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Id Subject Object Predicate Lexical cue
T266 0-4 Sentence denotes 2.3.
T267 5-43 Sentence denotes Hydroxychloroquine Biological Activity
T268 44-149 Sentence denotes Besides the antiviral effects, HCQ possesses several other demonstrated biological activities (Figure 6).
T269 150-421 Sentence denotes Most of all, it showed immunosuppressive properties, allowing its employment (alone or in combination) in the first-line treatment of several auto-immune diseases, like rheumatoid arthritis, lupus erythematosus, primary Sjögren’s syndrome, and anti-phospholipid syndrome.
T270 422-700 Sentence denotes Moreover, HCQ was revealed to be effective in preclinical and clinical trials to dampening autoimmune disease-dependent cardiovascular complications (Figure 7), as well as in the amelioration of disease-independent hyperglycemia, hyperlipidemia, and gastrointestinal complaints.
T271 701-789 Sentence denotes HCQ exerts anticancer effects by acting synergistically with common chemotherapic drugs.
T272 790-987 Sentence denotes Although it has a well-defined and favorable toxicity profile, the necessity of increasing the dose, in some cases, limits the utilization, due to the toxicity, mainly at cardiac and ocular levels.
T273 988-1095 Sentence denotes A two-compartment model, with first-order absorption and a lag time, describes the pharmacokinetics of HCQ.
T274 1096-1216 Sentence denotes The long-terminal half-life prolongs the time to reach steady-state concentrations, then delays the therapeutic effects.
T275 1217-1295 Sentence denotes The next-generation formulations allow modulating the pharmacokinetics of HCQ.
T276 1296-1435 Sentence denotes Avoiding systemic absorption, then liver first-pass metabolism, HCQ may be used in site-specific inflammation, without toxicity [72,73,74].
T277 1436-1560 Sentence denotes The selected studies’ primary outcomes are the extent to which HCQ may limit disease progression or exacerbations (Table 2).
T278 1562-1568 Sentence denotes 2.3.1.
T279 1569-1589 Sentence denotes Rheumatoid Arthritis
T280 1590-1708 Sentence denotes Rheumatoid arthritis is a systemic autoimmune disease, characterized by chronic inflammation and damage to the joints.
T281 1709-1939 Sentence denotes Immune dysregulation underlies the pathogenesis of rheumatoid arthritis, leading to uncontrolled production of antibodies, mainly rheumatoid factor and citrullinate, involved in the autoreactivity against cartilage and bone [117].
T282 1940-2036 Sentence denotes It is estimated that the prevalence of rheumatoid arthritis is around 1%, mainly in women [118].
T283 2037-2212 Sentence denotes The immunosuppressive effects of HCQ are due to the ability to modulate T-cell and B-cell hyperactivity, resulting in a reduction of pro-inflammatory cytokine gene expression.
T284 2213-2449 Sentence denotes As the involvement of neutrophils in this disease, Jancinova, Pazourekova, Lucova, Perecko, Mihalova, Bauerova, Nosal and Drabikova [75] investigated the impact of oral HCQ administration on these cells, in rats with adjuvant arthritis.
T285 2450-2661 Sentence denotes At doses of 40 mg/kg daily, per oral administration (p.o.), it strongly decreased the blood concentration of neutrophil-derived oxidants, involved in the tissue damage and the onset of chronic inflammation [75].
T286 2662-2871 Sentence denotes A 36-week randomized, double-blind, placebo-controlled trial has evaluated the effect of the administration of HCQ in a dose of up to 7 mg/kg per day (maximum 400 mg/day) in patients with rheumatoid arthritis.
T287 2872-3063 Sentence denotes Within 36 weeks and during the study, HCQ showed statistically significant benefits on physical function, mainly on synovitis and joint pain, without side effects with respect to the control.
T288 3064-3139 Sentence denotes Moreover, HCQ was associated with a decrement of corticosteroid injections.
T289 3140-3223 Sentence denotes By contrast, no improvements in psychological function have been demonstrated [76].
T290 3224-3474 Sentence denotes Two comparative double-blind, randomized trials, involving 60 patients each, with sulfasalazine and HCQ have demonstrated that HCQ showed no significant differences among overall clinical effects respect to sulfasalazine, but presented a later onset.
