Search Results (1,515)

The conventional method of flue gas desulfurization gypsum (FGDG) application, i.e., blending with flood irrigation, is hindered by low water efficiency and significant amendment loss due to runoff and uncontrolled leaching, particularly in arid and semi-arid regions in which water scarcity is a major constraint. This study aimed to evaluate a novel integration of FGDG band application with drip irrigation to enhance targeting and resource efficiency. A laboratory-scale experiment investigated the effects of two FGDG application methods (band and blend application) and drip rates (0.3 and 0.6 L h⁻¹) on soil water movement and chemical properties. Band application significantly accelerated initial wetting front advancement by up to 44.9 cm h⁻¹ near the emitter and sustained horizontal propagation, while blend application promoted a more uniform water distribution. Chemically, band application created localized zones of reduced pH (7.57–8.62) and elevated water-soluble Ca²⁺ (up to 492.2 mmol kg⁻¹), facilitating a 79.1% reduction in exchangeable Na⁺ near the emitter. In contrast, blend application resulted in broader but shallower amendment distribution, reducing exchangeable sodium percentage uniformly to 1.99–4.16% across the soil profile. The combination of banded FGDG and drip irrigation achieves targeted amelioration, with superior Na⁺/Ca²⁺ exchange and favorable moisture dynamics resulting from the synergy between amendment placement and water delivery. This approach is a viable strategy for precision reclamation in arid regions. Full article

Background: Triple-negative breast cancer (TNBC) remains primarily treated with chemotherapy due to the lack of effective therapeutic targets, but this approach carries significant systemic toxicity and a high risk of drug resistance. Curcumin (Cur), despite its multifaceted antitumor activity, faces limitations in clinical application due to poor water solubility and weak targeting properties. This study aims to develop a folate/mitochondria dual-targeted curcumin–copper chelate liposome (Cu-Cur DTLPs) formulation that enables copper accumulation within tumor cells and induces copper-mediated cell death, thereby providing an effective and relatively low-toxicity therapeutic strategy for triple-negative breast cancer. Methods: Curcumin–copper chelates (Cu-Cur) were first synthesized and characterized using mass spectrometry, NMR, and infrared spectroscopy. Subsequently, dual-targeted liposomes (Cu-Cur DTLPs) were prepared via the thin-film dispersion method, with systematic evaluation of particle size, zeta potential, encapsulation efficiency, and in vitro release profiles. In vitro cytotoxicity was assessed against 4T-1 and MDA-MB-231 cells using the MTT assay. In a 4T-1 tumor-bearing BALB/c mouse model, comprehensive evaluation of targeting efficiency, antitumor efficacy, and mechanisms of action was conducted via in vivo imaging, tumor volume monitoring, immunohistochemistry (detecting FDX1 and DLAT proteins), and TUNEL staining. Results: Cu-Cur DTLPs with a uniform particle size of approximately 104.4 nm were successfully synthesized. In vitro and in vivo studies demonstrated that compared to free curcumin and conventional liposomes, Cu-Cur DTLPs significantly enhanced drug accumulation in tumor tissues and exhibited effective tumor growth inhibition. Mechanistic studies confirmed that this formulation specifically accumulates copper ions within tumor cells, upregulates FDX1, promotes DLAT oligomerization, and induces mitochondrial dysfunction, thereby driving copper death. TUNEL staining ruled out apoptosis as the primary mechanism. Safety evaluation revealed no significant toxicity in major organs. Conclusions: The Cu-Cur DTLPs developed in this study effectively induce copper-mediated death in TNBC through a dual-targeted delivery system, significantly enhancing antitumor activity with favorable safety profiles. This establishes a highly promising novel nanotherapeutic strategy for TNBC treatment. Full article

