Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures.

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation - hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.

Bacteria Synergized with PD-1 Blockade Enhance Positive Feedback Loop of Cancer Cells-M1 Macrophages-T Cells in Glioma.

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti-PD-1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD-1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells-M1 macrophages-T cells. Collectively, the bacteria synergized with PD-1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma.

Hydrogen production promotion and energy saving in anaerobic co-fermentation of heat-treated sludge and food waste.

The objective of this paper is to gain insights into the synergistic advantage of anaerobic co-fermentation of heat-treated sludge (HS) with food waste (FW) and heat-treated food waste (HFW) for hydrogen production. The results showed that, compared with raw sludge (RS) mixed with FW (RS-FW), the co-substrate of HS mixed with either FW (HS-FW) or HFW (HS-HFW) effectively promoted hydrogen production, with HS-HFW promoted more than HS-FW. The maximum specific hydrogen production (MSHP) and the maximum hydrogen concentration (MHC) of HS-HFW were 40.53 mL H2/g dry weight and 57.22%, respectively, and 1.21- and 1.45-fold as high as those from HS-FW. The corresponding fermentation was ethanol type for HS-HFW and butyric acid type for HS-FW. The net energy production from RS-FW and HS-FW was both negative, but it was positive (2.57 MJ) from 40% HFW addition to HS-HFW. Anaerobic fermentation was more viable for HS-HFW.

Low-frequency stimulation in the zona incerta attenuates seizure via driving GABAergic neuronal activity.

BACKGROUND: Managing refractory epilepsy presents a significant a substantial clinical challenge. Deep brain stimulation (DBS) has emerged as a promising avenue for addressing refractory epilepsy. However, the optimal stimulation targets and effective parameters of DBS to reduce seizures remian unidentified. OBJECTIVES: This study endeavors to scrutinize the therapeutic potential of DBS within the zona incerta (ZI) across diverse seizure models and elucidate the associated underlying mechanisms. METHODS: We evaluated the therapeutic potential of DBS with different frequencies in the ZI on kainic acid (KA)-induced TLE model or M1-cortical seizures model, pilocarpine-induced M1-cortical seizure models, and KA-induced epilepsy model. Further, employing calcium fiber photometry combined with cell-specific ablation, we sought to clarified the causal role of ZI GABAergic neurons in mediating the therapeutic effects of DBS. RESULTS: Our findings reveal that DBS in the ZI alleviated the severity of seizure activities in the KA-induced TLE model. Meanwhile, DBS attenuated seizure activities in KA- or pilocarpine-induced M1-cortical seizure model. In addition, DBS exerts a mitigating influence on KA induced epilepsy model. DBS in the ZI showed anti-seizure effects at low frequency spectrum, with 5 Hz exhibiting optimal efficacy. The low-frequency DBS significantly increased the calcium activities of ZI GABAergic neurons. Furthermore, selective ablation of ZI GABAergic neurons with taCasp3 blocked the anti-seizure effect of low-frequency DBS, indicating the anti-seizure effect of DBS is mediated by the activation of ZI GABAergic neurons. CONCLUSION: Our results demonstrate that low-frequency DBS in the ZI attenuates seizure via driving GABAergic neuronal activity. This suggests that the ZI represents a potential DBS target for treating both hippocampal and cortical seizure through the activation of GABAergic neurons, thereby holding therapeutic significance for seizure treatment.

Evaluation of Reactive Oxygen Species Scavenging of Polydopamine with Different Nanostructures.

Reactive oxygen species (ROS) play an important role in cellular metabolism and many oxidative stress-related diseases, while excessive accumulation of ROS will lead to genetic changes in cells and promote the occurrence of inflammatory diseases or cell death. Nature-inspired polydopamine (PDA) with tailored nanostructures emerges as an ROS scavenger and is considered as an effective approach to inflammation-related diseases. However, the effects of nanoparticle structure on PDA scavenging efficacy and efficiency remain uncovered. In this work, three typical PDA nanoparticles including solid PDA, mesoporous PDA, and hollow PDA are synthesized, and of which physiochemical properties are characterized. Furthermore, their ROS scavenging performance is investigated by in vitro evaluation of radical removal. Among the three nanoparticles, mesoporous PDA is demonstrated to have the highest scavenging capability, mainly due to its specific surface area. Finally, the study on three in vivo inflammation models is constructed. The results confirm that mesoporous PDA is the most potent scavenger of ROS and more effective in reducing reperfusion injury, improving renal function, and preventing periodontitis progression, respectively. Together with the good biosafety and biocompatibility profiles, PDA nanoparticles, mesoporous PDA in particular, can be a promising avenue of ROS scavenging in fight against the inflammatory diseases.

Pathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke.

Ischemic stroke is lethal cerebrovascular disease, and reperfusion as the main strategy of blood supply restoration can cause severe ischemic brain damage. Considered as the major obstacle in medication for stroke, neuroinflammation after reperfusion undergoes dynamic progression, making precision treatment for stroke a Herculean task. In this work, we report a pathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke. Intrinsic free radical scavenging and tailored mesostructure of the nanosystem can attenuate oxidative stress at the initial stage. Upon microglial overactivation at the later stage, minocycline-loaded nanosystem can timely reverse the pro-inflammatory transition in response to activated matrix metalloproteinase-2, providing on-demand regulation. Further in vivo stroke study demonstrates a higher survival rate and improved brain recovery of the sequential strategy, compared with mono-therapy and combined therapy. Complemented with satisfactory biosafety results, this adaptive nanosystem for sequential and on-demand regulation of post-stroke neuroinflammation is a promising approach to ischemic stroke therapy.

Using a Hybrid Multiattribute Decision-Making Model for Evaluating the Sustainable Development Potential of Characteristic Towns and Exploring Development Planning Strategies.

In recent years, with the development of 'China's new urbanization, the "characteristic town movement" with the development of industrial economy first has brought problems to a large number of rural settlements, such as no cultural planning, no consumption of industry, and no soul. Then, in reality, there are still a large number of rural settlements under the planning of the upper-level local government, with the goal of developing into a characteristic town in the future. Therefore, this study believes that there is an urgent need to build a framework for evaluating the construction potential of rural settlements with sustainable characteristic towns. Not only that but also a decision analysis model should be provided for real-world empirical cases. This model needs to cover the assessment of the sustainable development potential of characteristic towns as the goal and the formulation of improvement strategies. This study combines the data collection of current characteristic town development rating reports, applies data exploration technology to extract core impact elements and obtain hierarchical decision rules, integrates expert domain knowledge with DEMATEL technology, and establishes an impact network relationship diagram between core impact elements. At the same time, the representative characteristic town cases are assessed for their sustainable development potential, and the modified VIKOR technique is applied to clarify the actual problems of the empirical cases, in an attempt to determine whether the development potential and development plan of the characteristic town meet the sustainable development needs from the pre-evaluation mechanism.

Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model.

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

Electro-responsive micelle-based universal drug delivery system for on-demand therapy in epilepsy.

A universal drug delivery system (DDS) with brain-targeted ability is demanded to enhance antiepileptic therapeutic efficacy and reduce side effects in multiple types of epileptic seizures. In this study, we reported a micelle-based DDS possessing the brain-targeted ability and electro-responsive feature for universal delivery of antiepileptic drugs (AEDs). The system is fabricated by ferrocene (Fc)-conjugated D-a-tocopherol polyethylene glycol succinate and amphiphilic block copolymer, which improve the drug encapsulation of different AEDs. Interestingly, the intrinsic nature of TPGS-Fc including transferrin receptor-mediated transcytosis and efflux pump inhibition endows the system with high permeability across the blood-brain barrier. Based on the hydrophobic-hydrophilic transition of Fc, the micelles can respond to epileptiform discharges and thus release the loaded AEDs. Improved antiepileptic efficacy of the micelles has been demonstrated in acute, continuous, and chronic epilepsy models. In summary, we have developed a universal micelle-based DDS for various AEDs delivery, which provides a promising approach to on-demand therapy of different epileptic seizures.

Pegriseofamines A-E: Five cyclopiazonic acid related indole alkaloids from the fungus Penicillium griseofulvum.

