wound rat model. This multifunctional hydrogel holds potential as a wound dressing for skin trauma, offering both hemostasis and expedited healing.

ROS-responsive thioketal-linked alginate/chitosan carriers for irritable bowel syndrome with diarrhea therapy.

A colon-specific carrier that can protect drugs from the destruction in the gastrointestinal tract is critical for treating irritable bowel syndrome with diarrhea (IBS-D). In this study, chitosan was cross-linked by the thioketal (TK) bond to serve as a ROS-sensitive core of microspheres. Then the chitosan core was coated with an alginate shell. The alginate/chitosan microspheres can protect puerarin against the destruction and elimination in the gastrointestinal tract and release puerarin at the lesion sites in large quantities. The microspheres were characterized using differential scanning calorimetry, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The swelling study showed that microspheres would shrink in an acidic environment. The in vitro release analysis indicated that little puerarin was released at gastric pH but burst release was observed in simulated colonic fluid containing H2O2. Fluorescent tracer revealed that the fluorescence of microspheres lasted up to 30 h in the colon, which was beneficial to prolong the action time between puerarin and colon. The in vivo studies indicated that puerarin-loaded microspheres are more effective in the treatment of IBS-D than free puerarin. Altogether, the ROS-responsive alginate/chitosan microspheres may be a promising strategy for IBS-D.

A Review of Non-Invasive Drug Delivery through Respiratory Routes.

With rapid and non-invasive characteristics, the respiratory route of administration has drawn significant attention compared with the limitations of conventional routes. Respiratory delivery can bypass the physiological barrier to achieve local and systemic disease treatment. A scientometric analysis and review were used to analyze how respiratory delivery can contribute to local and systemic therapy. The literature data obtained from the Web of Science Core Collection database showed an increasing worldwide tendency toward respiratory delivery from 1998 to 2020. Keywords analysis suggested that nasal and pulmonary drug delivery are the leading research topics in respiratory delivery. Based on the results of scientometric analysis, the research hotspots mainly included therapy for central nervous systems (CNS) disorders (Parkinson's disease, Alzheimer's disease, depression, glioblastoma, and epilepsy), tracheal and bronchial or lung diseases (chronic obstructive pulmonary disease, asthma, acute lung injury or respiratory distress syndrome, lung cancer, and idiopathic pulmonary fibrosis), and systemic diseases (diabetes and COVID-19). The study of advanced preparations contained nano drug delivery systems of the respiratory route, drug delivery barriers investigation (blood-brain barrier, BBB), and chitosan-based biomaterials for respiratory delivery. These results provided researchers with future research directions related to respiratory delivery.

Antioxidant Activities of Natural Polysaccharides and Their Derivatives for Biomedical and Medicinal Applications.

Many chronic diseases such as Alzheimer's disease, diabetes, and cardiovascular diseases are closely related to in vivo oxidative stress caused by excessive reactive oxygen species (ROS). Natural polysaccharides, as a kind of biomacromolecule with good biocompatibility, have been widely used in biomedical and medicinal applications due to their superior antioxidant properties. In this review, scientometric analysis of the highly cited papers in the Web of Science (WOS) database finds that antioxidant activity is the most widely studied and popular among pharmacological effects of natural polysaccharides. The antioxidant mechanisms of natural polysaccharides mainly contain the regulation of signal transduction pathways, the activation of enzymes, and the scavenging of free radicals. We continuously discuss the antioxidant activities of natural polysaccharides and their derivatives. At the same time, we summarize their applications in the field of pharmaceutics/drug delivery, tissue engineering, and antimicrobial food additives/packaging materials. Overall, this review provides up-to-date information for the further development and application of natural polysaccharides with antioxidant activities.