Background: As a widely used chemotherapeutic agent, cisplatin frequently induces acute kidney injury (AKI), which severely compromises patient survival and limits its clinical use. While the natural flavonoid diosmetin (Dio) shows promise in mitigating cisplatin-induced nephrotoxicity, its clinical translation is challenged by poor solubility, low bioavailability, and incompletely elucidated mechanisms. This study aimed to overcome these limitations by developing a novel drug delivery system using the microalgae Dunaliella salina (D. salina, Ds) to load Dio (Ds-Dio), thereby enhancing its efficacy and exploring its therapeutic potential. Methods: We first characterized the physicochemical properties of Ds and Dio, and then Ds-Dio complex was synthesized via co-incubation. Its nephroprotective efficacy and safety were systematically evaluated in a cisplatin-induced mouse AKI model by assessing renal function (serum creatinine, blood urea nitrogen), injury biomarkers, histopathology, body weight, and organ index. The underlying mechanism was predicted by network pharmacology and subsequently validated experimentally. Results: The novel Ds-Dio delivery system has been successfully established. In the AKI model, Ds-Dio significantly improved renal function and exhibited a superior protective effect over Dio alone; this benefit is attributed to the enhanced bioavailability provided by Ds carrier. In addition, Ds-Dio also demonstrated safety performance, with no evidence of toxicity to major organs. Network pharmacology analysis predicted the involvement of PI3K/AKT pathway, which was experimentally verified. Specifically, we confirmed that Ds-Dio alleviates AKI by modulating the PI3K/AKT pathway, resulting in concurrent suppression of NF-κB-mediated inflammation and activation of NRF2-dependent antioxidant responses. Conclusions: This study successfully developed a microalgae-based drug delivery system, Ds-Dio, which significantly enhances the nephroprotective efficacy of Dio against cisplatin-induced AKI. The nephroprotective mechanism is associated with modulation of the PI3K/AKT pathway, resulting in the simultaneous attenuation of oxidative stress and inflammation. Full article

Pulmonary drug delivery represents a promising approach in the treatment of respiratory diseases, allowing for passive targeting and enhanced drug efficacy. Background/Objectives: The aim of the present study was to develop inhalable dry powders from lyophilized sildenafil citrate (SC)-loaded liposomes made from phosphatidylcholine and either cholesterol (CH) or resveratrol (RSV). Methods: Liposomes were prepared via a pH gradient method to increase drug entrapment efficiency and drug loading, and then the liposomes were lyophilized using different proportions of ethanol, mannitol, and lactose as excipients. The resulting dry cakes were converted into powders and evaluated for aerodynamic performance using a custom-designed air-blowing device. Notably, this is the first time that resveratrol has been used as a substitute for cholesterol in SC-loaded liposomes. Results: Our results demonstrate that RSV is a suitable liposome bilayer component and improves drug loading. Our findings prove that lyophilized cakes containing liposomes produce a dry powder that is suitable for aerosolization with potential application to pulmonary delivery of sildenafil citrate. The results suggest that RSV represents a potential alternative to traditional cholesterol-based liposomal formulations. Conclusions: This work presents a novel strategy for the pulmonary delivery of sildenafil, using biocompatible and FDA-approved mannitol and lactose for this administration route. Full article

Background: Oral insulin improves compliance and convenience in patients with diabetes who require regular needle injections. However, the clinical application of oral insulin preparations has been limited due to instability and inefficient permeation through the gastrointestinal tract. In this study, a novel cationic polysaccharide nanodrug delivery platform was designed for efficient oral insulin delivery. Methods: The innovative thiolated trimethyl chitosan-grafted β-cyclodextrin (NCT) was synthesized by utilizing N-trimethyl chitosan (TMC) as the polymer backbone. This involved modifying TMC with thiol group-containing N-acetylcysteine and carboxymethyl-β-cyclodextrin that possesses hydrophobic cavities via an amide condensation reaction. Subsequently, this polymer was employed to construct the NCT nanoparticle system using an ionic cross-linking method. The physicochemical properties of the NCT nanoparticles were systematically analyzed, and their therapeutic efficacy was comprehensively evaluated in streptozotocin (STZ)-induced animal models. Results: The NCT nanoparticles demonstrated mucus adhesion, permeability, and pH sensitivity, which facilitated a slow and controlled release within the gastrointestinal microenvironment due to both ionic electrostatic interactions and disulfide bonding interactions. The experiments revealed in vivo that insulin/NCT nanoparticles extended the retention time of insulin in the small intestine. Blood glucose levels decreased to approximately 39% of the initial level at 5 h post-administration while exhibiting smooth hypoglycemic efficacy. Simultaneously, insulin bioavailability increased to 12.58%. Conclusions: The NCT nanoparticles effectively protect insulin from degradation in the gastrointestinal microenvironment while overcoming intestinal barriers, thereby providing a promising approach to oral biomolecule delivery. Full article

