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Viruses Jun 2024Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable...
BACKGROUND
Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis.
METHODS
Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications.
RESULTS
The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including , , , , , , and , were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers.
CONCLUSIONS
The lipophagy-related genes , , , , , , and can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.
Topics: Humans; SARS-CoV-2; COVID-19 Drug Treatment; Biomarkers; COVID-19; Lipid Metabolism; Antiviral Agents; Computational Biology; Machine Learning; Lactams, Macrocyclic; Hydroxamic Acids; Benzoquinones
PubMed: 38932215
DOI: 10.3390/v16060923 -
European Journal of Case Reports in... 2021Colonic pseudo-obstruction is characterized by dilatation of the colon without a structural lesion causing the obstruction. It usually involves the caecum and right side...
UNLABELLED
Colonic pseudo-obstruction is characterized by dilatation of the colon without a structural lesion causing the obstruction. It usually involves the caecum and right side of the colon and is commonly observed in patients with severe illness or after surgery; it is rarely caused by pheochromocytoma. The diagnosis of colonic pseudo-obstruction can be established by abdominal imaging including computed tomography (CT) of the abdomen or use of a water-soluble contrast enema. In additional to conservative or surgical treatment, alpha-blockers can be used in this setting to relieve the pseudo-obstruction.
LEARNING POINTS
Colonic pseudo-obstruction is a rare manifestation of pheochromocytoma.A typical radiological feature of colonic pseudo-obstruction is the presence of a gradual transition at the splenic flexure of the colon.Alpha-blockers can be used in this setting to relieve pseudo-obstruction.
PubMed: 33869102
DOI: 10.12890/2021_002421 -
Behavioural Brain Research Sep 2017Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that...
Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment.
Topics: Adrenergic Antagonists; Amphetamine; Animals; Central Nervous System Stimulants; Cerebral Cortex; Disease Models, Animal; Male; Motor Activity; Norepinephrine; Perceptual Disorders; Phenoxybenzamine; Propranolol; Rats, Long-Evans; Receptors, Adrenergic; Recovery of Function
PubMed: 28756213
DOI: 10.1016/j.bbr.2017.07.035 -
Journal of Separation Science Jun 2020Inspired by the distinct chemical and physical properties of nanoparticles, here a novel open-tubular capillary electrochromatography column was prepared by...
Inspired by the distinct chemical and physical properties of nanoparticles, here a novel open-tubular capillary electrochromatography column was prepared by electrostatic assembly of poly(diallydimethylammonium chloride) onto the inner surface of a fused-silica capillary, followed by self-adsorption of negatively charged SH-β-cyclodextrin/gold nanoparticles. The formation of the SH-β-cyclodextrin/gold nanoparticles coated capillary was confirmed and characterized by scanning electron microscopy and energy dispersive spectrometry. The results of scanning electron microscopy and energy dispersive spectrometry studies indicated that SH-β-cyclodextrin/gold nanoparticles were successfully coated on the inner wall of the capillary column. The performance of the SH-β-cyclodextrin/gold nanoparticles coated capillary was validated by the analysis of six pairs of chiral drugs, namely zopiclone, carvedilol, salbutamol, terbutaline sulfate, phenoxybenzamine hydrochloride, and ibuprofen. Satisfactory enantioseparation results were achieved, confirming the use of gold nanoparticles as the support could enhance the phase ratio of the open-tubular capillary column. Additionally, the stability and reproducibility of the SH-β-cyclodextrin/gold nanoparticles coated capillary column were also investigated. Then, this proposed method was well validated with good linearity (≥0.999), recovery (90.0-93.5%) and repeatability, and was successfully used for enantioseparation of ibuprofen in spiked plasma samples, which indicated the new column's potential usage in biological analysis.
Topics: Albuterol; Azabicyclo Compounds; Capillary Electrochromatography; Carvedilol; Gold; Ibuprofen; Metal Nanoparticles; Phenoxybenzamine; Piperazines; Stereoisomerism; Terbutaline; beta-Cyclodextrins
PubMed: 32160391
DOI: 10.1002/jssc.201901323 -
Frontiers in Endocrinology 2022Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due...
Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due to the non-specific nature of signs and symptoms. In many patients, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could lead to long-term symptoms including fatigue, headaches, and cognitive dysfunction. Here, we present the case of a patient incidentally diagnosed with an adrenal mass that proved to be a PCC after imaging was performed due to persisting complaints after coronavirus disease 2019 (COVID-19) infection. A 37-year-old male patient was referred to our center because of a right-sided inhomogeneous adrenal mass, incidentally found during a computed tomographic scan of the thorax performed due to cough and dyspnea that persisted after COVID-19 infection. Other complaints that were present prior to COVID-19 infection included profuse sweating, dizziness, exhaustion with chronic fatigue, and concentration difficulties. The patient had no history of hypertension, his blood pressure was normal, and the 24-h ambulatory blood pressure monitoring confirmed normotension but with the absence of nocturnal dipping. Plasma normetanephrine was 5.7-fold above the upper limit (UL) of reference intervals (738 pg/ml, UL = 129 pg/ml), whereas plasma metanephrine and methoxytyramine were normal at 30 pg/ml (UL = 84 pg/ml) and <4 pg/ml (UL = 16 pg/ml), respectively. Preoperative preparation with phenoxybenzamine was initiated, and a 4-cm tumor was surgically resected. Profuse sweating as well as dizziness was resolved after adrenalectomy pointing toward PCC and not COVID-19-associated patient concerns. Altogether, this case illustrates the difficulties in recognizing the possibility of PCC due to the non-specific nature of signs and symptoms of the tumor, which in this case did not include hypertension and coincided with some of the symptoms of long COVID-19.
Topics: Adrenal Gland Neoplasms; Adult; Blood Pressure Monitoring, Ambulatory; COVID-19; Dizziness; Humans; Hypertension; Male; Metanephrine; Normetanephrine; Phenoxybenzamine; Pheochromocytoma; SARS-CoV-2; Post-Acute COVID-19 Syndrome
PubMed: 36237184
DOI: 10.3389/fendo.2022.967995 -
Cureus May 2022A 51-year-old patient was admitted with chest pain and broad complex ventricular tachycardia. He received three consecutive direct cardioversion (DC) shocks and was...
A 51-year-old patient was admitted with chest pain and broad complex ventricular tachycardia. He received three consecutive direct cardioversion (DC) shocks and was commenced on amiodarone infusion via a central venous catheter or central line (CVC). He responded to treatment and normal sinus rhythm (NSR) was achieved. He had elevated troponin I and underwent coronary angiogram which initially was thought to be responsible for his ventricular tachycardia. Coronary angiogram (CAG) showed unobstructed coronary arteries. He was recently diagnosed with pheochromocytoma and was commenced on Phenoxybenzamine 10 mg two months back. He developed ventricular tachycardia (VT) again the next day that did not respond to four consecutive direct cardioversion shocks (DC) and antiarrhythmic medications. He was intubated and ventilated to terminate his VT and was transferred to the intensive care unit (ICU). He remained intubated for 48 hours and he remained in NSR, after which he was extubated. He was commenced on bisoprolol and was later stepped down to the coronary care unit (CCU). Cardiac magnetic resonance imaging (CMR) showed left ventricular non-compaction (LVNC) or possibly myocarditis in view of patient's known history of pheochromocytoma. He was discussed with surgical team at another hospital for surgical resection of the adrenal tumor and had a few further runs of VT while he was waiting to be transferred. The patient finally underwent surgical resection of the tumor and was booked for implantable cardioverter defibrillator (ICD) in view of his VT. This was an interesting case of treatment-resistant VT driven by pheochromocytoma and LVNC, and it is important to be familiar with the fact that conventional therapies may fail in these patients and may require intubation and ventilation to terminate VT storms.
PubMed: 35800814
DOI: 10.7759/cureus.25483 -
Journal of Pharmaceutical and... Nov 2020The current United States Pharmacopeia-National Formulary (USP-NF) and the British Pharmacopoeia phenoxybenzamine (PBA) hydrochloride drug substance and drug product...
The current United States Pharmacopeia-National Formulary (USP-NF) and the British Pharmacopoeia phenoxybenzamine (PBA) hydrochloride drug substance and drug product monographs describe an HPLC procedure for the determination of a specified impurity "tertiary amine phenoxybenzamine" and use the resolution of an "unknown related substance" from PBA as a system suitability criterion; however, neither structural information of the "unknown related substance" is provided nor reference standards of the two impurities are available. The ambiguity in pharmacopeias poses difficulties in implementing the procedure for quality control. To clarify the degradation pathways, and incorporate the impurity profile of PBA into the USP monographs, the degradation of PBA was revisited. PBA undergoes rapid degradation in neutral or basic aqueous solutions to generate the "tertiary amine phenoxybenzamine" as the predominant degradation product, which was confirmed as phenoxybenzamine hydroxide (PBA-OH). In addition, the "unknown related substance" was proposed as the phenoxybenzamine nitrile (PBA-CN) on the basis of LC-MS studies. The identity of PBA-CN was unambiguously verified via chemical synthesis, HPLC and NMR analyses. A stability-indicating method was developed and validated for the determination of PBA and its impurities, and was used to support USP monograph modernization.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Contamination; Mass Spectrometry; Phenoxybenzamine
PubMed: 32942108
DOI: 10.1016/j.jpba.2020.113618 -
Frontiers in Pharmacology 2017Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor consists of the...
Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of Akrinor and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings. Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37°C. CGP 20712A and ICI 118,551 were used to elaborate β- and β-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction. Clinically relevant concentrations of Akrinor (4.2-420 mg/l) robustly increased force in human atrial trabeculae (EC 41 ± 3 mg/l). This direct sympathomimetic action was mediated via β-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of Akrinor increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of Akrinor (4.2-168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC 6.18 ± 0.08 to 5.23 ± 0.05 M. Akrinor increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an α-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of Akrinor differs from noradrenaline and norephedrine . We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of Akrinor.
PubMed: 28588484
DOI: 10.3389/fphar.2017.00272 -
Annals of Surgical Oncology Jan 2017The optimal preoperative α-blockade strategy is debated for patients undergoing laparoscopic adrenalectomy for pheochromocytomas. We evaluated the impact of selective...
BACKGROUND
The optimal preoperative α-blockade strategy is debated for patients undergoing laparoscopic adrenalectomy for pheochromocytomas. We evaluated the impact of selective versus non-selective α-blockade on intraoperative hemodynamics and postoperative outcomes.
METHODS
We identified patients having laparoscopic adrenalectomy for pheochromocytomas from 2001 to 2015. As a marker of overall intraoperative hemodynamics, we combined systolic blood pressure (SBP) > 200, SBP < 80, SBP < 80 and >200, pulse > 120, vasopressor infusion, and vasodilator infusion into a single variable. Similarly, the combination of vasopressor infusion in the post-anesthesia care unit (PACU) and the need for intensive care unit (ICU) admission provided an overview of postoperative support.
RESULTS
We identified 52 patients undergoing unilateral laparoscopic adrenalectomy for pheochromocytoma. Selective α-blockade (i.e. doxazosin) was performed in 35 % (n = 18) of patients, and non-selective blockade with phenoxybenzamine was performed in 65 % (n = 34) of patients. Demographics and tumor characteristics were similar between groups. Patients blocked selectively were more likely to have an SBP < 80 (67 %) than those blocked with phenoxybenzamine (35 %) (p = 0.03), but we found no significant difference in overall intraoperative hemodynamics between patients blocked selectively and non-selectively (p = 0.09). However, postoperatively, patients blocked selectively were more likely to require additional support with vasopressor infusions in the PACU or ICU admission (p = 0.02). Hospital stay and complication rates were similar.
CONCLUSION
Laparoscopic adrenalectomy for pheochromocytoma is safe regardless of the preoperative α-blockade strategy employed, but patients blocked selectively may have a higher incidence of transient hypotension during surgery and a greater need for postoperative support. These differences did not result in longer hospital stay or increased complications.
Topics: Adrenal Gland Neoplasms; Adrenalectomy; Adrenergic alpha-1 Receptor Antagonists; Doxazosin; Female; Hemodynamics; Humans; Laparoscopy; Male; Middle Aged; Phenoxybenzamine; Pheochromocytoma; Treatment Outcome
PubMed: 27561909
DOI: 10.1245/s10434-016-5514-7 -
Frontiers in Endocrinology 2020Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ)... (Review)
Review
Metastatic pheochromocytoma/paraganglioma (MPP) therapy mainly involves radionuclide therapy, chemotherapy, and targeted therapy. In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with germline mutation. We reported a patient with MPP who did not have any known germline genetic change and responded remarkably well to TMZ monotherapy. The patient was a 41-year-old woman with local and distant recurrence (soft tissues and bone metastases) of retroperitoneal paraganglioma. She suffered from dizziness, palpitation, sweating, weight loss and constipation, with the blood pressure fluctuating substantially from 130/100 mmHg to 190/120 mmHg, although she was on phenoxybenzamine and metoprolol medication. The patient showed clinical and radiological response after 3-cycle TMZ therapy. Upon 15 cycles of TMZ therapy, her symptoms were dramatically alleviated, urinary norepinephrine excretion decreased from 1,840 μg/24 h to 206 μg/24 h, and CT showed that the lesions further shrank. Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase () promoter and a negative immunostaining for MGMT. Globally, only 26 cases of MPP treated with TMZ have been described so far. TMZ is effective, especially in patients with mutation, which can be explained by the silencing of MGMT expression as a consequence of promoter hypermethylation in -mutated tumors. Although, in general, patients with mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions. Severe side effects are uncommon, with only 17.4% patients experiencing Grade 3 toxicities, including lymphopenia, and hypertension. TMZ is effective and safe in MPP patients, and, it may work better on patients with -related MPP. Measurement of MGMT expression might help assess the tumor sensitivity to TMZ but this needs further systematic investigation.
Topics: Adrenal Gland Neoplasms; Adult; Antineoplastic Agents, Alkylating; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Humans; Mutation; Paraganglioma; Pheochromocytoma; Prognosis; Promoter Regions, Genetic; Succinate Dehydrogenase; Temozolomide; Tumor Suppressor Proteins
PubMed: 32132978
DOI: 10.3389/fendo.2020.00061