-
Evidence-based Complementary and... 2022Alzheimer's disease (AD) is the most common type of dementia, and the abnormal hyperphosphorylation of the tau protein is the main component of its pathogenesis. Calpain...
Alzheimer's disease (AD) is the most common type of dementia, and the abnormal hyperphosphorylation of the tau protein is the main component of its pathogenesis. Calpain was found to be abnormally activated in neurofibrillary tangles (NFTs) in a previous report. Cornel iridoid glycosides (CIG) have been reported to reduce the hyperphosphorylation of tau protein. Nevertheless, the role of calpain in the reduction tau hyperphosphorylation by CIG remains unclear. In the present study, we investigated the effect of CIG on calpain activity through in vitro and in vivo experiments. Western blotting results suggested that CIG decreased the phosphorylation of tau at Ser 404 and Ser 262 sites in P301S mice. Moreover, CIG inhibited the activity of calpain and glycogen synthase kinase 3 (GSK-3) and enhanced the activity of protein phosphatase 2A (PP2A) both in vivo and in vitro. CIG also inhibited the activation of PP2A and reduced the GSK-3 activity caused by the calpain activator dibucaine. In addition, the main components of CIG, morroniside and loganin, play an equivalent role in reducing calpain activity, as the effect of their combined use is equivalent to that of CIG. The abovementioned findings revealed that CIG improved PP2A activity and reduced GSK-3 activity by adjusting the activity of calpain 1, leading to a reduction in the phosphorylation of tau. This study highlights the remarkable therapeutic potential of CIG for managing AD.
PubMed: 35096120
DOI: 10.1155/2022/9213046 -
Science Advances Jan 2022Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus...
Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as fluoxetine and dibucaine, but how they inhibit 2C is unknown. Here, we present a crystal structure of the soluble and monomeric fragment of coxsackievirus B3 2C protein in complex with ()-fluoxetine (SFX), revealing an allosteric binding site. To study the functional consequences of SFX binding, we engineered an adenosine triphosphatase (ATPase)–competent, hexameric 2C protein. Using this system, we show that SFX, dibucaine, HBB [2-(α-hydroxybenzyl)-benzimidazole], and guanidine hydrochloride inhibit 2C ATPase activity. Moreover, cryo–electron microscopy analysis demonstrated that SFX and dibucaine lock 2C in a defined hexameric state, rationalizing their mode of inhibition. Collectively, these results provide important insights into 2C inhibition and a robust engineering strategy for structural, functional, and drug-screening analysis of 2C proteins.
PubMed: 34985963
DOI: 10.1126/sciadv.abj7615 -
Environmental Toxicology and Chemistry Feb 2022In spite of recent reports about the presence of pharmaceuticals in African water bodies, their prevalence has still not been sufficiently quantified. The few available...
Target and Suspect Screening of Pharmaceuticals and their Transformation Products in the Klip River, South Africa, using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry.
In spite of recent reports about the presence of pharmaceuticals in African water bodies, their prevalence has still not been sufficiently quantified. The few available studies have mostly focused on a limited number of pharmaceuticals. In the present study, a suspect screening of 92 compounds (mainly pharmaceuticals and their transformation products) along the Klip River, South Africa was conducted, followed by target monitoring of 21 of the detected pharmaceuticals. The experimental approach was based on solid-phase extraction followed by analysis with ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS). The results revealed 47 pharmaceuticals, 31 of which were detected for the first time in South African waters. Seven detected pharmaceuticals (propyphenazole, sulfamerazine, levamisole, tryptophan, dibucaine, albuterol, and fenpropimorph) are not approved medications in South Africa. Six pharmaceutical metabolites were detected for the first time in South Africa. Pharmaceuticals with the highest concentrations in river water were flumequine (0.257 µg L ), oxolinic acid (0.355 µg L ), and acetaminophen (0.432 µg L ). Oxolinic acid presented the highest hazard quotient, 48.6, indicating a risk of toxicity to aquatic organisms. Hazard quotients for other pharmaceuticals were below 1, except that of flumequine, which reached 1.285. These results suggest a need for further research into the fate of pharmaceuticals in surface waters, and a quantification of the risks associated with the identified drugs because they are likely to accumulate in the tissues of fish/aquatic organisms, thus affecting humans. Environ Toxicol Chem 2022;41:437-447. © 2021 SETAC.