Background: Direct selective laser trabeculoplasty (DSLT) is a novel option for intraocular pressure (IOP) control in patients with glaucoma or ocular hypertension. The automated and touchless translimbal delivery of laser energy to 360 degrees of the trabecular meshwork (TM) improves aqueous outflow and lowers IOP. DSLT is faster, simpler, and less invasive than routinely performed SLT. Few studies have compared the two techniques. Objective: To retrospectively compare the safety and efficacy of DSLT and SLT over a 1-year follow-up period. Methods: In total, 16 eyes that underwent DSLT and 16 eyes that underwent SLT were included. The primary outcome measures were mean absolute and percent IOP reduction, number of medications, and BCVA at 1, 3, 6, and 12 months. Survival analysis on 1-year data was performed based on the presence of one or more of the following failure criteria: (1) IOP > 21 mmHg or less than 20% reduction in IOP from baseline at two consecutive visits; (2) increase in the number of IOP-lowering drops from baseline at two consecutive visits; (3) further procedures. Results: The survival rates in the DSLT vs. SLT group were 81% vs. 78%, 44% vs. 62%, and 37% vs. 43% at 3, 6, and 12 months, respectively. No statistically significant differences were reported. DSLT does not seem inferior to conventional SLT in terms of safety and efficacy in reducing IOP. Conclusions: The advantages of an automated, rapid, contactless technique may enlarge the cohort of patients eligible for a drop-free first-line IOP control procedure. Full article

The opto-mechanical automated manufacturing process, characterized by stringent process constraints, dynamic disturbances, and conflicting optimization objectives, presents significant control challenges for traditional scheduling and control approaches. We formulate the scheduling problem within a closed-loop control paradigm and propose a novel bi-level intelligent control framework integrating Deep Reinforcement Learning (DRL) and Bayesian Optimization (BO). The core of our approach is a bi-level intelligent control framework. An inner DRL agent acts as an adaptive controller, generating control actions (scheduling decisions) by perceiving the system state and learning a near-optimal policy through a carefully designed reward function, while an outer BO loop automatically tunes the DRL’s hyperparameters and reward weights for superior performance. This synergistic BO-DRL mechanism facilitates intelligent and adaptive decision-making. The proposed method is extensively evaluated against standard meta-heuristics, including Genetic Algorithm (GA) and Particle Swarm Optimization (PSO), on a complex 20-jobs × 20-machines flexible job shop scheduling benchmark specific to opto-mechanical automated manufacturing. The experimental results demonstrate that our BO-DRL algorithm significantly outperforms these benchmarks, achieving reductions in makespan of 13.37% and 25.51% compared to GA and PSO, respectively, alongside higher machine utilization and better on-time delivery. Furthermore, the algorithm exhibits enhanced convergence speed, superior robustness under dynamic disruptions (e.g., machine failures, urgent orders), and excellent scalability to larger problem instances. This study confirms that integrating DRL’s perceptual decision-making capability with BO’s efficient parameter optimization yields a powerful and effective solution for intelligent scheduling in high-precision manufacturing environments. Full article

Biomedical antennas are essential components in modern healthcare systems, supporting wireless communication, physiological monitoring, diagnostic imaging, and therapeutic energy delivery. Their performance is strongly influenced by proximity to the human body, creating challenges such as impedance detuning, signal absorption, and size constraints that motivate new materials and fabrication approaches. This work reviews recent advances enabling next-generation wearable and implantable antennas, with emphasis on printed electronics, additive manufacturing, flexible hybrid integration, and metamaterial design. Methods discussed include 3D printing and inkjet, aerosol jet, and screen printing for fabricating conductive traces on textiles, elastomers, and biodegradable substrates, as well as multilayer Flexible Hybrid Electronics that co-integrate sensing, power management, and RF components into thin, body-conforming assemblies. Key results highlight how metamaterial and metasurface concepts provide artificial control over dispersion, radiation, and near-field interactions, enabling antenna miniaturization, enhanced gain and focusing, and improved isolation from lossy biological tissue. These approaches reduce SAR, stabilize impedance under deformation, and support more efficient communication and energy transfer. The review concludes that the convergence of novel materials, engineered electromagnetic structures, and AI-assisted optimization is enabling biomedical antennas that are compact, stretchable, personalized, and highly adaptive, supporting future developments in unobtrusive monitoring, wireless implants, point-of-care diagnostics, and continuous clinical interfacing. Full article

