Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Insights into the Mechanisms of Reuterin against Staphylococcus aureus Based on Membrane Damage and Untargeted Metabolomics.

Reuterin is a dynamic small-molecule complex produced through glycerol fermentation by Limosilactobacillus reuteri and has potential as a food biopreservative. Despite its broad-spectrum antimicrobial activity, the underlying mechanism of action of reuterin is still elusive. The present paper aimed to explore the antibacterial mechanism of reuterin and its effects on membrane damage and the intracellular metabolome of S. aureus. Our results showed that reuterin has a minimum inhibitory concentration of 18.25 mM against S. aureus, based on the 3-hydroxypropionaldehyde level. Key indicators such as extracellular electrical conductivity, membrane potential and permeability were significantly increased, while intracellular pH, ATP and DNA were markedly decreased, implying that reuterin causes a disruption to the structure of the cell membrane. The morphological damage to the cells was confirmed by scanning electron microscopy. Subsequent metabolomic analysis identified significant alterations in metabolites primarily involved in lipid, amino acid, carbohydrate metabolism and phosphotransferase system, which is crucial for cell membrane regulation and energy supply. Consequently, these findings indicated that the antibacterial mechanism of reuterin initially targets lipid and amino acid metabolism, leading to cell membrane damage, which subsequently results in energy metabolism disorder and, ultimately, cell death. This paper offers innovative perspectives on the antibacterial mechanism of reuterin, contributing to its potential application as a food preservative.

Histamine bidirectionally regulates the intrinsic excitability of parvalbumin-positive neurons in the lateral globus pallidus and promotes motor behaviour.

BACKGROUND AND PURPOSE: Parvalbumin (PV)-positive neurons are a type of neuron in the lateral globus pallidus (LGP) which plays an important role in motor control. The present study investigated the effect of histamine on LGPPV neurons and motor behaviour. EXPERIMENTAL APPROACH: Histamine levels in LGP as well as its histaminergic innervation were determined through brain stimulation, microdialysis, anterograde tracing and immunostaining. Mechanisms of histamine action were detected by immunostaining, single-cell qPCR, whole-cell patch-clamp recording, optogenetic stimulation and CRISPR/Cas9 gene-editing techniques. The effect of histamine on motor behaviour was detected by animal behavioural tests. KEY RESULTS: A direct histaminergic innervation in LGP from the tuberomammillary nucleus (TMN) and a histamine-induced increase in the intrinsic excitability of LGPPV neurons were determined by pharmacological blockade or by genetic knockout of the histamine H1 receptor (H1 R)-coupled TWIK-related potassium channel-1 (TREK-1) and the small-conductance calcium-activated potassium channel (SK3), as well as by activation or overexpression of the histamine H2 receptor (H2 R)-coupled hyperpolarization-activated cyclic nucleotide-gated channel (HCN2). Histamine negatively regulated the STN → LGPGlu transmission in LGPPV neurons via the histamine H3 receptor (H3 R), whereas blockage or knockout of H3 R increased the intrinsic excitability of LGPPV neurons. CONCLUSIONS AND IMPLICATIONS: Our results indicated that the endogenous histaminergic innervation in the LGP can bidirectionally promote motor control by increasing the intrinsic excitability of LGPPV neurons through postsynaptic H1 R and H2 R, albeit its action was negatively regulated by the presynaptic H3 R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).

Receptor and Ionic Mechanism of Histamine on Mouse Dorsolateral Striatal Neurons.

The dorsolateral striatum (DLS) is the critical neural substrate that plays a role in motor control and motor learning. Our past study revealed a direct histaminergic projection from the tuberomammillary nucleus (TMN) of the hypothalamus to the rat striatum. However, the afferent of histaminergic fibers in the mouse DLS, the effect of histamine on DLS neurons, and the underlying receptor and ionic mechanisms remain unclear. Here, we demonstrated a direct histaminergic innervation from the TMN in the mouse DLS, and histamine excited both the direct-pathway spiny projection neurons (d-SPNs) and the indirect-pathway spiny projection neurons (i-SPNs) of DLS via activation of postsynaptic H1R and H2R, albeit activation of presynaptic H3R suppressed neuronal activity by inhibiting glutamatergic synaptic transmission on d-SPNs and i-SPNs in DLS. Moreover, sodium-calcium exchanger 3 (NCX3), potassium-leak channels linked to H1R, and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) coupled to H2R co-mediated the excitatory effect induced by histamine on d-SPNs and i-SPNs in DLS. These results demonstrated the pre- and postsynaptic receptors and their downstream multiple ionic mechanisms underlying the inhibitory and excitatory effects of histamine on d-SPNs and i-SPNs in DLS, suggesting a potential modulatory effect of the central histaminergic system on the DLS as well as its related motor control and motor learning.

