Search

Background: Depression is a prevalent nonmotor symptom in Parkinson disease and can greatly reduce the quality of life for patients; the dopamine receptors found in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) play a role in regulating local field activity, which in turn affects behavioural and mood disorders. Given research showing that glial cell-derived neurotrophic factor (GDNF) may have an antidepressant effect, we sought to evaluate the impact of exogenous GDNF on depression-like behaviour in mouse models of Parkinson disease. Methods: We used an established subacute model of Parkinson disease in mice involving intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by brain stereotaxic injection of GDNF into the mPFC region. Subsequently, we assessed depression-like behaviour using the sucrose preference test, forced swimming test and tail suspension test, while also evaluating protein expression in the mPFC. Results: We included 60 mice, divided into 3 groups, including a control group (saline injection), an MPTP plus saline injection group and an MPTP plus GDNF injection group. We found that exogenous GDNF injection into the mPFC led to an increase in dopamine receptor D1 (DRD1) protein levels. We also observed that activating the protein kinase A pathway through DRD1 produced a prolonged antidepressant response. Under GDNF stimulation, the expression of dopamine receptor D2 (DRD2) remained constant, suggesting that the DRD2 signal was ineffective in alleviating depression-like symptoms. Moreover, our investigation involved Golgi staining and Western blot techniques, which found enhanced synaptic plasticity, including increased dendritic branches, dendritic spines and retrograde protection after GDNF treatment in Parkinson disease models. Limitations: A subtle motor phenotype became evident only toward the conclusion of the behavioural testing period. The study exclusively involved male mice, and no separate control group receiving only GDNF treatment was included in the experimental design. Conclusion: Our findings support a positive effect of exogenous GDNF on synaptic plasticity, mediated by DRD1 signalling in the mPFC, which could facilitate depression remission in Parkinson disease., Introduction Parkinson disease is the world's second most common degenerative neurologic disorder, and nonmotor symptoms cannot be ignored in most patients with Parkinson disease, including cognitive decline, sleep disturbance, fatigue, [...]

Objective To summarize and analyze what the listing in market of orphan drugs in China, the United States, the European Union, and Japan in 2023, and to provide empirical reference to Chinese pharmaceutical enterprises, pharmaceutical management, and new drug research and development departments. Methods Collect the 2023 drug market data released by official drug regulatory agencies in four countries and international organization-China, the United States, the European Union, and Japan categorize the market of rare disease drugs and and their indications, approval dates, R&D status in China, component therapeutic areas, and special review and approval pathways were analyzed. Results Findings in 2023, 28 orphan drugs were listed in the United States, mostly anti-tumor related, accounting for 32.1% (9 out of 28); 17 orphan drugs were listed in the European Union, anti-tumor related accounting for 47.0% (8 of 17); 22 listed in Japan; and 45 listed in China. In 2023, over 70% orphan drugs listed in the European Union and Japan entered the phase of clinical trials/marketing and applications/approved clinical applications in China (86.4% from Japan and 70.6% from European Union). Conclusions Currently, there is no qualification accreditation mechanism for orphan drugs in China. However, in 2023, the number of rare disease drugs listed in China was the greatest among the four countries/international organization. It reflects that China′s Catalog for Rare Diseases played a guiding role in drug research and development. Meanwhile, the reform of drug approval and review in China and the issue of rare disease catalogs took place in a short period of time, so the review and approval, as well as research and development of rare disease drugs are still in the catching up stage.

We studied the patients diagnosed with X-linked hypophosphatemicrickets(XLH) and treated with burosumab in Peking Union Medical College Hospital from January 2021 to December 2022. In addition, we described the clinical characteristics of the patients, the changes of clinical indexes before and after burosumab treatment, and the adverse drug reactions during treatment. We also evaluated the efficacy and safety of burosumab for XLH. The results showed that three children XLH patients and one adult XLH patients received burosumab treatment. After treatment, the serum phosphorus level of all patients increased; the serum phosphorus of 3 children patients increased above the lower limit of the reference value range; the serum alkaline phosphatase(ALP) of all patients was lower than that of before treatment; the serum ALP of one adult patient was close to the normal range after 2.5 years of treatment. One child patient showed small crystals in kidney through ultrasound 48 weeks after treatment; one child and one adult showed increased serum parathyroid hormone(PTH)level before treatment and serum PTH continued increasing after treatment. Finally, it may be concluded that burosumab increased serum phosphorus levels in XLH patients, kept the level relatively stable, and reduced serum ALP levels. No serious adverse reactions occurred during treatment, in order to provide reference for the use of burosumab in patients with XLH.

Abstract Transport of rodlike particles in confinement environments of macromolecular networks plays crucial roles in many important biological processes and technological applications. The relevant understanding has been limited to thin rods with diameter much smaller than network mesh size, although the opposite case, of which the dynamical behaviors and underlying physical mechanisms remain unclear, is ubiquitous. Here, we solve this issue by combining experiments, simulations and theory. We find a nonmonotonic dependence of translational diffusion on rod length, characterized by length commensuration-governed unconventionally fast dynamics which is in striking contrast to the monotonic dependence for thin rods. Our results clarify that such a fast diffusion of thick rods with length of integral multiple of mesh size follows sliding dynamics and demonstrate it to be anomalous yet Brownian. Moreover, good agreement between theoretical analysis and simulations corroborates that the sliding dynamics is an intermediate regime between hopping and Brownian dynamics, and provides a mechanistic interpretation based on the rod-length dependent entropic free energy barrier. The findings yield a principle, that is, length commensuration, for optimal design of rodlike particles with highly efficient transport in confined environments of macromolecular networks, and might enrich the physics of the diffusion dynamics in heterogeneous media.