Multi-baseline phase unwrapping (PU) is an extension of single-baseline PU. Its accuracy directly affects the reliability of results in engineering tasks, such as InSAR topographic mapping and geological hazard monitoring, in complex scenarios. Meanwhile, its efficiency determines the timeliness of data delivery in emergency scenarios. The cluster-analysis (CA)-based algorithm represents a significant advancement in multi-baseline PU algorithms, wherein a strategy for pixel clustering and uniform PU is introduced. However, in the CA algorithm, phase noise degrades pixel clustering performance, leading to deviations in the determination of intercept centerlines and ultimately errors in ambiguity number search. In addition, the computational complexity is increased by the search for intercept peaks and ambiguity numbers. To address these limitations and ensure that accuracy and efficiency requirements are met in practical applications, an improved closed-form multi-baseline PU algorithm is proposed in this article. Compared with conventional CA algorithms, this algorithm offers the following four improvements. First, differential phase processing is introduced into the algorithm, which not only mitigates the impact of phase noise on pixel clustering but also provides new inputs for subsequent ambiguity-number solution. Secondly, a novel method for calculating the theoretical intercept is proposed, which depends solely on the external reference DEM and the ambiguity height. Thirdly, to eliminate the need for peak-intercept search and to suppress error propagation from incorrect intercepts, an intercept filtering method is introduced into the algorithm. In this method, a categorized filtering of actual intercepts for all pixels is performed. Fourthly, to address the phase-noise sensitivity and low efficiency in ambiguity-number search, the algorithm proposes a closed-form ambiguity-number solution method based on the Chinese Remainder Theorem (CRT). In this method, calculation accuracy can be ensured and solution efficiency improved by constructing and solving CRT equation groups with filtered error-free intercepts as remainders. The aforementioned four points are not independent of each other, but are strongly logically dependent and correlated. The effectiveness of the proposed algorithm is validated through one simulated data experiment and two real data experiments. The proposed algorithm achieves improvements in accuracy and efficiency across the three datasets. In terms of accuracy, the RMSE is reduced by at least 11.52%, while the PUSR increases by at least 1.36%. In terms of efficiency, runtime is shortened by at least 29.75%. Full article

Background/Objectives: Empagliflozin (EMPA) was repurposed for Alzheimer’s disease (AD) treatment via buccal delivery, exploiting novel nanofibers (NFs) integrating chitosan (Cs), silk fibroin (Fb), and poly(lactic acid) (PLA). Methods: EMPA-loaded Cs/Fb/PLA NFs were electrospun in different formulations to optimize the formulation parameters. The optimized formulation was then investigated for its enhanced in vivo effect. Results: Optimized nanofiber diameters ranged from 459 ± 173 to 668 ± 148 nm, possessing bead-free morphology confirmed by SEM and satisfactory mechanical properties. EMPA was successfully well-dispersed in the polymer matrix as evidenced by FTIR, XRD, and drug content. The optimized NFs displayed a hydrophilic surface (contact angle < 90°), and biphasic drug release with sustained EMPA liberation (84.98% over 24 h). In vivo, buccal EMPA-Cs/Fb/PLA NFs in an AlCl₃-induced AD rat model significantly reduced brain-amyloid-β, phosphorylated tau, IL-1β, and AGER expression by 2.88-, 2.64-, 2.87-, and 2.50-fold, respectively, compared to positive controls, and improved locomotor activity (1.86-fold) and cognitive performance (T-maze) (4.17-fold). Compared to pure EMPA, the nanofiber formulation achieved further reductions in amyloid-β (1.78-fold), p-tau (1.42-fold), IL-1β (1.89-fold), and AGER (1.38-fold), with efficacy comparable to memantine. Histopathological examination revealed preservation of the hippocampal neuronal structure. Conclusions: The findings suggest EMPA-loaded Cs/Fb/PLA NFs as a promising non-invasive, sustained-release buccal delivery platform for AD therapy, offering multimodal neuroprotection through modulation of the Aβ–AGER–p-tau axis. Full article