T291 3475-3905 Sentence denotes In the first study, patients treated with HCQ (400 mg/day for 6 months and 200 mg/day for the next 6 months) experienced time-dependent statistically significant improvements in morning stiffness, pain, swollen joints, together with a decrease in blood levels of immunoglobulin M and erythrocyte sedimentation rate [77], while, in the second study, the same treatment was associated to no erosions in the 12% of the patients [78].
T292 3906-4026 Sentence denotes In patients with rheumatoid arthritis, the cardiovascular risk is more than doubled, compared to the healthy population.
T293 4027-4201 Sentence denotes Chronic inflammatory status leads to an intensification of the atherosclerotic process, resulting in a higher susceptibility to hypertension, obesity, and metabolic syndrome.
T294 4202-4322 Sentence denotes The overproduction of IL-6 is strictly related to lipid profile alterations, given its role in adipose tissue lipolysis.
T295 4323-4400 Sentence denotes The inflammation and endothelial damage are exacerbated by leptin production.
T296 4401-4538 Sentence denotes Batun-Garrido, Salas-Magana and Juarez-Rojop [79] found a significant correlation between HCQ treatment and lower IL-6 and leptin levels.
T297 4539-4904 Sentence denotes The positive effect of HCQ on dyslipidemia was also confirmed by Morris, Wasko, Antohe, Sartorius, Kirchner, Dancea and Bili [80] in a cohort study involving 706 rheumatoid arthritis diagnosed patients, finding a significant and stable cholesterol-lowering, mainly Low-Density Lipoprotein (LDL), and triglyceride decrease associated with HCQ intake (6.5 mg/kg/day).
T298 4905-5135 Sentence denotes A small but statistically significant amelioration in total cholesterol and LDL under HCQ treatment at the same dosage was also highlighted by a randomized, double-blind cross-over trial on patients with rheumatoid arthritis [81].
T299 5136-5293 Sentence denotes The correlation between HCQ and cardiovascular risk was also assessed in a cross-sectional observational study involving 177 women with rheumatoid arthritis.
T300 5294-5430 Sentence denotes At doses of 200 mg/kg/day, HCQ usage led to lower fasting glucose in women, arising as a valuable tool to enhance glycemic control [82].
T301 5431-5646 Sentence denotes However, apparent different outcomes were derived from a randomized double-blind crossover trial, recruiting 23 non-diabetic subjects with stable rheumatoid arthritis to receive 6.5 mg/kg/day of HCQ for eight weeks.
T302 5647-5733 Sentence denotes For these patients, no significant changes in insulin resistance were observable [81].
T303 5734-5866 Sentence denotes This study evaluated only insulin sensitivity, by Homeostatic Model Assessment (HOMA) index, without considering insulin metabolism.
T304 5867-5969 Sentence denotes Thus, inconsistency should be explained by this factor, together with the short duration of treatment.
T305 5970-6096 Sentence denotes The anti-diabetic properties of HCQ have been also assessed in patients without arthritis, as reported in the next paragraphs.
T306 6098-6104 Sentence denotes 2.3.2.
T307 6105-6124 Sentence denotes Lupus Erythematosus
T308 6125-6287 Sentence denotes Systemic lupus erythematosus is a multisystemic autoimmune chronic inflammatory disorder that mainly involves joints, mucosae, skin, and endothelial vessels [90].
T309 6288-6377 Sentence denotes For a long time, HCQ has played a marginal role in the overall management of the disease.
T310 6378-6533 Sentence denotes Since the 90s, the first evidence of HCQ effectiveness in controlling lupus erythematosus manifestations allowed its employment as a first-line medicament.
T311 6534-6683 Sentence denotes Although it was not recommended in single therapy, the immunomodulating properties of HCQ seem to play an important role in the disease pathogenesis.
T312 6684-6816 Sentence denotes It is associated with a decrement of exacerbation events, as well as protective effects towards vascular and thrombotic events [85].
T313 6817-7064 Sentence denotes Indeed, a 24-week randomized, double-blind placebo-controlled trial demonstrated that the discontinuing of HCQ treatment (100–400 mg/kg/day for at least six months) increased the risk of exacerbations by 2.5 times in patients with quiescent lupus.
T314 7065-7201 Sentence denotes People who interrupted the therapy exhibited constitutional symptoms of the disease, as well as skin rashes, arthritis, and ulcers [83].
