The novel hyaluronic acid granular hydrogel attenuates osteoarthritis progression by inhibiting the TLR-2/NF-κB signaling pathway through suppressing cellular senescence.

In patients with mild osteoarthritis (OA), two to four monthly injections are required for 6 months due to the degradation of hyaluronic acid (HA) by peroxidative cleavage and hyaluronidase. However, frequent injections may lead to local infection and also cause inconvenience to patients during the COVID-19 pandemic. Herein, we developed a novel HA granular hydrogel (n-HA) with improved degradation resistance. The chemical structure, injectable capability, morphology, rheological properties, biodegradability, and cytocompatibility of the n-HA were investigated. In addition, the effects of the n-HA on the senescence-associated inflammatory responses were studied via flow cytometry, cytochemical staining, Real time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis. Importantly, the treatment outcome of the n-HA with one single injection relative to the commercial HA product with four consecutive injections within one treatment course in an OA mouse model underwent anterior cruciate ligament transection (ACLT) was systematically evaluated. Our developed n-HA exhibited a perfect unification of high crosslink density, good injectability, excellent resistance to enzymatic hydrolysis, satisfactory biocompatibility, and anti-inflammatory responses through a series of in vitro studies. Compared to the commercial HA product with four consecutive injections, a single injection of n-HA contributed to equivalent treatment outcomes in an OA mouse model in terms of histological analysis, radiographic, immunohistological, and molecular analysis results. Furthermore, the amelioration effect of the n-HA on OA development was partially ascribed to the attenuation of chondrocyte senescence, thereby leading to inhibition of TLR-2 expression and then blockade of NF-κB activation. Collectively, the n-HA may be a promising therapeutic alternative to current commercial HA products for OA treatment.

Microdroplet-Facilitated Assembly of Thermally Activated Delayed Fluorescence-Encoded Microparticles with Non-interfering Color Signals.

Encoded microparticles (EMPs) have shown demonstrative value for multiplexed high-throughput bioassays such as drug discovery and diagnostics. Herein, we propose for the first time the incorporation of thermally activated delayed fluorescence (TADF) dyes with low-cost, heavy metal-free, and long-lived luminescence properties into polymer matrices via a microfluidic droplet-facilitated assembly technique. Benefiting from the uniform droplet template sizes and polymer-encapsulated structures, the resulting composite EMPs are highly monodispersed, efficiently shield TADF dyes from singlet oxygen, well preserve TADF emission, and greatly increase the delayed fluorescence lifetime. Furthermore, by combining with phase separation of polymer blends in the drying droplets, TADF dyes with distinct luminescent colors can be spatially separated within each EMP. It eliminates optical signal interference and generates multiple fluorescence colors in a compact system. Additionally, in vitro studies reveal that the resulting EMPs show good biocompatibility and allow cells to adhere and grow on the surface, thereby making them promising optically EMPs for biolabeling.

Neuroprotective Effect of Modified Electroconvulsive Therapy for Schizophrenia: A Proton Magnetic Resonance Spectroscopy Study.

The underlying mechanism of modified electroconvulsive therapy (MECT) treatment for drug-resistant and catatonic schizophrenia remains unclear. Here, we aim to investigate whether MECT exerts its antipsychotic effects through elevating N-acetylaspartate (NAA) concentration measured by proton magnetic resonance spectroscopy (H-MRS). Multiple-voxel H-MRS was acquired in the bilateral prefrontal cortex (PFC) and thalamus to obtain measures of neurochemistry in 32 MECT, 34 atypical antipsychotic-treated schizophrenic patients, and 34 healthy controls. We found that both MECT and atypical antipsychotic treatments showed significant antipsychotic efficacy. MECT and atypical antipsychotic treatments reversed the reduced NAA/creatine ratio (NAA/Cr) in the left PFC and left thalamus in schizophrenic patients compared with healthy controls. Furthermore, the NAA/Cr ratio after treatments was significant higher in the MECT group, but not in the medication group. Our findings demonstrate that eight times of MECT elevated the relative NAA concentration to display neuroprotective effect, which may be the underlying mechanism of rapid antipsychotic efficacy.

A longitudinal study on intrinsic connectivity of hippocampus associated with positive symptom in first-episode schizophrenia.

Hippocampal pathology has been considered to underlie clinical, functional and cognitive impairments in schizophrenia. While longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive gray matter reduction of the hippocampus during the early phases of schizophrenia (SCZ), very little is known about whether functional connectivity (FC) between the hippocampus and other brain regions also exhibit progressive changes. In this study, resting state functional MRI (fMRI) was used to examine changes in hippocampal connectivity at baseline and follow-up scans comparing 68 patients with first episode SCZ and 62 matched controls. At baseline and follow-up, in the bilateral hippocampal network, SCZ mainly showed decreased FC with bilateral cerebellum posterior lobe, frontal gyrus temporal gyrus, precuneus, and cingulate cortex compared to controls. Furthermore, in the bilateral hippocampus, there was a significant interaction effect of group and time for FC with cerebellum posterior lobe, temporal gyrus, frontal gyrus, and posterior cingulate cortex. Interestingly, longitudinal changes of bilateral hippocampal connectivity with right middle frontal gyrus negatively correlated with positive symptom scores in SCZ. These results provide novel evidence for the progressive changes of FC between hippocampus and other brain regions in SCZ. It further suggests that longitudinal changes of bilateral hippocampal connectivity with right middle frontal gyrus can contribute to the formation and emergence of positive symptom of SCZ.