Background: Lactate Dehydrogenase C (LDHC) is a promising therapeutic target due to its highly tumor-specific expression, immunogenicity, and oncogenic functions. We previously showed that LDHC silencing in triple-negative breast cancer (TNBC) cells enhances treatment response to DNA-damage response-related drugs, supporting its therapeutic potential. However, no selective LDHC inhibitors exist, highlighting the need for innovative targeting strategies. Methods: We assessed the physicochemical properties and evaluated the delivery efficiency, anti-tumor activity, and safety of four cell-penetrating peptides (CPPs)—R10, 10R-RGD, cRGD-10R, and iRGD-10R—for siRNA-mediated LDHC silencing in TNBC. Clonogenic assays were used to evaluate effects on olaparib sensitivity, and TNBC zebrafish xenografts were utilized to study in vivo anti-tumor activity. Results: All CPP:siRNA complexes formed uniform nanocomplexes (129–168 nm) with low polydispersity indices (<0.25) and positive zeta potentials (+6.47 to +29.6 mV). Complexes remained stable in human serum for 24 h and showed no significant cytotoxicity in TNBC and non-cancerous cell lines. The 10R-RGD and cRGD-10R:siLDHC complexes achieved 40% LDHC protein knockdown, reduced TNBC clonogenicity by 30–36%, and enhanced olaparib sensitivity. Treatment of TNBC zebrafish xenografts with 10R-RGD or cRGD-10R:siLDHC complexes significantly reduced tumor growth by approximately 50% without major toxicity. Conclusions: These results demonstrate that CPP-mediated siRNA delivery enables selective LDHC silencing with tumor growth inhibition in triple-negative breast cancer models. This approach represents a novel, effective, and safe proof-of-concept therapeutic strategy to target LDHC, with potential translational relevance as a standalone therapy or in combination with common anti-cancer drugs. Full article

The mammary gland is a valuable model in cancer research and developmental biology. Gene delivery techniques are crucial for mammary tissue research to understand how genes function and study on diseases such as cancer. Viral vector-based approaches provide a high degree of transduction efficiency, but they raise safety and immunogenicity concerns, whereas non-viral vector-based approaches are considered safer and have lower immunogenicity than viral methods. Unfortunately, non-viral gene delivery has rarely been applied to the mammary glands because it is technically challenging. Here, we developed a novel method for in vivo transfection of epithelial cells lining murine mammary glands via intraductal injection of plasmid DNA using a breath-controlled glass capillary and subsequent electroporation (EP) of the injected area. Female mice were transfected with plasmids harboring the enhanced green fluorescent protein (EGFP) gene. Widespread EGFP fluorescence was observed in the mammary epithelial cells of the ducts and adipocytes adjacent to the ducts. As this in vivo gene delivery method is simple, safe, and efficient for gene transfer to the mammary glands, we named this technique “Mammary Intraductal Gene Electroporation” (MIGE). The MIGE method is a useful experimental tool for studies on mammary gland development and differentiation as well as breast cancer research. Full article

Background/Objectives: Impaired intestinal barrier function is a hallmark of inflammatory bowel disease (IBD). Akkermansia muciniphila and its outer membrane protein Amuc_1100 can enhance this barrier, but the clinical application of Amuc_1100 is limited by the fastidious growth of its native host. This study aimed to overcome this by utilizing the robust probiotic Lacticaseibacillus paracasei L9 for targeted Amuc_1100 delivery. Methods: We engineered Lc. paracasei L9 to express Amuc_1100 via intracellular (pA-L9), secretory (pUA-L9), and surface-display (pUPA-L9) strategies. Their efficacy was assessed in Lipopolysaccharide (LPS)-induced macrophages and a dextran sulfate sodium (DSS)-induced colitis mouse model, evaluating inflammation, barrier integrity, and mucosal repair. Results: The secretory (pUA-L9) and surface-display (pUPA-L9) strains most effectively suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in macrophages. In mice, both strains alleviated colitis and outperformed native A. muciniphila in improving disease activity. Crucially, they exhibited distinct, specialized functions: pUA-L9 acted as a systemic immunomodulator, reducing pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), elevating anti-inflammatory mediators (IL-4 and IL-10), and promoting goblet cell differentiation; notably, the inhibitory effect of pUA-L9 on IL-6 expression was approximately 2-fold greater than that of pUPA-L9. In contrast, pUPA-L9 excelled in local barrier repair, uniquely restoring mucus layer integrity (Muc1, Muc2, and Tff3) and reinforcing tight junctions (ZO-1, Occludin, Claudin1, Claudin3, and Claudin4). In particular, pUPA-L9 increased Muc2 expression by approximately 3.6-fold compared with pUA-L9. Conclusions: We demonstrate that the subcellular localization of Amuc_1100 within an engineered probiotic dictates its therapeutic mode of action. The complementary effects of secretory and surface-displayed Amuc_1100 offer a novel, spatially targeted strategy for precision microbiome therapy in IBD. Full article

