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BMC Chemistry Oct 2023[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process....
[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process. [1,8]-Naphthyridine derivatives (1a-1l) were evaluated for inhibitory potential for isozymes of carbonic anhydrase (CA) and alkaline phosphatase (ALP). CAs have been reported to carry out reversible hydration of CO into HCO, secretion of electrolytes, acid-base regulation, bone resorption, calcification, and biosynthetic reactions. Whereas ALPs hydrolyze monophosphate esters with the release of inorganic phosphate and play an important role in bone mineralization. Both enzymes have been found to be over-expressed and raised functional activities in patients suffering from rheumatoid arthritis. The discovery of dual inhibitors of these enzymes may provide a synergistic effect to cure bone disorders such as rheumatoid arthritis and ankylosing spondylitis. Among the test compounds, the most potent inhibitors for CA-II, CA-IX, and CA-XII were 1e, 1g, and 1a with IC values of 0.44 ± 0.19, 0.11 ± 0.03 and 0.32 ± 0.07 µM, respectively. [1,8]-Naphthyridine derivatives (1a-1l) were approximately 4 folds more potent than standard CA inhibitor acetazolamide. While in the case of ALPs, the most potent compounds for b-TNAP and c-IAP were 1b and 1e with IC values of 0.122 ± 0.06 and 0.107 ± 0.02 µM, respectively. Thus, synthesized derivatives proved to be 100 to 800 times more potent as compared to standard inhibitors of b-TNAP and c-IAP (Levamisole and L-phenyl alanine, respectively). In addition, selectivity and dual inhibition of [1,8]-Naphthyridine derivatives confer precedence over known inhibitors. Molecular docking and molecular simulation studies were also conducted in the present studies to define the type of interactions between potential inhibitors and enzyme active sites.
PubMed: 37880684
DOI: 10.1186/s13065-023-01052-8 -
Brain Communications 2023Ashton C report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common...
Ashton C report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common feature of episodic ataxia and other episodic features, as well as the inefficacy of acetazolamide in these patients.
PubMed: 37705681
DOI: 10.1093/braincomms/fcad239 -
ACS Omega May 2024The abnormal levels of the human carbonic anhydrase isoenzymes I and II (hCA I and II) and cholinesterase enzymes, namely, acetylcholinesterase (AChE) and...
The abnormal levels of the human carbonic anhydrase isoenzymes I and II (hCA I and II) and cholinesterase enzymes, namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are linked with various disorders including Alzheimer's disease. In this study, six new nicotinic hydrazide derivatives (-) were designed and synthesized for the first time, and their inhibitory profiles against hCA I, hCA II, AChE, and BChE were investigated by assays and studies. The structures of novel molecules were elucidated by using spectroscopic techniques and elemental analysis. These molecules showed inhibitory activities against hCA I and II with IC values ranging from 7.12 to 45.12 nM. Compared to reference drug acetazolamide (AZA), compound was the most active inhibitor against hCA I and II. On the other hand, it was determined that IC values of the tested molecules ranged between 21.45 and 61.37 nM for AChE and between 18.42 and 54.74 nM for BChE. Among them, compound was the most potent inhibitor of AChE and BChE, with IC values of 21.45 and 18.42 nM, respectively. In order to better understand the mode of action of these new compounds, state-of-the-art molecular modeling techniques were also conducted.
PubMed: 38737075
DOI: 10.1021/acsomega.3c10182 -
Journal of Enzyme Inhibition and... Dec 2023A β-class carbonic anhydrase (CA, EC 4.2.1.1) present in the genome of the Monogenean platyhelminth a fish parasite, GsaCAβ, has been investigated for its inhibitory...
A β-class carbonic anhydrase (CA, EC 4.2.1.1) present in the genome of the Monogenean platyhelminth a fish parasite, GsaCAβ, has been investigated for its inhibitory effects with a panel of sulphonamides and sulfamates, some of which in clinical use. Several effective GsaCAβ inhibitors were identified, belonging to simple heterocyclic sulphonamides, the deacetylated precursors of acetazolamide and methazolamide (sof 81.9-139.7 nM). Many other simple benezene sulphonamides and clinically used agents, such as acetazolamide, methazolamide, ethoxzolamide, dorzolamide, benzolamide, sulthiame and hydrochlorothiazide showed inhibition constants <1 µM. The least effective GsaCAβ inhibitors were 4,6-disubstituted-1,3-benzene disulfonamides, with s in the range of 16.9-24.8 µM. Although no potent GsaCAβ-selective inhibitors were detected so far, this preliminary investigation may be helpful for better understanding the inhibition profile of this parasite enzyme and for the potential development of more effective and eventually parasite-selective inhibitors.
