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1.
Article in English | MEDLINE | ID: mdl-38798270

ABSTRACT

Substance P (SP) is released from sensory nerves in arteries and heart. It activates neurokinin-1 receptors (NK1R) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested that SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11 and SP 8-11. In NK1R expressing HEK293 cells, SP and some C-terminal SP metabolites stimulate the NK1R promoting dissociation of several Ga proteins including Gas and Gaq from their bg subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic AMP (cAMP) accumulation with similar -log EC50 values of 8.5±0.3 and 7.8±0.1 M, respectively. N-Terminal metabolism of SP by up to 5 amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-Terminal metabolism results in loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared on cAMP-mediated activities in NK1R expressing 3T3 fibroblasts. SP inhibits NFkB activity, cell proliferation and wound healing and stimulates collagen production. SP 6-11 had little or no activity. COX-2 expression is increased by SP but not SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or re-directing the second messenger signaling pathway activated by the NK1R.

2.
Chemistry ; : e202401023, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807442

ABSTRACT

Flexible optoelectronics is the need of the hour as the market moves toward wearable and conformable devices. Crystalline π-conjugated materials offer high performance as active materials compared to their amorphous counterpart, but they are typically brittle. This poses a significant challenge that needs to be overcome to unfold their potential in optoelectronic devices. Unveiling the molecular packing topology and identifying interaction descriptors that can seamlessly accommodate strain offers essential guiding principles for developing conjugated materials as active components in flexible optoelectronics. The molecular packing and interaction topology of eight crystal systems of dicyano-distyrylbenzene derivatives are investigated. Face-to-face π-stacks in an inclined orientation relative to the bending surface can accommodate expansion and compression with minimal molecular motion from their equilibrium positions. This configuration exhibits good compliance towards mechanical strain, while a similar structure with a criss-cross arrangement capable of distributing applied strain equally in opposite directions enhances the flexibility. Molecular arrangements that cannot reversibly undergo expansion and compression exhibit brittleness. In the isometric CT crystals, the disproportionate strength of the interactions along the bending plane and orthogonal directions makes these materials sustain a moderate bending strain. These results provide an updated explanation for the elastic bending in semiconducting π-conjugated crystals.

3.
Nat Struct Mol Biol ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38714890

ABSTRACT

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases-for example, the parasitic blood fluke infection schistosomiasis-are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPMPZQ), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPMPZQ that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad-spectrum flukicide.

5.
Antioxidants (Basel) ; 13(2)2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38397753

ABSTRACT

Butein is a flavonoid found in many plants, including dahlia, butea, and coreopsis, and has both antioxidant and sirtuin-activating activities. In light of the postulated role of free radicals in aging, we examined the effects of butein on aging and on genetic or nutritional models of age-related diseases in Caenorhabditis elegans. Butein showed radical scavenging activity and increased resistance to oxidative stress in Caenorhabditis elegans. The mean lifespan of Caenorhabditis elegans was significantly increased by butein, from 22.7 days in the untreated control to 25.0 days in the butein-treated group. However, the lifespan-extending effect of butein was accompanied by reduced production of progeny as a trade-off. Moreover, the age-related decline in motility was delayed by butein supplementation. Genetic analysis showed that the lifespan-extending effect of butein required the autophagic protein BEC-1 and the transcription factor DAF-16 to regulate stress response and aging. At the genetic level, expression of the DAF-16 downstream target genes hsp-16.2 and sod-3 was induced in butein-treated worms. Butein additionally exhibited a preventive effect in models of age-related diseases. In an Alzheimer's disease model, butein treatment significantly delayed the paralysis caused by accumulation of amyloid-beta in muscle, which requires SKN-1, not DAF-16. In a high-glucose-diet model of diabetes mellitus, butein markedly improved survival, requiring both SKN-1 and DAF-16. In a Parkinson's disease model, dopaminergic neurodegeneration was completely inhibited by butein supplementation and the accumulation of α-synuclein was significantly reduced. These findings suggest the use of butein as a novel nutraceutical compound for aging and age-related diseases.

6.
J Biol Chem ; 300(1): 105528, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38043794

ABSTRACT

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.