Five new cyclopiazonic acid related indole alkaloids, pegriseofamines A-E (1-5), were isolated from the fungus Penicillium griseofulvum. Their structures and absolute configurations were determined by NMR, HRESIMS, quantum-chemical calculation, and X-ray diffraction experiments. Among them, pegriseofamine A (1) possesses an undescribed 6/5/6/7 tetracyclic ring system generated by the fusion of an azepine and an indole unit via a cyclohexane, and the postulated biosynthetic origin of 1 was discussed. Compound 4 could relieve liver injury and prevent hepatocyte apoptosis in ConA-induced autoimmune liver disease.

The adsorption mechanism of sludge-based biochar toward highly concentrated organic membrane concentrates from landfill leachate.

In this study, the sludge-based biochar (BC) was prepared by dewatered sludge from a membrane bioreactor to treat the membrane concentrate. Then, the adsorbed and saturated BC was regenerated (RBC) by pyrolysis and deashing treatment to further treat the membrane concentrate. Afterward, the composition of membrane concentrate before and after BC or RBC treatment was detected, and the biochars' surface characteristics were characterized. The results showed that RBC outperformed BC in the abatement of chemical oxygen demand (CODCr), ammonia nitrogen (NH3-N), and total nitrogen (TN), with their removal rates of 60.07%, 51.55%, and 66.00%, respectively, an improvement of 9.49%, 9.00% and 16.50% of the removal rate compare to BC. The specific surface area of BC and RBC was about 109 times as much as the original dewatered sludge, and the pore size of BC and RBC belonged to mesopore which was a benefit for removing small and mediate size pollutants. The increase of the oxygen-containing functional group in RBC and the ash abatement contributed much to the improvement of RBC adsorption performance. In addition, cost analysis showed that BC+RBC had a cost of 0.76$/kg for COD removal, which was a lower cost than other common membrane concentrate treatment technologies.

Lasiodiplodiapyrones A and B, Pyrone-Preussomerin Adducts with Highly Strained Polycyclic Ring Systems from Lasiodiplodia pseudotheobromae.

Lasiodiplodiapyrones A and B (1 and 2), two new preussomerin derivatives, possessing an unexpected 6-methyl-4H-furo[3,2-c]pyran-4-one moiety and a highly functionalized conjoint and complicated polycyclic ring system, along with two known congeners (3 and 4), were isolated from the fungus Lasiodiplodia pseudotheobromae. Their structures including absolute configurations were determined by spectroscopic analyses, Mosher's method, and ECD calculations. A biosynthetic pathway was proposed to explain the origin of lasiodiplodiapyrones A and B as well as their relationship with preussomerins. Compounds 1-4 showed suppressive effects on the production of NO with IC50 values of 4.8 ± 0.3, 8.5 ± 1.1, 5.9 ± 0.8, and 12.8 ± 1.3 µM, respectively.

Caryophyllene sesquiterpenoids with various ring systems from the fungus Pestalotiopsis chamaeropis.

Six undescribed caryophyllene sesquiterpenoids named pestalotiopsins O-T, along with eight known analogues, were obtained from the fungus Pestalotiopsis chamaeropis. Their structures and absolute configurations were assigned by NMR spectroscopic analyses, HRESIMS, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations, Mo2(OAc)4-induced ECD, and chemical derivatization. Pestalotiopsin P represents the first example of a caryophyllene sesquiterpenoid possessing an oxatricyclo [7.2.2.03.6]tridecane decorated with a rare bridgehead double bond, while pestalotiopsin Q has an oxatricyclic [6.3.1.01,4]dodecane skeleton with an unusual ether bridge between C-1 and C-5. These undescribed caryophyllene sesquiterpenoids were screened for their cytotoxic and anti-inflammatory activities.

Role of trace TEMPO as electron shuttle in enhancing chloroquine phosphate elimination in UV-LED-driven persulfate activation process.