Atypical antipsychotic drug treatment for 6 months restores N-acetylaspartate in left prefrontal cortex and left thalamus of first-episode patients with early onset schizophrenia: A magnetic resonance spectroscopy study.

Early onset schizophrenia (EOS) is often associated with poorer outcomes, including lack of school education, higher risk of mental disability and resistance to treatment. But the knowledge of the neurobiological mechanism of EOS is limited. Here, using proton magnetic resonance spectroscopy, we investigated the possible neurochemical abnormalities in prefrontal cortex (PFC) and thalamus of first-episode drug-naïve patients with EOS, and followed up the effects of atypical antipsychotic treatment for 6 months on neurochemical metabolites and clinical symptoms. We measured the ratios of N-acetylaspartate (NAA), choline (Cho) to creatine (Cr) in 41 adolescents with first episode of EOS and in 28 healthy controls matched for age, gender, and years of education. The EOS patients presented with abnormally low NAA/Cr values in the left PFC and left thalamus with a reduced tendency in the right PFC compared with healthy controls. No significant differences were detected between groups for Cho/Cr in PFC and thalamus in any hemisphere. After atypical antipsychotic treatment for 6 months, the reduced NAA/Cr in the left PFC and left thalamus in EOS patients was elevated to the normal level in healthy controls, without any alteration in Cho/Cr. We also found that there was no significant correlation between the neurochemical metabolite ratios in the PFC and thalamus in patients with EOS, and clinical characteristics. Our results suggest that there was neurochemical metabolite abnormalities in PFC and thalamus in EOS patients, atypical antipsychotic treatment can effectively relieve the symptoms and restore the reduced NAA in PFC and thalamus.

Neuroactive steroid pregnenolone sulphate inhibits long-term potentiation via activation of alpha2-adrenoreceptors at excitatory synapses in rat medial prefrontal cortex.

Pregnenolone sulphate (PREGS) is one of the most important neuroactive steroids. Previous study showed that PREGS enhanced long-term potentiation (LTP) via activation of post-synaptic NMDA receptors at excitatory synapses in the hippocampus. The present paper studied the effect of PREGS on LTP at excitatory synapses in the pyramidal cells of layers V-VI of the medial prefrontal cortex (mPFC) using whole-cell patch-clamp in slices and made a comparison with that in the hippocampus. We also studied the mechanism of the effect of PREGS in the mPFC. We found that PREGS inhibited induction of LTP in the mPFC and had no influence on NMDA currents, which was different from its effect in the hippocampus. Moreover, the effect of PREGS on LTP in the mPFC was cancelled by alpha2-adrenoreceptor antagonist, alpha2A-adrenoreceptor antagonist, Gi protein inhibitor, adenylate cyclase inhibitor and protein kinase A inhibitor. These results suggest that PREGS inhibits LTP via activation of the alpha2-adrenoreceptor-Gi protein-adenylate cyclase-protein kinase A signalling pathway in the mPFC.

Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors.

Dehydroepiandrosterone sulphate is one of the most important neurosteroids. In the present paper, we studied the effect of dehydroepiandrosterone sulphate on persistent sodium currents and its mechanism and functional consequence with whole-cell patch clamp recording method combined with a pharmacological approach in the rat medial prefrontal cortex slices. The results showed that dehydroepiandrosterone sulphate inhibited the amplitude of persistent sodium currents and the inhibitory effect was significant at 0.1 microM, reached maximum at 1 microM and decreased with the increase in the concentrations of above 1 microM. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was canceled by the Gi protein inhibitor and the protein kinase C inhibitor, but not by the protein kinase A inhibitor. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was also canceled by the sigma-1 receptor blockers and the sigma-1 receptor agonist could mimic the effect of dehydroepiandrosterone sulphate. Dehydroepiandrosterone sulphate had no significant influence on neuronal excitability but could significantly inhibit chemical inhibition of mitochondria-evoked increase in persistent sodium currents. These results suggest that dehydroepiandrosterone sulphate inhibits persistent sodium currents via the activation of sigma-1 receptors-Gi protein-protein kinase C-coupled signaling pathway, and the main functional consequence of this effect of DHEAS is presumably to protect neurons under ischemia.

Neurosteroid dehydroepiandrosterone sulfate enhances spontaneous glutamate release in rat prelimbic cortex through activation of dopamine D1 and sigma-1 receptor.