Subject(s)
Anthelmintics , Clonazepam , Schistosomiasis mansoni , TRPM Cation Channels , Animals , Humans , Anthelmintics/pharmacology , Benzodiazepines/pharmacology , Benzodiazepinones/pharmacology , Clonazepam/analogs & derivatives , Clonazepam/pharmacology , Praziquantel/pharmacology , Schistosoma mansoni/drug effects , Schistosoma mansoni/metabolism , Schistosomiasis mansoni/drug therapy , TRPM Cation Channels/agonists
7.
Neurosurgery ; 94(3): 597-605, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-37800926

ABSTRACT

BACKGROUND AND OBJECTIVE: Perioperative low-dose aspirin (ASA) management for open craniotomy surgery lacked information. We analyze to establish the perioperative ASA strategy to minimize both hemorrhagic and thromboembolic complications. METHODS: The investigators designed a multicenter retrospective study, which included patients scheduled to have clipping surgery for unruptured intracranial aneurysm. The incidence and risk factors were analyzed for postoperative hemorrhagic complications and major cardio- and cerebrovascular events (MACCEs) within 1 month postoperation. RESULTS: This study included 503 long-term ASA users of 3654 patients at three tertiary centers. The incidence of hemorrhagic complications and MACCEs was 7.4% (37/503) and 8.8% (44/503), respectively. Older age (>70 years, odds ratio [OR]: 2.928, 95% CI [1.337-6.416]), multiple aneurysms operation (OR: 2.201, 95% CI [1.017-4.765]), large aneurysm (>10 mm, OR: 4.483, 95% CI [1.485-13.533]), and ASA continuation (OR: 2.604, 95% CI [1.222-5.545]) were independent risk factors for postoperative hemorrhagic complications. Intracranial hemorrhage was the only type of hemorrhagic complication that increased in the ASA continuation group (10.6% vs 2.9%, P = .001). Between the ASA continuation and discontinuation groups, the overall incidence of MACCEs was not significantly different (log-rank P = .8). In the subgroup analysis, ASA discontinuation significantly increased the risk of MACCEs in the secondary prevention group (adjusted hazard ratio: 2.580, 95% CI [1.015-6.580]). CONCLUSION: ASA continuation increased the risk of postoperative intracranial hemorrhage. Simultaneously, ASA discontinuation was the major risk factor for postoperative MACCEs in the high-risk group. Without evidence of intracranial hemorrhage, early ASA resumption was indicated (a total cessation duration <7-10 days) in the secondary prevention group.


Subject(s)
Aspirin , Intracranial Aneurysm , Humans , Retrospective Studies , Aspirin/adverse effects , Postoperative Hemorrhage/chemically induced , Postoperative Hemorrhage/epidemiology , Postoperative Hemorrhage/prevention & control , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Intracranial Aneurysm/surgery , Intracranial Aneurysm/drug therapy , Risk Factors , Intracranial Hemorrhages/chemically induced , Intracranial Hemorrhages/epidemiology , Platelet Aggregation Inhibitors/adverse effects
8.
ACS Med Chem Lett ; 14(11): 1537-1543, 2023 Nov 09.
Article in English | MEDLINE | ID: mdl-37970586

ABSTRACT

The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPMPZQ, has recently been identified. Intriguingly, certain praziquantel derivatives show different activities against different parasites: for example, some praziquantel analogs are considerably more active against cestodes than against schistosomes. Here we interrogate whether the different activities of praziquantel analogs against different parasites are also reflected by unique structure-activity relationships at the TRPMPZQ channels found in these different organisms. To do this, several praziquantel analogs were synthesized and functionally profiled against schistosome and cestode TRPMPZQ channels. Data demonstrate that structure-activity relationships are closely mirrored between parasites and their TRPMPZQ orthologs, providing further support for TRPMPZQ as the therapeutically relevant target of praziquantel.

9.
bioRxiv ; 2023 Sep 22.
Article in English | MEDLINE | ID: mdl-37790347

ABSTRACT

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases - for example, the parasitic blood fluke infection, schistosomiasis - are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPMPZQ), in Fasciola species. Here we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPMPZQ dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad spectrum flukicide.

10.
Article in English | MEDLINE | ID: mdl-37813697

ABSTRACT

Hyperplastic anterior choroidal artery (AchA) is an extremely rare congenital vascular variant that can be mistaken for other cerebral arteries. This case report presents a 38-year-old man who presented with a severe sudden-onset headache and was diagnosed with a ruptured aneurysm originating from a hyperplastic AchA. The aneurysm was successfully treated with coil embolization, but recurrence was detected after eight months, leading to additional surgical intervention. The discussion highlights the classification of hyperplastic AchA and emphasizes the importance of recognizing this anatomical variant to avoid complications during treatment. This case report underscores the need for awareness and understanding of hyperplastic AchA in the management of cerebral aneurysms.