Effect of visual endotracheal tube combined with bronchial occluder on pulmonary ventilation and arterial blood gas in patients undergoing thoracic surgery.

Background: To investigate the effect of visual endotracheal tube combined with bronchial occluder on pulmonary ventilation and arterial blood gas in patients undergoing thoracic surgery. Methods: Ninety patients who underwent thoracic surgery under anesthesia and required pulmonary ventilation at our hospital from May 2020 to December 2021 were collected. The patients were divided into three groups according to different intubation methods: visual double-lumen endotracheal tube group (VDLT group), bronchial occluder group (BO group), and VDLT + BO group. Clinical data and laboratory test data were collected from the three groups. Additionally, the three groups were compared in terms of peak airway pressure, time to correct positioning, pulmonary ventilation time, hemodynamics before and after intubation, intubation success rate, and postoperative recovery. Results: The VDLT + BO group was superior to the BO group or VDLT group in airway peak pressure, time to correct positioning, pulmonary ventilation time, intubation success rate, and hemodynamics after intubation (P < 0.05). In the comparison of postoperative recovery, the postoperative pain score, white blood cell level, incidence rate of pneumonia, hospital stay and hospitalization costs in the VDLT + BO group were significantly lower than those in the BO group or VDLT group (P < 0.05). Conclusion: The visual endotracheal tube combined with bronchial occluder is effective in pulmonary ventilation during thoracic surgery under anesthesia, and can improve arterial blood gas in patients.

Compensation: a contemporary regulatory machinery in cardiovascular diseases?

Both clinical and experimental findings at the molecular, cellular, tissue, organ and systematic levels have depicted the presence of a contemporary regulatory machinery namely compensation in various forms of cardiovascular diseases. Compensation is believed to be present and regulated within the scope of a biological entity and represents the initiation of dyshomeostasis. Compensation can be identified in multiple categories and organs in cardiovascular diseases at multiple levels. The capacity to reduce the unfavorable pathological compensation may be a criterion to evaluate the therapeutic effectiveness for cardiovascular diseases. This mini-review tries to take compensation into consideration in the understanding of onset and progression of cardiovascular diseases in particular, and thus, better or optimal therapeutic approaches may be achieved for the prevention and management of cardiovascular diseases.

Genetic analysis of the P1 region of human enterovirus 71 strains and expression of the 55 F strainVP1 protein.

Enterovirus 71 (EV71) is a member of the Entero-virus genus of the Picornaviridae family and is the major cause of Hand, foot, and mouth disease (HFMD) in children. Different strains from Gansu were cloned and the P1 protein was sequenced and analysed. Results indicate that there are three kinds of EV71 infections prevalent in Gansu. The VP1 protein from one of these strains, 55F, was expressed. The recombinant protein was expressed with high level and reacted specifically with the EV71 patient antibody, the recombinant protein was also applied to raise antiserum in rabbits and after the fourth injection a high titer of antiserum was detected by ELISA assay. These data are useful for further clarification of prevalent EV71 strains in the north of China at the molecular level and provide a basis for EV71 diagnosis.

Homeostasis and compensatory homeostasis: bridging Western medicine and traditional chinese medicine.