Current Research Trends in Cytokine Storm: A Scientometric Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is currently rampant worldwide, resulting in unpredictable harm to humans. High blood levels of cytokines and chemokines have been marked in patients with COVID-19 infection, leading to cytokine storm syndrome. Cytokine storms are violent inflammatory immune responses that reveal the devastating effect of immune dysregulation and the critical role of an effective host immune response. METHODS: Scientometric analysis summarizes the literature on cytokine storms in recent decades and provides a valuable and timely approach to tracking the development of new trends. This review summarizes the pathogenesis and treatment of diseases associated with cytokine storms comprehensively based on scientometric analysis. RESULTS: Field distribution, knowledge structure, and research topic evolution correlated with cytokine storms are revealed, and the occurrence, development, and treatment of disease relevant to cytokine storms are illustrated. CONCLUSION: Cytokine storms can be induced by pathogens and iatrogenic causes and can also occur in the context of autoimmune diseases and monogenic diseases as well. These reveal the multidisciplinary nature of cytokine storms and remind the complexity of the pathophysiological features, clinical presentation, and management. Overall, this scientometric study provides a macroscopic presentation and further direction for researchers who focus on cytokine storms.

Dan-Lou tablets reduces inflammatory response via suppression of the MyD88/p38 MAPK/NF-κB signaling pathway in RAW 264.7 macrophages induced by ox-LDL.

ETHNOPHARMACOLOGICAL EVIDENCE: The anti-inflammatory effect of Dan-Lou tablets (DLT) have been reported; however, the signaling pathways involved and their role in foam cell formation remains unclear. AIM OF THE STUDY: The purpose of this study was to determine the molecular target and mechanism of DLT in the treatment of coronary heart disease (CHD), and investigate the role of DLT in inhibiting foam cell formation and the anti-inflammatory effects of RAW 264.7 macrophages. MATERIALS AND METHODS: This study explored and elucidated the main active components, therapeutic targets, and pharmacological mechanisms of DLT treatment for CHD using network pharmacology. Secondly, the accuracy of the interaction of key active compounds with key proteins was verified by molecular docking analysis. Eight chemical compositions were determined from the ethanol extract of DLT (EEDL) by high-performance liquid chromatography. Finally, this study used EEDL intervention with oxidized low-density lipoprotein (ox-LDL) to induce RAW264.7 macrophages to verify the results of network pharmacology. RESULTS: According to network pharmacological analysis, 269 common targets of DLT and CHD were obtained from an online database, and 24 key targets were obtained from further analysis. GO enrichment and KEGG analyses were performed, mainly involving the cAMP, cGMP-PKG, MAPK, and NF-κB signaling pathways, and vascular smooth muscle contraction. Molecular docking showed that the active components in DLT docked well with MyD88, NF-κB, and p38 MAPK. The eight compounds from the EEDL have been identified as gallic acid, salvianolic acid, puerarin, daidzein, paeoniflorin, salvianolic acid B, cryptotanshinone, and tanshinone IIA with concentrations of 4.62, 4.76, 23.73, 34.24, 14.59, 21.69, 0.34, and 0.47 µg/mg, respectively. Further in vitro experiments showed that the levels of MyD88 and p-p38 MAPK in RAW 264.7 macrophages induced by ox-LDL increased noticeably. Stimulating the NF-κB signaling pathway increased the release of pro-flammatory factors (TNF-α and IL-1ß) and strengthened the inflammatory response (P < 0.05 or P < 0.01), while the levels of MyD88, p38 MAPK, NF-κB, TNF-α, and IL-1ß decreased after EEDL treatment (P < 0.05 or P < 0.01). CONCLUSION: The study demonstrated that the anti-inflammatory activity of the DLT intervention of ox-LDL-induced RAW 264.7 macrophages may involve the MyD88/p38 MAPK/NF-κB signaling pathway.

Intranasal co-delivery of berberine and evodiamine by self-assembled thermosensitive in-situ hydrogels for improving depressive disorder.