Background/Objectives: Chronic wounds are considered a silent epidemic, affecting a significant portion of the global population and often leading to severe complications. In particular, wounds resulting from burns or trauma can give rise to squamous cell carcinoma (SCC), a form of skin cancer that arises under chronic inflammatory conditions. This study aims to develop and evaluate pH-responsive gelatin-based hydrogel films incorporating 5-fluorouracil (5-FU) for targeted treatment of SCC in chronic wound environments. Methods: Hydrogel films were formulated using gelatin and loaded with 5-FU. The design leveraged the pH differences between healthy skin and chronic wounds to enable stimuli-responsive drug release. The hydrofilms were characterized by evaluating their surface properties, including transparency, contact angle, and nanoscale morphology. In vitro swelling and dissolution behaviors were analyzed under varying pH conditions. Hemocompatibility was assessed through standard blood interaction assays. Cytotoxicity and selective toxicity were tested using both non-tumoral and tumoral representative skin cell lines. Results: The hydrogel films demonstrated pH-dependent swelling and dissolution, aligning with the neutral and basic environment of chronic wounds. Surface analysis revealed suitable transparency, wettability, and nanoscale uniformity for wound application. In vitro studies showed excellent hemocompatibility. Cytotoxicity assays confirmed good selective toxicity against the A431 skin carcinoma cell line, with minimal effects on healthy cells. Conclusions: The developed gelatin-based hydrogel films exhibit promising characteristics for targeted SCC therapy in chronic wounds. Their pH responsiveness, biocompatibility, and selective antitumor activity support their potential as effective and safe delivery systems. This platform may offer a novel therapeutic approach for managing malignancies arising in non-healing wound environments. Full article

Background: The regulation of the synthesis of the nerve growth factor and other neurotrophins is one of the dynamically developing areas of pharmacotherapy of neurological and mental disorders. Despite a large number of studies of various ligands of neurotrophin receptors, only a few have reached clinical application and only for ocular diseases. The aim of this narrative review was to systematize the main progress on neurotrophin-based pharmaceutics; to perform a comparative critical analysis of various therapeutic strategies, elucidate the underlying causes of clinical trial failures, and identify the most promising avenues for future development. Methods: The literature search was conducted in PubMed, Google Scholar, Medline, and EBSCO, and the ClinicalTrials.gov database was used to track current clinical studies, along with the official websites of pharmaceutical companies. The search covered original studies published up to October 2025, with inclusion restricted to articles published in English. Articles describing specific pharmacological compounds that had reached the clinical trial stage were selected. Foundational biological research was referenced to contextually explain the mechanisms of action of the drugs and their therapeutic implications. Results: Recombinant neurotrophins and synthetic molecules, the agonists and antagonists of their receptors, and cell-based gene therapy are promising means for the prevention and rehabilitation of ischemic conditions, as well as the treatment of neuropathic pain and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Some of these have undergone clinical trials, yet only neurotrophins for ocular diseases have been implemented in clinical practice: recombinant NGF—cenegermin and recombinant CNTF—Revakinagene taroretcel. The success of these eye drugs is likely attributable to their local administration, improved bioavailability, and low ocular immunoresistance. Conclusions: The study identified limitations and future prospects for neurotrophin-based pharmaceuticals. For future clinical trials, attention should be paid to the pharmacogenetic profiles of the patients and the evaluation of the inflammatory status of the disease. Novel plasma biomarkers of the effectiveness are needed as well as TSPO-PET imaging. Drug delivery systems remain insufficient; therefore, efforts should focus on inducing endogenous neurotrophin production and developing highly selective agonists and antagonists of neurotrophin receptors. It is crucial to establish a favorable premorbid background before neurotrophin therapy to minimize immunoresistance. Full article