Chloroquine Phosphate (CP) is an antiviral drug used for treatment of COVID-19. It is released into wastewater and eventually contaminates natural water. This study reports an effective homogeneous catalysis way for CP degradation by the 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) enhanced persulfate (PDS) activation under UVB-LEDs irradiation at 305 nm. TEMPO at a low concentration (0.1 µM) enhanced CP degradation in UV305/PDS process in deionized water at different pHs, in different anions and different molecular weight dissolved organic matter solutions and in real surface water. The enhancement was verified to be attributed to the electron shuttle role of TEMPO, which promoted the yield of SO4 •- by enhancing electron donating capacity of the reacting system. The degradation products of CP and their acute toxicities suggested that UV305/PDS/TEMPO process has better performance on CP detoxification than UV305/PDS process. This study provides a new way to tackle the challenge of pharmaceutical pollutions in homogeneous photocatalysis process for natural water and sewage restoration.

Virenscarotins A-M, thirteen undescribed carotane sesquiterpenes from the fungus Trichoderma virens.

A document investigation on the fungus Trichoderma virens led to the isolation of thirteen undescribed carotane sesquiterpenes and homologous. All structures were elucidated on the basis of NMR and HRESIMS data, and their absolute configurations were assigned by ECD calculation. Especially, virenscarotins A and B were first ramifications forged by aldol condensation of 4-hydroxy-3-isopentenyl-benzaldehyde with two hydroxyl groups in ring A of traditional carotane sesquiterpenes. Ring rearrangement/expansion and oxidative cleavage of normal carotane sesquiterpenes lead to the six-membered ring A of compound virenscarotin C and the ring A cleavage of compound virenscarotin D. All compounds were evaluated for cytotoxic, anti-inflammatory, and seed germination inhibitory activities.

The role of trace N-Oxyl compounds as redox mediator in enhancing antiviral ribavirin elimination in UV/Chlorine process.

Ribavirin (RBV) is an antiviral drug used for treating COVID-19 infection. Its release into natural waters would threaten the health of aquatic ecosystem. This study reports an effective approach to degrade RBV by the trace N-oxyl compounds (2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and N-Hydroxyphthalimide (NHPI)) enhanced UV activated free chlorine (UV/Chlorine) process. The results indicated that TEMPO and NHPI at low concentrations (0.1 µM and 1 µM, respectively) could strongly enhance RBV degradation in both deionized water with different pHs and practical surface water. The enhancement was verified to be attributed to the transformation of TEMPO and NHPI into their reactive forms (i.e., TEMPO+ and PINO), which generations deeply relied on radicals. The two N-oxyl compounds inhibit ClO• yield by hindering the reaction of free chlorine vs. HO• and Cl•. The analyses on acute toxicities of RBV degradation products indicate that UV/Chlorine/N-oxyl compounds process can detoxify RBV more efficiently than UV/Chlorine process.

30-norlanostane triterpenoids and steroid derivatives from the endophytic fungus Aspergillus nidulans.

Two undescribed 30-norlanostane triterpenoids, named nidulanoids A and B, one ergostane-type steroid with an unusual double bond between C-17 and C-20 designated (17E,22E,24R)-3ß,5α-dihydroxyergosta-7,17,22-trien-6,16-dione, and one pregnane, (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al, along with six known steroids were isolated from the extract of the fungus Aspergillus nidulans. Among them, nidulanosides A and B represents the first example of naturally occurred 30-norlanostane triterpenoids featuring a C9 side-chain moiety at C-17 and a hemiacetal system formed between C-3 and C-19, as an intermediate between lanostane and the regular steriods; the structure of (17E,22E,24R)-3ß,5α-dihydroxyergosta-7,17,22-trien-6,16-dione possesses an untypical Δ17,20 double bond; meanwhile, (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al represents the first example of C-21 steroid with an aldehyde group at C-13. Their structures and absolute stereochemistry were elucidated based on spectroscopic data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17 (20)-trien-18-al showed moderate inhibitory activities against rat brain cancer (PC12) cell lines, with IC50 value of 7.34 µM. This study enriches the diversified structures of triterpenoids and steroids analogues from A. nidulans and indicated (7Z,9Z,17Z)-,2α,3ß-dihydroxypregna-7,9,17(20)-trien-18-al to be a promising lead compound against PC12 cell lines.