T315 7202-7417 Sentence denotes A long-term randomized study evaluated the withdrawal effects of HCQ on quiescent lupus erythematosus patients, revealing that a reduction by up to 57% is associated with HCQ maintaining treatment (272 mg/day) [84].
T316 7418-7539 Sentence denotes A case-control study was carried out in order to define the role of HCQ in the survival of individuals affected by lupus.
T317 7540-7717 Sentence denotes The positive correlation between HCQ and survival led to the consideration of this drug as a great therapeutic option at the proper dose (6.5 mg/kg/bw) in lupus management [85].
T318 7718-7947 Sentence denotes If these clinical trials demonstrated the advantages of keeping up the therapy with HCQ in preventing disease exacerbations, doubts persisted about the efficacy of this treatment in the control of more severe clinical forms [83].
T319 7948-8122 Sentence denotes As the important role of the imbalance between immune cell populations, several preclinical and clinical studies have evaluated the role of HCQ in restoring this equilibrium.
T320 8123-8379 Sentence denotes In particular, elevated levels of effector lymphocyte T (Th17) that mediate the autoimmune answer and decreased levels of regulatory lymphocyte T (Treg) that guarantees the immune homeostasis, may be observed in autoimmune diseases, in particular in lupus.
T321 8380-8472 Sentence denotes Lately, autophagy had risen among the emerging strategies to reestablish the immune balance.
T322 8473-8634 Sentence denotes As HCQ is a well-known autophagy inhibitor, An, N. et al. [86] evaluated the influence of HCQ intake (100 mg/kg/day) in MRL/lpr mice with the lupus-like disease.
T323 8635-8785 Sentence denotes After four weeks of treatment, HCQ clearly restored the immune balance, by both inhibiting Th17 response and enhancing Treg immunosuppressive effects.
T324 8786-9068 Sentence denotes The levels of autoantibodies and the expression of inflammatory cytokines, mainly in Th17 cells, were remarkably lowered, due to the inhibition of the activated autophagy, as demonstrated by the increase of autophagic flux marker expression in Th17 and Treg, compared with controls.
T325 9069-9253 Sentence denotes This randomized trial further evidenced that HCQ treatment also remarkably attenuated kidney inflammation, by limiting the migration of lymphoplasmacytic cells into renal tissues [86].
T326 9254-9405 Sentence denotes Preclinical outcomes have been confirmed by a prospective cohort study, involving 41 patients with a diagnosis of lupus treated with 400 mg/day of HCQ.
T327 9406-9756 Sentence denotes Dysregulated cytokine and autoantibody production, deriving from high autoreactivity that characterizes lupus disease, has been restored by two months of HCQ administration, demonstrating its ability in modulating inflammatory response, with normalized complement activity and reduced levels of pro-inflammatory cytokines, mainly IL-6 and TNF-α [87].
T328 9757-10049 Sentence denotes In a multiethnic US cohort on 35 lupus patients, HCQ treatment resulted in significant clinical benefits towards disease progression, probably due to the inhibition of toll-like receptor activation, resulting in down-regulation of IFN-α, which plays a pivotal role in lupus pathogenesis [88].
T329 10050-10181 Sentence denotes Infiltrating cells, most of all mast cells, could involve skin tissues, causing one of the most common signs of lupus, skin rashes.
T330 10182-10343 Sentence denotes The consequences of HCQ intake on skin lesions have been investigated on a MRL/lpr murine model of lupus at low (4 mg/kg/day) and high (40 mg/kg/day) oral doses.
T331 10344-10578 Sentence denotes The number of mast cells decreased with respect to the drinking-water control (from 81 to 50 in low-dose and 12 in high dose), while the mortality rate decreased by up to three times in both treated groups with respect to the control.
T332 10579-10751 Sentence denotes These in vivo results, together with a significant histopathological alteration regression, suggest that HCQ is a good tool against skin injury in lupus erythematosus [89].
T333 10752-10883 Sentence denotes The chronic inflammatory status that features lupus erythematosus leads to a higher susceptibility to cardiovascular complications.
T334 10884-11038 Sentence denotes Lupus, indeed, is often characterized by endothelial dysfunction, the earliest marker of cardiovascular disease, as well as hypertension and renal damage.