Topics: Animals; Acetazolamide; Carbonic Anhydrases; Methazolamide; Carbonic Anhydrase Inhibitors; Parasites; Platyhelminths; Salmon; Structure-Activity Relationship; Sulfonamides; Sulfanilamide
PubMed: 36647786
DOI: 10.1080/14756366.2023.2167988 -
Biomedicine & Pharmacotherapy =... Nov 2023Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast...
Para-toluenesulfonamide, a novel potent carbonic anhydrase inhibitor, improves hypoxia-induced metastatic breast cancer cell viability and prevents resistance to αPD-1 therapy in triple-negative breast cancer.
Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl-induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer.
Topics: Humans; Animals; Mice; Female; Carbonic Anhydrase Inhibitors; Triple Negative Breast Neoplasms; Carbonic Anhydrases; Cell Survival; Vascular Endothelial Growth Factor A; Antigens, Neoplasm; Hypoxia; Cell Hypoxia; p38 Mitogen-Activated Protein Kinases; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line, Tumor; Breast Neoplasms
PubMed: 37748406
DOI: 10.1016/j.biopha.2023.115533 -
Respiratory Physiology & Neurobiology Aug 2023This study aimed to evaluate changes in lung function assessed by spirometry and blood gas content in healthy high-altitude sojourners during a trek in the Himalayas. A...
This study aimed to evaluate changes in lung function assessed by spirometry and blood gas content in healthy high-altitude sojourners during a trek in the Himalayas. A group of 19 Italian adults (11 males and 8 females, mean age 43 ± 15 years, and BMI 24.2 ± 3.7 kg/m) were evaluated as part of a Mount Everest expedition in Nepal. Spirometry and arterial blood gas content were evaluated at baseline in Kathmandu (≈1400 m), at the Pyramid Laboratory - Observatory (peak altitude of ≈5000 m), and on return to Kathmandu 2-3 days after arrival at each site. All participants took 250 mg of acetazolamide per os once daily during the ascent. We found that arterial hemoglobin saturation, O and CO partial pressures, and the bicarbonate level all decreased (in all cases, p < 0.001 with R =0.70-0.90), while pHa was maintained stable at the peak altitude. Forced vital capacity (FVC) remained stable, while forced expiratory volume in 1 s (FEV1) decreased (p = 0.010, n =0.228), resulting in a lower FEV1/FVC ratio (p < 0.001, n =0.380). The best predictor for acute mountain sickness was the O partial pressure at the peak altitude (p = 0.004, R =0.39). Finger pulse oximetry overestimated peripheral saturation relative to arterial saturation. We conclude that high-altitude hypoxia alters the respiratory function and the oxygen saturation of the arterial blood hemoglobin. Additionally, air rarefaction and temperature reduction, favoring hypoxic bronchoconstriction, could affect respiration. Pulse oximetry seems not enough to assist medical decisions at high altitudes.
Topics: Adult; Male; Female; Humans; Middle Aged; Altitude; Altitude Sickness; Hypoxia; Forced Expiratory Volume; Oxygen
PubMed: 37257573
DOI: 10.1016/j.resp.2023.104086 -
Cureus Feb 2024Idiopathic intracranial hypertension (IIH) and multiple sclerosis (MS) are rare neurological disorders that largely affect females within the reproductive age group....
Idiopathic intracranial hypertension (IIH) and multiple sclerosis (MS) are rare neurological disorders that largely affect females within the reproductive age group. The clinical pictures of both diseases can overlap, which therefore places great importance on accurately studying and reporting their concurrence. Therein, we report a case of IIH presenting and progressing simultaneously with MS. This young, previously healthy female presented with the primary complaint of a severe right-sided headache associated with blurred vision and a finding of papilledema. The initial investigations including a lumbar puncture (LP) that revealed high opening pressure (more than 25 mm HO) with normal cerebrospinal fluid (CSF) analysis led to an impression of idiopathic intracranial hypertension, and she was treated accordingly with acetazolamide and scheduled for regular follow-ups with both neurology and neuro-ophthalmology. However, about two months after the initial presentation, she complained of unusual headaches, and a neuro-ophthalmology clinical evaluation revealed complete right homonymous hemianopia, suggesting a lesion in the left temporo-parietal occipital region. The patient was thus admitted as a case of cerebral edema following an urgent brain magnetic resonance imaging (MRI). After obtaining thorough imaging and workup, the patient was given steroids and markedly improved, favoring a diagnosis of tumefactive MS with IIH.
PubMed: 38314385
DOI: 10.7759/cureus.53374 -
Journal of Clinical Medicine Nov 2023To analyze the etiology and implications of optic disc swelling in cancer patients treated at a specialized tertiary cancer center in Jordan.