11.
Microorganisms ; 11(9)2023 Sep 11.
Article in English | MEDLINE | ID: mdl-37764128

ABSTRACT

Nitric oxide (NO) is a free radical associated with physiological functions such as blood pressure regulation, cardiovascular health, mitochondrial production, calcium transport, oxidative stress, and skeletal muscle repair. This study aimed to isolate Latilactobacillus curvatus strains with enhanced NO production from the traditional Korean fermented food, jangajji, and evaluate their probiotic properties for industrial purposes. When cells were co-cultured with various bacterial stimulants, NO production generally increased, and NO synthesis was observed in the range of 20-40 mg/mL. The selected strains of Lat. curvatus were resistant to acid and bile conditions and with variable effectiveness (1-14%) in adhering to Caco-2 cells. Most bacterial strains can inhibit the growth of various pathogens. In addition, they are capable of reducing cholesterol levels via assimilation of cholesterol at 10-50%. Among the selected NO synthases from Lat. curvatus strains, the strain JBCC38 showed the highest capacity to scavenge ABTS (30.1%) and DPPH radicals (39.4%). Moreover, these strains exhibited immunomodulatory properties. The production of TNF-α and IL-6 in the macrophages treated with various bacterial stimulants was induced in all the selected strains.

12.
Microorganisms ; 11(8)2023 Jul 28.
Article in English | MEDLINE | ID: mdl-37630480

ABSTRACT

To understand the biological roles of Pediococcus pentosaceus strains as probiotics isolated from the traditional Korean fermented food, Jangajji, Pediococcus pentosaceus was selected based on its high cinnamoyl esterase (CE) and antioxidant activities. The acid and bile stability, intestinal adhesion, antagonistic activity against human pathogens, cholesterol-lowering effects, and immune system stimulation without inflammatory effects were evaluated. Nitric oxide (NO) levels were measured in co-culture with various bacterial stimulants. Fermentation ability was measured by using a broccoli matrix and the sulforaphane levels were measured. Resistance to acidic and bilious conditions and 8% adherence to Caco-2 cells were observed. Cholesterol levels were lowered by 51% by assimilation. Moreover, these strains exhibited immunomodulatory properties with induction of macrophage TNF-α and IL-6 and had microstatic effects on various pathogens. Co-culture with various bacterial stimulants resulted in increased NO production. Fermentation activity was increased with the strains, and higher sulforaphane levels were observed. Therefore, in the future, the applicability of the selected strain to broccoli matrix-based fermented functional foods should be confirmed.

13.
PLoS One ; 18(8): e0289493, 2023.
Article in English | MEDLINE | ID: mdl-37531332

ABSTRACT

Additive manufacturing, or 3D printing, has revolutionized the way we create objects. However, its layer-by-layer process may lead to an increased incidence of local defects compared to traditional casting-based methods. Factors such as light intensity, depth of light penetration, component inhomogeneity, and fluctuations in nozzle temperature all contribute to defect formations. These defective regions can become sources of toxic component leakage, but pinpointing their locations in 3D printed materials remains a challenge. Traditional toxicological assessments rely on the extraction and subsequent exposure of living organisms to these harmful agents, thus only offering a passive detection approach. Therefore, the development of an active system to both identify and locate sources of toxicity is essential in the realm of 3D printing technologies. Herein, we introduce the use of the nematode model organism, Caenorhabditis elegans (C. elegans), for toxicity evaluation. C. elegans exhibits distinctive 'sensing' and 'locomotion' capabilities that enable it to actively navigate toward safe zones while steering clear of hazardous areas. This active behavior sets C. elegans apart from other aquatic and animal models, making it an exceptional choice for immediate and precise identification and localization of toxicity sources in 3D printed materials.


Subject(s)
Caenorhabditis elegans , Nematoda , Animals , Locomotion , Models, Animal
14.
ChemMedChem ; 18(18): e202300140, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37272317

ABSTRACT

Praziquantel (PZQ) is an essential anthelmintic drug recently established to be an activator of a Transient Receptor Potential Melastatin (TRPMPZQ ) ion channel in trematode worms. Bioinformatic, mutagenesis and drug metabolism work indicate that the cyclohexyl ring of PZQ is a key pharmacophore for activation of trematode TRPMPZQ , as well as serving as the primary site of oxidative metabolism which results in PZQ being a short-lived drug. Based on our recent findings, the hydrophobic cleft in schistosome TRPMPZQ defined by three hydrophobic residues surrounding the cyclohexyl ring has little tolerance for polarity. Here we evaluate the in vitro and in vivo activities of PZQ analogues with improved metabolic stability relative to the challenge of maintaining activity on the channel. Finally, an estimation of the respective contribution to the overall activity of both the parent and the main metabolite of PZQ in humans is reported.