T335 11039-11168 Sentence denotes In a NZB/W F1 mice model of lupus, oral HCQ gavage of 10 mg/kg/day for five weeks reduced the incidence of thromboembolic events.
T336 11169-11386 Sentence denotes Moreover, improvements in hypertension, renal damage, and heart hypertrophy occurred, probably due to the normalized endothelium response and reduction of Reactive Oxygen Species (ROS) attributable to HCQ intake [90].
T337 11387-11516 Sentence denotes The same effect of normalizing nitric oxide and ROS production have been confirmed in a NZB/W F1 murine model at different times.
T338 11517-11631 Sentence denotes HCQ at 3 mg/kg/day p.o. protected vascular endothelium, with a strong improvement of endothelial dysfunction [91].
T339 11632-11714 Sentence denotes The benefits on atherosclerosis also pass through the lipid-lowering power of HCQ.
T340 11715-11941 Sentence denotes A clinical study on 155 autoimmune patients revealed a statistically significant association between HCQ (400 mg/day) and a lessening of triglyceride and cholesterol levels, mainly LDL, while no HDL changes were observed [92].
T341 11942-12049 Sentence denotes By contrast, HCQ in patients with a mild or inactive condition had no significant effects on lipid profile.
T342 12050-12277 Sentence denotes A survey involving 65 Chinese lupus patients, treated with HCQ (244 ± 86 mg/day), demonstrated that only triglycerides tended to be lowered, while no statistically significant changes are observable in cholesterol levels [119].
T343 12278-12394 Sentence denotes The use of HCQ may be helpful in minimizing cardiovascular risk by improving glycemic homeostasis in lupus patients.
T344 12395-12648 Sentence denotes A cross-sectional study performed between 2000 and 2005 on 149 nondiabetic women affected by lupus estimated that a mean dose of 400 mg of HCQ affects insulin sensitivity and resistance, as assessed by HOMA index, as well as fasting glucose levels [82].
T345 12649-12790 Sentence denotes HCQ remains a worthwhile primary or additional therapy in lupus patients, considering the low cost and its safety profile, also in pregnancy.
T346 12791-12962 Sentence denotes A randomized double-blind study reported the safety of HCQ during pregnancy, correlating this drug with less disease activity and a lower required dose of prednisone [93].
T347 12963-13073 Sentence denotes A 5-year prospective study evaluated the effect of HCQ discontinuation on lupus progression in pregnant women.
T348 13074-13184 Sentence denotes As it occurs in no pregnant people, interruption of HCQ treatment is linked to an exacerbation of the disease.
T349 13185-13381 Sentence denotes Moreover, there are no statistically significant differences regarding pregnant complications with respect to the control, showing no fetal toxicity at a dose of 6.5 mg/kg/day in breast milk [94].
T350 13382-13585 Sentence denotes Fetal safety has been also assessed in women with lupus nephritis by a multicenter study, reporting a reduction of 85% of the possibility of having a small for gestational age baby in patients under HCQ.
T351 13586-13648 Sentence denotes Moreover, it exerted protective effects on fetal growth [120].
T352 13650-13656 Sentence denotes 2.3.3.
T353 13657-13682 Sentence denotes Antiphospholipid Syndrome
T354 13683-13795 Sentence denotes Antiphospholipid syndrome is an autoimmune disorder characterized by antiphospholipid autoantibodies production.
T355 13796-13878 Sentence denotes If it is not associated with other autoimmune diseases, it is called primary [97].
T356 13879-14088 Sentence denotes The incidence of the pathology is greater in young women of reproductive age and it often has a negative impact on pregnancy, with unfortunate outcomes due to the development of placental ischemic pathologies.
T357 14089-14221 Sentence denotes Resonance spectroscopy, indeed, revealed that the fetal brain and placenta are the main targets of autoantibodies localization [95].
T358 14222-14382 Sentence denotes As complement activation plays a central role in the occurrence of the disease, many studies have evaluated the role of HCQ in inhibiting complement activation.
T359 14383-14604 Sentence denotes In a mouse model of obstetric antiphospholipid syndrome, HCQ, administered in a daily dose of 200 μg per mouse limited placental abnormalities, with an increase of fetal survival, by inhibiting complement activation [95].
T360 14605-14751 Sentence denotes A case report on the use of HCQ on a pregnant woman with recurrent venous thromboembolism confirmed the efficacy of HCQ also in clinical practice.