Topics: Animals; Aquatic Organisms; Chromatography, High Pressure Liquid; Environmental Monitoring; Mass Spectrometry; Oxolinic Acid; Pharmaceutical Preparations; Rivers; South Africa; Water; Water Pollutants, Chemical
PubMed: 34888926
DOI: 10.1002/etc.5265 -
Contact Dermatitis Mar 2022The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin)... (Review)
Review
The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin) and systemic drugs (oral, parenteral, rectal) may be responsible for the disorder. The topical route appears to be rare with 41 culprit topical drugs found to cause SAD in 95 patients. Most reactions are caused by budesonide (especially from inhalation), bufexamac, and dibucaine. SAD from systemic drugs is infrequent with 95 culprit drugs found to cause SAD in 240 patients. The drugs most frequently implicated are mitomycin C, methylprednisolone (salt, ester), and hydrocortisone (salt). The largest group of culprit drugs consisted of corticosteroids (19%), being responsible for >30% of the reactions, of which nearly 40% were not caused by therapeutic drugs, but by drug provocation tests. The most frequent manifestations of SAD from drugs are eczematous eruptions (scattered, widespread, generalized, worsening, reactivation), maculopapular eruptions, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE [baboon syndrome]) and widespread erythema or erythroderma. Therapeutic systemic drugs hardly ever cause reactivation of previously positive patch tests and infrequently of previous allergic contact dermatitis. The pathophysiology of SAD has received very little attention. Explanations for the rarity of SAD are suggested.
Topics: Dermatitis, Allergic Contact; Drug Eruptions; Drug-Related Side Effects and Adverse Reactions; Humans; Skin Tests
PubMed: 34837391
DOI: 10.1111/cod.14016 -
Evidence-based Complementary and... 2021Linn. (CQ) is a medicinal plant with good evidence for the treatment of hemorrhoids, listed in the Thai National List of Herbal Products in the oral dosage form. (Wall...
BACKGROUND
Linn. (CQ) is a medicinal plant with good evidence for the treatment of hemorrhoids, listed in the Thai National List of Herbal Products in the oral dosage form. (Wall ex. DC.) R. K. Jansen. (AP) is a medicinal plant with a local anesthetic effect.
OBJECTIVE
To investigate the potential of rectal suppositories containing CQ and AP extracts to alleviate symptoms of hemorrhoids compared with the commercialized rectal suppository containing hydrocortisone and cinchocaine.
MATERIALS AND METHODS
Hemorrhoid outpatients ( = 105) with different severity grades (I, II, or III) from eight hospitals in northern Thailand were included in this study. Hemorrhoid severity was graded by proctoscopy associated with either anal pain or bleeding related to hemorrhoids or both. The patients were randomly allocated to two groups: CQ-AP group ( = 52) or the commercialized rectal suppository group ( = 53). One suppository was rectally administered twice daily in the morning and at bedtime for seven days. Evaluations were performed by physicians on days 1, 4, and 8 of the study. The primary endpoints were bleeding and prolapse size, while the secondary endpoint was anal pain.
RESULTS
Baseline demographics, lifestyle, constipation, number of prolapses, grade of hemorrhoid severity, and duration of experiencing hemorrhoids were comparable in both groups of patients. The effects of CQ-AP and the commercialized rectal suppository on bleeding, prolapse size, and anal pain were comparable. The patients in both groups were satisfied with both products at comparable levels and stated a preference for further use in the case of hemorrhoids recurrence. In terms of safety, the patients in the commercialized rectal suppository group experienced a higher incidence of adverse events, including anal pain and bleeding.
CONCLUSION
Rectal suppositories containing a combined extract of CQ and AP show potential in alleviating hemorrhoidal symptoms with a good safety profile.
PubMed: 34765003
DOI: 10.1155/2021/5605323 -
Journal of Pharmacy & Bioallied Sciences Jun 2021To compare and analyze the clinical adequacy of two topical anesthetic gels, Precaine (8% lidocaine + 0.8% dibucaine) and Precaine B (20% benzocaine) in children before...