Subject(s)
Anthelmintics , Parasites , TRPM Cation Channels , Transient Receptor Potential Channels , Humans , Animals , Praziquantel/pharmacology , Praziquantel/chemistry , Anthelmintics/pharmacology , Anthelmintics/therapeutic use , Schistosoma mansoni
15.
Nanotechnology ; 34(32)2023 May 25.
Article in English | MEDLINE | ID: mdl-37146599

ABSTRACT

Ambipolar field-effect transistors (FETs) possessing both electron and hole carriers enable implementation of novel reconfigurable transistors, artificial synaptic transistors, and output polarity controllable (OPC) amplifiers. Here, we fabricated a two-dimensional (2D) material-based complementary ambipolar FET and investigated its electrical characteristics. Properties of ohmic-like contacts at source/drain sides were verified from output characteristics and temperature-dependent measurements. The symmetry of electron and hole currents can be easily achieved by optimization of the MoS2or WSe2channels, different from the conventional ambipolar FET with fundamental issues related to Schottky barriers. In addition, we demonstrated successful operation of a complementary inverter and OPC amplifier, using the fabricated complementary ambipolar FET based on 2D materials.

16.
Leuk Res ; 129: 107070, 2023 06.
Article in English | MEDLINE | ID: mdl-37019050

ABSTRACT

Juvenile myelomonocytic leukemia (JMML) is a life-threatening myeloproliferative neoplasm. The chemotherapeutic effect on survival remains unclear, and feasible standardized response criteria are yet to be established. We aimed to evaluate the chemotherapeutic response and its effect on survival in patients with JMML. A retrospective registry was reviewed for children diagnosed with JMML between 2000 and 2019. Response was assessed according to the criteria proposed by the International JMML Symposium in 2007 (criteria I) and the updated version in 2013 with its modifications (criteria II). A total of 73 patients were included in this study. Complete response (CR) rates were 46.6% and 28.8% using the criteria I and criteria II, respectively. A platelet count ≥ 40 × 109/L at diagnosis was associated with higher CR rates using the criteria II. Patients with criteria I-based CR had a better overall survival (OS) than those without CR (81.1% vs. 49.1% at 5 years). Patients with criteria II-based CR showed better OS (85.7% vs. 55.5% at 5 years) and event-free survival (EFS) (71.1% vs. 44.7% at 5 years) than those without CR. Additionally, a trend toward better EFS was observed in patients with criteria II-based CR than in those with criteria I-based CR but without criteria II-based CR (71.1% vs. 53.8% at 5 years). Chemotherapeutic response is associated with better survival outcomes. Along with splenomegaly, the addition of platelet count recovery, existence of extramedullary leukemic infiltration, and more stringent leukocyte counts to the response criteria allows for a more sensitive prediction of survival outcomes.


Subject(s)
Hematology , Leukemia, Myelomonocytic, Juvenile , Child , Humans , Leukemia, Myelomonocytic, Juvenile/drug therapy , Leukemia, Myelomonocytic, Juvenile/diagnosis , Retrospective Studies , Progression-Free Survival , Republic of Korea/epidemiology
17.
Acta Neurochir (Wien) ; 165(5): 1251-1260, 2023 05.
Article in English | MEDLINE | ID: mdl-36930365

ABSTRACT

BACKGROUND: Chronic subdural hematoma (cSDH) is a unique hemorrhagic complication associated with microsurgical clipping. We aimed to investigate the risk factors of subdural hygroma (SDG) formation and its hemorrhagic conversion to cSDH. METHODS: We reviewed the medical records of 229 patients who underwent microsurgical clipping for unruptured intracranial aneurysms (UIA) from 2016 to 2019. Risk factors for SDG and cSDH formation were analyzed. RESULTS: Male sex, age ≥ 60 years, higher degree of arachnoid dissection, severe brain atrophy, and a large volume of subdural fluid collection (SFC) before discharge were independent risk factors for SDG formation. The risk factors for hemorrhagic conversion from SDG were continuous use or early resumption of antiplatelet drugs (odds ratio (OR): 15.367, 95% CI: 1.172-201.402) and a larger volume of SFC before discharge (OR: 0.932, 95% CI: 0.886-0.980). In the early resumption group, antiplatelet drug was resumed at a mean duration of 7.48 days postoperatively, and hemorrhagic conversion was detected earlier than that in the late resumption or no-use groups (4.09 vs. 7.18 weeks, P = 0.046). Following the receiver operating characteristic analysis, the SFC cutoff volume for hemorrhagic conversion was determined to be 23.55 mL. CONCLUSION: These findings can assist clinicians in identifying patients at a high risk of SDG and cSDH formation. Antiplatelet resumption and its timing should be determined with consideration of the risk of cSDH formation as well as individual medical conditions.