Four undescribed ergostane-type steroids from Lasiodiplodia pseudotheobromae and their neuroprotective activity.

Four undescribed ergostane-type steroids, (22E,24R)-4α,5α-epoxyergosta-9α,14ß-dihydroxy-7,22-diene-3,6-dione, (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione, 12α-hydroxyergosta-7,22,24(28)-triene-3-one, and 3ß,12α-dihydroxyergosta-7,24(28)-diene, along with a known congener (22E,24R)-9α,14ß-dihydroxyergosta-4,7,22-triene-3,6-dione, were isolated from the fungus Lasiodiplodia pseudotheobromae. Their structures were elucidated using NMR, HRESIMS, ECD calculation, and X-ray diffraction analyses. (22E,24R)-4α,5α-epoxyergosta-9α,14ß-dihydroxy-7,22-diene-3,6-dione and (22E,24R)-4α,5α-epoxyergosta-9α,14α-dihydroxy-7,22-diene-3,6-dione are a pair of C-14 epimers possessing an unusual epoxy group between C-4 and C-5, which was demonstrated using single-crystal X-ray diffraction analyses. The absolute configurations of 12α-hydroxyergosta-7,22,24(28)-triene-3-one and 3ß,12α-dihydroxyergosta-7,24(28)-diene were determined by ECD calculations. Moreover, 3ß,12α-dihydroxyergosta-7,24(28)-diene exhibited neuroprotective activity in vitro in glutamate-treated SH-SY5Y cell lines.

Nanoengineered on-demand drug delivery system improves efficacy of pharmacotherapy for epilepsy.

Long-term pharmacotherapy, serving as the main therapeutic approach for epilepsy prophylaxis, has suffered from limited efficacy and potential side effects because of the blood-brain barrier (BBB) and untimely medication. Here, we reported a nanoengineered drug delivery system for synergistic brain-targeting delivery and on-demand drug release of antiepileptic drugs (AEDs). The dopamine-pyrrole hybrid system can improve delivery efficiency through a combination of receptor-mediated transcytosis and BBB disruption­enabled transport induced by photothermal conversion of near-infrared light. Incorporation of polydopamine endowed the delivery system with enhanced conductivity and sensitivity, giving sustained (2 hours) and rapid (30 s) drug release in response to epileptiform discharges. Acute, continuous, and spontaneous seizure models validated that the delivery system could inhibit seizures upon epileptiform abnormalities, treated by one-fifth of the conventional dosage. Complemented with satisfactory biosafety results, this "smart" modality is promising to be an effective and safe strategy to improve the therapeutic index of AEDs for epilepsy.

Enhanced Deep Utilization of Low-Organic Content Sludge by Processing Time-Extended Low-Temperature Thermal Pretreatment.

Anaerobic digestion is an important way for maintaining sewage sludge stability, reduction, and resource recovery. However, the low organic content generally limits methane production. Recently, thermal hydrolysis has been widely used for sludge pretreatment to improve the anaerobic digestion efficiency. Generally, an increased temperature is preferred to enhance the solubility of organic matters in the sludge. However, high energy requirement comes with increased temperature. Application of low-temperature thermal treatment could overcome this drawback. However, the appropriate low-temperature pretreatment time is still uncertain. In this study, an extended contact time with low thermal pretreatment (90 °C) was chosen to realize a more efficient and economical digestion process of low-organic content sludge. The results demonstrated that the solubilization of proteins and carbohydrates was significantly promoted by the contact time-extended thermal hydrolysis pretreatment. The following anaerobic digestion efficiency of low-organic content sludge was also dramatically improved with the prolonged contact time. The maximum methane production could reach around 294.73 mL/gVS after 36 h of 90 °C treatment, which was 5.56 times that of the untreated groups. Additionally, based on the energy balance calculation, extending the thermal hydrolysis time resulted in a more economically feasible anaerobic digestion than increasing the temperature. The dewatering properties and the stability of the heavy metals were also reinforced, implying the advanced deep utilization of the digested low-organic content sludge. In conclusion, sludge pretreated by low-temperature thermal hydrolysis with a prolonged contact time could be more effective for low-organic content sludge treatment and disposal.