AIM
To compare and analyze the clinical adequacy of two topical anesthetic gels, Precaine (8% lidocaine + 0.8% dibucaine) and Precaine B (20% benzocaine) in children before intraoral local anesthetic injections.
MATERIALS AND METHODS
This clinical study included thirty children who needed an inferior alveolar nerve block. They were divided into three groups: Group A: Precaine topical gel group, Group B: Precaine B topical gel Group, Group C: no anesthetic topical gel group (control group). These two effective topical gels were applied before giving intraoral local anesthesia, and afterward, the child's pain response was surveyed utilizing the Wong-Baker Faces Pain Rating Scale. The scores obtained were subjected to statistical analysis.
RESULTS
Intergroup comparison showed a significant mean difference between the control group and Precaine group ( > 0.05) as well as Precaine B group ( > 0.05). However, there is no significant difference obtained between Group A and Group B ( < 0.05).
CONCLUSION
It is psychologically and clinically beneficial to apply a topical anesthetic agent before injecting any intraoral anesthesia. In this study, both anesthetic gels showed a nonsignificant difference in reducing inferior alveolar injection pain, but Precaine B shows more promising results than Precaine.
PubMed: 34447172
DOI: 10.4103/jpbs.JPBS_772_20 -
Dermatitis : Contact, Atopic,...Topical medications may lead to allergic contact dermatitis. This study characterized positive patch test reactions associated with medications in patients evaluated by...
BACKGROUND/OBJECTIVES
Topical medications may lead to allergic contact dermatitis. This study characterized positive patch test reactions associated with medications in patients evaluated by the North American Contact Dermatitis Group (NACDG).
METHODS
This study is a retrospective analysis of the NACDG data (2001-2018). Patients with at least 1 positive patch test reaction associated with a medication source were included. Allergens, reaction characteristics, clinical relevance, and source details were tabulated.
RESULTS
Of 43,722 patients, 6374 (14.6%) had positive allergic patch test reactions associated with 1 or more topical medication sources. Patients with versus without allergic reactions to medications were more likely to be older than 40 years (P < 0.0001) and/or have primary sites of dermatitis on the legs, anal/genital region, or trunk (P < 0.0001). There were 8787 reactions to NACDG allergens; the most common were neomycin (29.4%), bacitracin (29.1%), propylene glycol 100% (10.6%), tixocortol-17-pivalate (10.0%), lidocaine (7.9%), budesonide (4.9%), and dibucaine (4.4%). Propylene glycol 100% was the most common inactive ingredient (10.6%). Current relevance was present in 61.0%. A total of 6.5% of the individuals with medication allergy would have had 1 or more positive patch test reactions missed if only tested to the NACDG screening series.
CONCLUSIONS
Positive patch test reactions associated with topical medications were common (14.6%), and most were clinically relevant. Patients with topical medication allergy were twice as likely to have anal/genital involvement. Active ingredients, especially neomycin, bacitracin, and tixocortol-17-pivalate, were frequent culprits.
Topics: Allergens; Dermatitis, Allergic Contact; Humans; North America; Patch Tests; Retrospective Studies
PubMed: 34405832
DOI: 10.1097/DER.0000000000000777 -
Revista Brasileira de Ginecologia E... May 2021The diagnosis of genital ulcers remains a challenge in clinical practice. Lipschütz ulcer is a non-sexually transmitted rare and, probably, underdiagnosed condition,...
The diagnosis of genital ulcers remains a challenge in clinical practice. Lipschütz ulcer is a non-sexually transmitted rare and, probably, underdiagnosed condition, characterized by the sudden onset of vulvar edema along with painful necrotic ulcerations. Despite its unknown incidence, this seems to be an uncommon entity, with sparse cases reported in the literature. We report the case of an 11-year-old girl who presented at the emergency department with vulvar ulcers. She denied any sexual intercourse. The investigation excluded sexually transmitted infections, so, knowledge of different etiologies of non-venereal ulcers became essential. The differential diagnoses are extensive and include inflammatory processes, drug reactions, trauma, and malignant tumors. Lipschütz ulcer is a diagnosis of exclusion. With the presentation of this case report, the authors aim to describe the etiology, clinical course, and outcomes of this rare disease, to allow differential diagnosis of genital ulceration.