Subject(s)
Hematoma, Subdural, Chronic , Intracranial Aneurysm , Subdural Effusion , Humans , Male , Middle Aged , Intracranial Aneurysm/surgery , Intracranial Aneurysm/complications , Postoperative Complications/etiology , Retrospective Studies , Hematoma, Subdural, Chronic/complications , Risk Factors
18.
Nat Commun ; 14(1): 1304, 2023 Mar 21.
Article in English | MEDLINE | ID: mdl-36944642

ABSTRACT

Cooperativity is used by living systems to circumvent energetic and entropic barriers to yield highly efficient molecular processes. Cooperative structural transitions involve the concerted displacement of molecules in a crystalline material, as opposed to typical molecule-by-molecule nucleation and growth mechanisms which often break single crystallinity. Cooperative transitions have acquired much attention for low transition barriers, ultrafast kinetics, and structural reversibility. However, cooperative transitions are rare in molecular crystals and their origin is poorly understood. Crystals of 2-dimensional quinoidal terthiophene (2DQTT-o-B), a high-performance n-type organic semiconductor, demonstrate two distinct thermally activated phase transitions following these mechanisms. Here we show reorientation of the alkyl side chains triggers cooperative behavior, tilting the molecules like dominos. Whereas, nucleation and growth transition is coincident with increasing alkyl chain disorder and driven by forming a biradical state. We establish alkyl chain engineering as integral to rationally controlling these polymorphic behaviors for novel electronic applications.

19.
Int J Parasitol ; 53(8): 415-425, 2023 07.
Article in English | MEDLINE | ID: mdl-36610556

ABSTRACT

Ion channels have proved to be productive targets for anthelmintic chemotherapy. One example is the recent discovery of a parasitic flatworm ion channel targeted by praziquantel (PZQ), the main clinical therapy used for treatment of schistosomiasis. The ion channel activated by PZQ - a transient receptor potential ion channel of the melastatin subfamily, named TRPMPZQ - is a Ca2+-permeable ion channel expressed in all parasitic flatworms that are PZQ-sensitive. However, little is currently known about the electrophysiological properties of this target that mediates the deleterious action of PZQ on many trematodes and cestodes. Here, we provide a detailed biophysical characterization of the properties of Schistosoma mansoni TRPMPZQ channel (Sm.TRPMPZQ) in response to PZQ. Single channel electrophysiological analysis demonstrated that Sm.TRPMPZQ when activated by PZQ is a non-selective, large conductance, voltage-insensitive cation channel that displays distinct properties from human TRPM paralogs. Sm.TRPMPZQ is Ca2+-permeable but does not require Ca2+ for channel gating in response to PZQ. TRPMPZQ from Schistosoma japonicum (Sj.TRPMPZQ) and Schistosoma haematobium (Sh.TRPMPZQ) displayed similar characteristics. Profiling Sm.TRPMPZQ responsiveness to PZQ has established a biophysical signature for this channel that will aid future investigation of endogenous TRPMPZQ activity, as well as analyses of endogenous and exogenous regulators of this novel, druggable antiparasitic target.


Subject(s)
Anthelmintics , Schistosomiasis mansoni , TRPM Cation Channels , Transient Receptor Potential Channels , Animals , Humans , Praziquantel/pharmacology , Praziquantel/therapeutic use , Transient Receptor Potential Channels/therapeutic use , TRPM Cation Channels/genetics , Anthelmintics/pharmacology , Anthelmintics/therapeutic use , Schistosoma mansoni , Schistosomiasis mansoni/drug therapy
20.
J Cerebrovasc Endovasc Neurosurg ; 25(2): 208-213, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36259164

ABSTRACT

Flow-diverting stents (FDSs) have proven advantageous for the treatment of large, fusiform, and dissecting aneurysms that are otherwise difficult to treat. Retreatment strategies for recurrent large or giant aneurysms after FDSs are limited to overlapping implantation of an additional FDS or definitive occlusion of the parent vessel. We report a recurrent giant aneurysm that was initially treated with an FDS with coils and was successfully treated with an additional FDS. Visual symptoms due to the mass effect of the recurrent aneurysm were completely resolved, and follow-up digital subtraction angiography revealed complete obliteration of the aneurysm. Additional FDS implantation for the retreatment of incompletely occluded aneurysms after the initial FDS treatment may be feasible and safe. Further studies are required to validate these results.

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