Compensation is a self-protective mechanism in diseases, which may lead to a unique form of homeostasis deviates from that in physiological conditions. The kind of compensatory homeostasis can be embodied as various degrees accompanying disease progression (denoted as compensatory degree). Compensatory homeostasis provides a window for the transition from disease to healthy state. The causes of compensatory homeostasis themselves may be identified as targets for effective measures to eliminate compensation. Compensatory homeostasis embodies significantly mostly in the developing process of chronic diseases, which may help to explain in theory why intensive therapeutic strategies led to unexpected outcome in clinical practice. In addition, a large body of clinical evidence has valued traditional Chinese medicine (TCM), which is based on shifting compensatory homeostasis to the overall human body homeostasis, complementary to Western medicine in the management of chronic disease. In this review, we will briefly summarize the concept of compensation and attempt to bridge Western and traditional Chinese medicine through homeostasis and compensatory homeostasis based on an ample of evidence obtained from both disciplines.

[Characteristics and loads of key sources of pollutions discharged into Beishi River, Changzhou City].

Choosing the Beishi river, Changzhou City as the study area, the sewage generation, pollutants characteristics and sewage discharge in catchment area of Beishi river were conducted, detailed investigated and monitored. After using pollution coefficients, the yearly loads of all sources of pollutions were calculated to determine the highest sewage. The results showed that: except pH, the high concentration of SS, COD, BOD5, ammonia nitrogen, TN and TP discharged from MSW collecting houses, MSW transfer stations, public toilets and dining in Changzhou city far exceeded the "Integrated Wastewater Discharge Standard" (GB 8978-1996) and "Effluent Discharged into the City Sewer Water Quality Standards" (CJ 3082-1999). Among which: the highest concentration of COD discharged from MSW transfer stations was up to 51 700 mg/L, while the ammonia nitrogen and TN were as high as 1 616 mg/L and 2 044 mg/L in the toilet wastewater. In addition to this, the ratio of wastewater discharged directly into the river through storm water pipe network was higher from MSW houses, MSW transfer stations, public toilets, dining and other waste in Changzhou city. The 125.2 t/a of COD and 40.53 t/a of BOD5 were the two highest concentrations of various sources of pollution. The highest annual polluting loads discharged into Beishi river is dining, followed by the sanitation facilities. Therefore, cutting pollution control of food and sanitation facilities along the river is particularly urgent.

Density functional theory calculations and molecular dynamics simulations of the adsorption of biomolecules on graphene surfaces.

There is increasing attention in the unique biological and medical properties of graphene, and it is expected that biomaterials incorporating graphene will be developed for the graphene-based drug delivery systems and biomedical devices. Despite the importance of biomolecules-graphene interactions, a detailed understanding of the adsorption mechanism and features of biomolecules onto the surfaces of graphene is lacking. To address this, we have performed density functional theory (DFT) and molecular dynamics (MD) methods exploring the adsorption geometries, adsorption energies, electronic band structures, adsorption isotherms, and adsorption dynamics of l-leucine (model biomolecule)/graphene composite system. DFT calculations confirmed the energetic stability of adsorption model and revealed that electronic structure of graphene can be controlled by the adsorption direction of l-leucine. MD simulations further investigate the potential energy and van der Waals energy for the interaction processes of l-leucine/graphene system at different temperatures and pressures. We find that the van der Waals interaction between the l-leucine and the graphene play a dominant role in the adsorption process under a certain range of temperature and pressure, and the l-leucine molecule could be adsorbed onto graphene spontaneously in aqueous solution.

[Heterogeneity of HIV strains isolated from different tissues of 3 AIDS patients].

BACKGROUND: To reveal the characteristics of genotype and phenotype of HIV strains in blood and some tissues of AIDS patients. METHODS: The virus was isolated from peripheral blood mononuclear cell (PBMC),cerebrospinal fluid (CSF)and lymph nodes of 3 AIDS patients by coculture with PBMC stimulated by PHA for 72 hours from uninfected donor. The cytopathic effect of the HIV isolates was determined in cultured MT2 cell line. The env gene sequences form proviral DNA were analyzed by GCG software. RESULTS: In one patient,there were differences between the strains from blood and different tissues both in genotype and phenotype. The biological phenotypes of two strains from CSF were non syncytium (NSI) type, their env sequences were similar to standard CNS tropic strain (SF162). CONCLUSIONS: The viral heterogeneity exists in different body compartments within an infected individual. The neurotropic isolate which is similar to international standard strain exists in some AIDS patients in China.