PURPOSE
To analyze the etiology and implications of optic disc swelling in cancer patients treated at a specialized tertiary cancer center in Jordan.
METHODS
This was a retrospective study of all cancer patients who had optic disc swelling between January 2019 and December 2020 at King Hussein Cancer Center (KHCC). Patients' data included age, sex, laterality, visual acuity, and the underlying cause and management for the optic disc swelling.
RESULTS
Optic disc swelling was present in 58 cancer patients (96 eyes), with 38 (65%) having bilateral involvement. Among these, 33 (57%) were female, and 43 (74%) were ≤40 years old. At diagnosis, 58 (63%) eyes had a best-corrected visual acuity (BCVA) better than 0.5, improving to 73 (76%) eyes at the last follow-up. High intracranial pressure (ICP) was the most common primary cause (30 patients/52%), followed by tumor infiltration of the optic nerve (10 patients/17%), optic nerve compression (7 patients/12%), and optic nerve inflammation (5 patients/9%). Four patients had pseudopapilledema. Among the 30 patients with high ICP, CNS tumors were predominant (21 patients/70%), with only 3 having idiopathic intracranial hypertension. Medications, including ATRA (All-Trans Retinoic Acid) and systemic steroids, contributed to increased ICP in six patients (20%). BCVA was less than 0.5 in all eyes (100%) affected by tumor infiltration, optic nerve inflammation, and ischemic optic neuropathy, while only eight eyes (14%) with optic disc swelling due to elevated ICP had a BCVA less than 0.5 ( < 0.0001). Management included steroids (53 patients/91%), acetazolamide (30 patients/52%), chemotherapy (20 patients/34%), radiation therapy (13 patients/22%), frequent lumbar punctures (12 patients/21%), and surgery (28 patients/48%). Visual acuity improved in 40 eyes (42%), with only 4 eyes (4%) experiencing deterioration. At a 12-month median follow-up period, 11 (19%) patients were dead, 10 (10%) eyes had poor vision (BCVA less than 0.1), and 21 (22%) eyes had BCVA 0.5 or better.
CONCLUSIONS
Various underlying pathologies can induce optic disc swelling in cancer patients, a grave condition capable of causing vision loss. Notably, tumor infiltration of the optic nerve tends to result in more profound visual impairment compared to papilledema due to elevated ICP. Timely detection is crucial, and immediate symptomatic treatment followed by addressing the underlying cause is essential to prevent irreversible optic nerve damage and vision loss in cancer patients.
PubMed: 38002752
DOI: 10.3390/jcm12227140 -
Cureus Sep 2023In this case report, a patient with neuroretinitis from a infection is described, and insights into methods to distinguish this type of case from more common...
In this case report, a patient with neuroretinitis from a infection is described, and insights into methods to distinguish this type of case from more common etiologies of optic nerve edema are presented. A 21-year-old female with a history of right monocular vision loss due to amblyopia presented to the emergency department (ED) with occipital headache, fever, dizziness, nasal congestion, and painless blurry vision in the left eye for one day. A lumbar puncture found a slightly high opening pressure but no evidence of meningitis. The patient was diagnosed with a viral illness and discharged with outpatient follow-up. The patient, however, had persistent central vision loss and recurring headaches and returned to the ED. Subsequent ultrasound of the patient's optic nerve revealed significant optic nerve swelling. A new working diagnosis of idiopathic intracranial hypertension was made, and the patient was started on oral acetazolamide. On the next day, she was seen by ophthalmology, and recent scratches from her cat were noted on her arm. She tested positive for and was started on doxycycline and rifampin. Nearly two weeks after the initial presentation, a macular star pattern, indicative of neuroretinitis, was noted on the fundoscopic exam. The patient had recovered her vision by three months later. In ED cases with unilateral vision loss, early use of point-of-care ultrasound and infection with should always be considered. Early serology testing may be warranted to allow for earlier treatment since classic signs of neuroretinitis may not be apparent at the onset.
PubMed: 37885521
DOI: 10.7759/cureus.45866 -
Endocrinology, Diabetes & Metabolism... Oct 2023A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around...
SUMMARY
A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered.
LEARNING POINTS
HFTC/HHS occurs on an autosomal recessive basis, but its clinical course and manifestations differ significantly throughout the cases. HFTC/HHS may be undiagnosed until later in life because of its rarity, unfamiliarity, and phenotype diversity; therefore, HFTC/HHS should be included in the differential diagnosis of elderly patients with unexplained hyperphosphataemia or ectopic calcinosis. Comorbidities, including rheumatologic disorders, may contribute to developing HFTC/HHS-associated calcinosis.
PubMed: 37787752
DOI: 10.1530/EDM-23-0071