Topics: Administration, Topical; Anti-Infective Agents, Local; Child; Diagnosis, Differential; Dibucaine; Epstein-Barr Virus Infections; Female; Humans; Rare Diseases; Treatment Outcome; Ulcer; Vulvar Diseases
PubMed: 34077985
DOI: 10.1055/s-0041-1729147 -
The Journal of Biological Chemistry 2021The mitochondrial calcium uniporter (MCU) and cyclophilin D (CyD) are key players in induction of the permeability transition pore (PTP), which leads to mitochondrial...
The mitochondrial calcium uniporter (MCU) and cyclophilin D (CyD) are key players in induction of the permeability transition pore (PTP), which leads to mitochondrial depolarization and swelling, the major signs of Ca-induced mitochondrial damage. Mitochondrial depolarization inhibits ATP production, whereas swelling results in the release of mitochondrial pro-apoptotic proteins. The extent to which simultaneous deletion of MCU and CyD inhibits PTP induction and prevents damage of brain mitochondria is not clear. Here, we investigated the effects of MCU and CyD deletion on the propensity for PTP induction using mitochondria isolated from the brains of MCU-KO, CyD-KO, and newly created MCU/CyD-double knockout (DKO) mice. Neither deletion of MCU nor of CyD affected respiration or membrane potential in mitochondria isolated from the brains of these mice. Mitochondria from MCU-KO and MCU/CyD-DKO mice displayed reduced Ca uptake and diminished extent of PTP induction. The Ca uptake by mitochondria from CyD-KO mice was increased compared with mitochondria from WT mice. Deletion of CyD prevented mitochondrial swelling and resulted in transient depolarization in response to Ca, but it did not prevent Ca-induced delayed mitochondrial depolarization. Mitochondria from MCU/CyD-DKO mice did not swell in response to Ca, but they did exhibit mild sustained depolarization. Dibucaine, an inhibitor of the Ca-activated mitochondrial phospholipase A2, attenuated and bovine serum albumin completely eliminated the sustained depolarization. This suggests the involvement of phospholipase A2 and free fatty acids. Thus, in addition to induction of the classical PTP, alternative deleterious mechanisms may contribute to mitochondrial damage following exposure to elevated Ca.
Topics: Animals; Brain; Calcium; Calcium Channels; Peptidyl-Prolyl Isomerase F; Gene Knockout Techniques; Mice; Mice, Knockout; Mitochondria; Mitochondrial Proteins
PubMed: 33864812
DOI: 10.1016/j.jbc.2021.100669 -
Spectrochimica Acta. Part A, Molecular... Jul 2021For the treatment of internal and external hemorrhoids, policresulen (POL) and cinchocaine hydrochloride (CIN) are used in combination. Using a new, simple, fast, and...
For the treatment of internal and external hemorrhoids, policresulen (POL) and cinchocaine hydrochloride (CIN) are used in combination. Using a new, simple, fast, and economical first-derivative synchronous fluorescence spectroscopic process, both drugs were simultaneously determined and validated. At Δλ60 nm and with a scanning rate of 600 nm/min, methanol was used as the solvent for both products. In the concentration ranges of 5.0-21.0 μg mL and 0.5-6.0 μg mL for POL and CIN, the amplitude-concentration plots were rectilinear. The detection limits were found to be 0.770 μg mL and 0.118 μg mL and the quantitation limits for POL and CIN were 2.541 μg mL and 0.391 μg mL. To evaluate all compounds in synthetic mixtures and medicinal dosage types, the proposed method has been successfully applied. These findings were in line with the results obtained using high-performance thin layer chromatography, the comparison process.
Topics: Cresols; Dibucaine; Drug Combinations; Formaldehyde; Ointments; Spectrometry, Fluorescence; Suppositories
PubMed: 33744839
DOI: 10.1016/j.saa.2021.119648