T361 14752-14946 Sentence denotes The addition of 400 mg daily of HCQ to a common therapeutic regimen of aspirin and heparin dramatically reduced the episodes of vascular thrombosis [96], showing great antithrombotic properties.
T362 14947-15045 Sentence denotes Given these results, the mechanisms underlying the use of HCQ in thromboprophylaxis were assessed.
T363 15046-15427 Sentence denotes Two similar preclinical studies, using one-week treatment with 12 μg/g/day of HCQ and three-weeks treatment with 20 mg/kg/day of HCQ, respectively, were in accordance to assess that the overall amelioration of thrombotic status in mice models of antiphospholipid syndrome was linked to endothelial function improvement by modulating the expression of nitric oxide synthase [97,98].
T364 15428-15539 Sentence denotes Moreover, the efficacy of HCQ in antithrombotic therapy may lie in the interference in the coagulation cascade.
T365 15540-15760 Sentence denotes HCQ, indeed, was revealed to decrease the levels of soluble tissue factor, a key initiator of the process, in patients with antiphospholipid syndrome after three months of therapy with a daily dose of HCQ of 200 mg [99].
T366 15762-15768 Sentence denotes 2.3.4.
T367 15769-15785 Sentence denotes Sjögren Syndrome
T368 15786-15900 Sentence denotes Sjögren syndrome is an autoimmune disease with a strong negative impact on the quality of life of affected people.
T369 15901-16030 Sentence denotes The main features of the disease are lymphocytic inflammation and alterations in major salivary glands, causing xerostomia [103].
T370 16031-16185 Sentence denotes Even if preliminary results about HCQ use in Sjögren syndrome were not encouraging, to date it arises as one of the first-line drugs in disease treatment.
T371 16186-16476 Sentence denotes Indeed, an earlier prospective, a two-year double-blind crossover trial on 19 subjects correlated an annual intake of a dose of 400 mg/day with no significant improvements in clinical symptoms and signs of pathology, including tear and salivary gland activity, respect to the placebo [121].
T372 16477-16588 Sentence denotes However, a few years later, the first evidence of HCQ effectiveness in Sjögren syndrome treatment was reported.
T373 16589-16822 Sentence denotes Annual treatment with a dose of 200 mg/day of HCQ showed anti-lymphoproliferative and anti-inflammatory effects, with a reduction of IgG and IgA immunoglobulins, anti-Sjögren autoantibodies, and erythrocyte sedimentation rates [100].
T374 16823-17083 Sentence denotes Moreover, the salivary flow rate increased in Sjögren syndrome women who received a daily dose of 400 mg of HCQ for 30 weeks [101], while eye dryness was alleviated by HCQ administration (6.5 mg/kg), as demonstrated by a prospective study on 32 patients [102].
T375 17084-17242 Sentence denotes Hypo-salivation deriving from acinar atrophy and fibrosis of salivary glands is often associated with over-expression of TGF-β (transforming growth factor-β).
T376 17243-17465 Sentence denotes Treatment with HCQ downregulated TGF-β levels in a randomized trial on NOD mice exposed to doses of 50 mg/kg/day intragastrically (i.g.) for 16 weeks, with significant results in delaying loss of saliva secretory function.
T377 17466-17592 Sentence denotes Moreover, HCQ intake was also accompanied by a decrease in autoantibody production and a lower lymphocytic infiltration [103].
T378 17593-17885 Sentence denotes These findings were confirmed by Wu, Pu, Yu and Li [104], showing that 8-weeks treatment with HCQ administered at a dose of 60 mg/kg i.g. in 40 randomized NOD mice led to lower lymphocytic infiltration, with a significant improvement in pathological changes in submandibular gland morphology.
T379 17887-17893 Sentence denotes 2.3.5.
T380 17894-17902 Sentence denotes Diabetes
T381 17903-18009 Sentence denotes As has already been demonstrated for autoimmune patients, HCQ demonstrated great anti-diabetic properties.
T382 18010-18355 Sentence denotes The first proofs of the role of HCQ in glucose and insulin homeostasis date back to 1999, when Emami, Gerstein, Pasutto, and Jamali [105] demonstrated that diabetic rats treated with oral doses of 80, 120, and 160 mg/kg/day of HCQ exhibited a dose-dependent increase in insulin blood levels, with a consequent reduction of glucose concentration.