The orally administrated antidepressants not only caused side effects such as dizziness, diarrhea, and drug resistance, but also worked slowly. Therefore, new antidepressants and preparations derived from natural medicines play an important role in the study of antidepressant drugs. It was reported that the two components of Zuojin pill, berberine (BBR) and evodiamine (EVO), were used in combination to improve depressive disorder. In our study, a self-assembled thermosensitive in-situ hydrogel was prepared to achieve sustained co-delivery of BBR and EVO. The preparation process of hydrogel consists of two steps, namely, the inclusion of the drugs and thermosensitive self-assembly of the hydrogel. In vitro experimental results indicated that the prepared hydrogel showed a good thermosensitive property under physiological temperature. The hydrogel had a slow and controlled release behavior for BBR and EVO, according with first-order equation. In vivo experimental results indicated that compared to intragastric administration of drug solution, the intranasal administration of hydrogel increased bioavailability of BBR and EVO, approximately 135 and 112 folds, respectively. The hydrogel at a low dose significantly reversed behavioral despair of the mice, improved depressive symptom of rats, and treated depressive disorder by regulating the abnormal levels of monoamine neurotransmitters (including 5-hydroxytryptamine, noradrenalin and dopamine) metabolism and related metabolic pathways such as purine, citrate cycle, scorbate and aldarate, butanoate, vitamin B6, and pyrimidine metabolism. Therefore, as a drug co-delivery system, the intranasally administrated hydrogels with a good release and high bioavailability provides a non-invasive therapeutic strategy for the clinical treatment of depression, which attains antidepressant effects by regulation of the monoamine neurotransmitters metabolism and related metabolic pathways.

Alginate nanogels-based thermosensitive hydrogel to improve antidepressant-like effects of albiflorin via intranasal delivery.

Depression is a primary public health problem. However, current antidepressants work slowly, and together with side effects. Herein, the alginate nanogels were constructed to load albiflorin (albiflorin nanogels), which further formed albiflorin nanogel loaded self-assembled thermosensitive hydrogel system (albiflorin-NGSTH) and were used to improve its antidepressant effects. The nanogel showed a nano-scaled particle size and stronger antioxidant activity. Rheological studies showed that albiflorin-NGSTH had a sol-gel transition at approximately 28 °C. Albiflorin-NGSTH quickly entered the brain by intranasal delivery, and had a continuously release for albiflorin. Preliminary results of mice behavioral despair tests found that albiflorin-NGSTH had no effects on independent exploratory behavior and anxiety of the mice, and significantly decreased immobility duration of the mice in tail suspension test (TST). Moreover, the intranasally administrated albiflorin-NGSTH at a low dose improved depressive behavior, decreased levels of proinflammatory cytokines, and repaired neuronal damage of chronic unpredictable mild stress (CUMS) rats, which indicated an excellent potential for depression therapy. The treatment of albiflorin-NGSTH on depressive disorder was achieved by regulating signal pathway related to depression. Therefore, albiflorin-NGSTH has an excellent potential for clinical application in intranasal drug delivery systems.

A novel idea for establishing Parkinson's disease mouse model by intranasal administration of paraquat.

Background: In this study, we sought to provide an idea for establishing a novel mouse model for Parkinson's disease (PD) through intranasal administration of paraquat instead of the conventional method of intraperitoneal injection. Intranasal administration has the potential to lower mortality caused by intraperitoneal paraquat administration.Methods: A paraquat-loaded thermosensitive hydrogel composed of poloxamer 407 and poloxamer 188 was prepared. The survival rate of the animals was monitored upon paraquat administration nasally and intraperitoneally. The animals' behavior was also observed. Immunofluorescence staining of tyrosine hydroxylase (TH) - positive cells and western blotting of α-synuclein (α-syn)in striatum were performed. HPLC method with electrochemical detection was used to quantify monoamine neurotransmitters in striatum. Real-time RT-PCR analysis of type 1 collagen, type 3 collagen and fibronectin expression was used to evaluate pulmonary fibrosis in mice after paraquat administration.Results: The results indicated that intranasal administration of paraquat-loaded thermosensitive hydrogel can elicit Parkinsonism-like symptoms in mice. Relative to the conventional intraperitoneal injection, this strategy significantly improves survival when modeling PD and resulted in a higher loss of TH positive neurons in substantia nigra pars compacta (SNpc) and more aggregation of α-syn in striatum. Moreover, animals receiving paraquat hydrogel nasally exhibited motor disorder as well as lower levels of dopamine and dopamine metabolites in striatum when compared to those receiving paraquat intraperitoneally. The mRNA expression of collagen and fibronectinindicated that intranasal administration of paraquat was not associated with lung fibrosis.Conclusion: This strategy provides a new idea and more convenient operation for the future study of mouse model of PD.