This paper studied the effect of neurosteroid dehydroepiandrosterone sulfate on spontaneous glutamate release in the prelimbic cortex by using electrophysiological and biochemical methods combined with a pharmacological approach and made some comparisons with those in the hippocampus. The results showed that dehydroepiandrosterone sulfate increased the frequency of miniature excitatory postsynaptic currents in the prelimbic cortex and hippocampus; sigma-1 receptor antagonist partially blocked the effect of dehydroepiandrosterone sulfate in the prelimbic cortex, but completely blocked it in the hippocampus; D1 receptor antagonist, adenylyl cyclase inhibitor and protein kinase A inhibitor completely blocked the effect of dehydroepiandrosterone sulfate in the prelimbic cortex; dehydroepiandrosterone sulfate increased the activity of protein kinase A in the prelimbic cortex and hippocampus; the effect of dehydroepiandrosterone sulfate on protein kinase A was completely blocked by sigma-1 receptor antagonist in the hippocampus, but was partially blocked in the prelimbic cortex; interestingly, here again, the effect of dehydroepiandrosterone sulfate on protein kinase A was completely blocked by D1 receptor antagonist in the prelimbic cortex. These results suggest that dehydroepiandrosterone sulfate promotes presynaptic glutamate release in the prelimbic cortex via activation of D1 and sigma-1 receptors.

[Influence of beginning time of hypothermia treatment on prognosis of extensive cerebral infarction].

OBJECTIVE: To study the influence of beginning time of cranial hypothermia treatment on the prognosis of extensive cerebral infarction(ECI) so as to establish the optimum time for such treatment. METHODS: Ninety-two ECI patients were divided into three groups. In group A hypothermia treatment was begun within 6 hours after cerebral infarction in 31 patients. In another 31 cases in group B it was begun in 7-10 hours, and in 30 cases in group C it was begun in 11-14 hours after the attack. The mortality rate, the volume of cerebral infarction, neurological deficiency score(NDS) and quality of life in survivors were determined respectively in three groups. RESULTS: The volume of cerebral infarction in group A and B was obviously smaller than that of group C after hypothermia treatment(P<0.01). The mortality rate was higher in group C (26.67% in group C, 3.23% in group A and 6.45% in group B, both P<0.05) The mortality rate was highest in cases with high body temperature in group C(P<0.05). NDS was significantly lower in survivors of groups A and B compared with group C (both P<0.05), groups A and B compared with group C(P<0.05). The NDS and quality of life of the survivors with high body temperature(P<0.05 or P<0.01). CONCLUSION: Cranial hypothermia treatment should be begun with 10 hours after illness to obtain best effect.

[Establishment of delayed encephalopathy rat model of carbon monoxide poisoning].

OBJECTIVE: To establish the delayed encephalopathy rat model of carbon monoxide (CO) poisoning. METHODS: 40 Wistar rats were randomly divided into 4 groups of 10 rats and were placed in the chambers of inside-built 10-chamber poisoning box. Mixed gas is ventilated with the volume fractions of 10.0 x 10(-4), 15.0 x 10(-4) and 16.5 x 10(-4) of CO in air into the chambers for group A, B and C respectively, and pure air was ventilated for group D. The gas flow rate was 800 L/h in the first 5 hours, 1,000 L/h in the middle 4 hours, and 1,200 L/h in the last 3 hours, with a whole ventilation time of 12 hours. Before and after CO poisoning maze test with radial eight-arm maze was conducted to assess the rats' intelligence. The appearance of coma or less than 3 correct arm-enterings in maze test between the 3rd and 28th day after poisoning was considered as the indications of delayed encephalopathy. TUNEL method, flow cytometry, and transmission electron microscopy were adopted to examine the cellular apoptosis in cerebral cortex and hippocampus area. RESULTS: There were 4 rats with delayed encephalopathy changes in groups B and C respectively, while no similar behavioral change appeared in groups A and D. TUNEL method showed an apoptotic rate of 45.0% to 65.0% in the rats with delayed encephalopathy of group B and an apoptotic rate of 55.0% to 80.0% in the rats with delayed encephalopathy of group C, most of the apoptotic cells being neurons. Flow cytometry showed an apoptotic rate of 50.5% +/- 4.2% in the rats with delayed encephalopathy of group B and an apoptotic rate of 55.9% +/- 7.8% in the rats with delayed encephalopathy of group C. By electron microscopy the percentage of typical apoptotic neurons was 5.0% approximately 15% in group B and 10.0% to 20.0% in group C, less than 5.0% in group A, and less than 1.6% in group D. CONCLUSION: A delayed encephalopathy rat model of CO poisoning has been successfully established based on the volume fraction of 15.0 x 10(-4) to 16.5 x 10(-4) of CO in air and a poisoning time of 12 hours. The pathological change is a mass neuron apoptosis in cerebral cortex and hippocampus.