T383 18356-18608 Sentence denotes Higher doses of HCQ (200 mg/kg/day) were tested by Abdel-Hamid, A.A. and El-Firgany Ael, D. [106] on diabetic rats, finding an HCQ-mediated decrease in the pancreas, as the mechanism underlying the improvement of the metabolic profile in diabetic rats.
T384 18609-18795 Sentence denotes The same authors associated the beneficial impact of HCQ on insulin resistance in diabetic rats with its ability to restore adipokine balance and reduce endothelial stress markers [113].
T385 18796-18937 Sentence denotes Given the positive outcomes deriving from preclinical studies, the therapeutic potential of HCQ was also assessed in several clinical trials.
T386 18938-19062 Sentence denotes Included in a randomized, double-blinded study of 18 months with 300 mg of HCQ twice a day were 135 diabetic obese patients.
T387 19063-19226 Sentence denotes HCQ treatment improved glycemic control, as demonstrated by the decrease of glycated hemoglobin by up to 1% respect to the placebo, without any side effects [107].
T388 19227-19463 Sentence denotes An open-label longitudinal study engaging 13 obese non-diabetic individuals examined the effects of a dose of 6.5 mg/kg/day of HCQ for six weeks, demonstrating a significant reduction in insulin resistance, assessed by HOMA index [108].
T389 19464-19653 Sentence denotes In a randomized, double-blinded, controlled trial on 39 prediabetic subjects, the effect of 12-week treatment with 6.5 mg/kg/day of HCQ on glycemic status and lipidic profile was evaluated.
T390 19654-19804 Sentence denotes Results reported a significant increase in insulin levels, demonstrating the potential use of HCQ to counteract the risk of developing diabetes [109].
T391 19805-20013 Sentence denotes A randomized double-blind study involving 267 type-2 diabetic patients compared the efficacy of HCQ (400 mg/day) and pioglitazone, a common anti-diabetic drug, in the control of glycemic and lipidic profiles.
T392 20014-20208 Sentence denotes No statistically significant differences emerged between the two medicines in terms of glycated hemoglobin and glucose levels, although both drugs produced an improvement in glycemic parameters.
T393 20209-20311 Sentence denotes Regarding lipidic status, total cholesterol and LDL levels were reduced more by HCQ than pioglitazone.
T394 20312-20430 Sentence denotes Given the good tolerability of the treatment, HCQ may arise as a therapeutic alternative in diabetes management [110].
T395 20432-20438 Sentence denotes 2.3.6.
T396 20439-20493 Sentence denotes Others (Cancer, Inflammation, Cardiovascular Diseases)
T397 20494-20657 Sentence denotes Given the well-recognized properties of HCQ against inflammation, it is easily intuitable that this agent could possess interesting insights into cancer treatment.
T398 20658-20754 Sentence denotes Chronic intestinal inflammation predisposes to the risk of colitis-associated colorectal cancer.
T399 20755-21028 Sentence denotes In vivo, HCQ was demonstrated to interfere with cancer growth at different stages of development, both preventing tumorigenesis in the early phases and inhibiting tumor growth in the late phases in mice treated with azoxymethane and dextran sodium sulfate to induce cancer.
T400 21029-21223 Sentence denotes In terms of animal survival, 120 days treatment with 50 mg/kg of HCQ intraperitoneal injection (i.p.) almost restored the survival rate to pre-treatment values and reduced the size of the tumor.
T401 21224-21502 Sentence denotes The therapeutic effects of HCQ may be attributed to the significant inhibition of pro-tumorigenic and pro-inflammatory cytokines, which not only limited the tumor progression by reducing inflammation of lamina propria, but also decreased the ROS production in macrophages [111].
T402 21503-21652 Sentence denotes Many others are the mechanisms by which HCQ exerts anticancer effects, mainly in synergism with conventional chemotherapic drugs, as discussed later.
T403 21653-21802 Sentence denotes Regarding the cardioprotective effect, this review has already focused on the positive impact of HCQ on cardiovascular issues in autoimmune patients.
T404 21803-22029 Sentence denotes A protective effect of HCQ on neonatal rat cardiomyocytes was proven by Bourke, McCormick, Taylor, Pericleous, Blanchet, Costedoat-Chalumeau, Stuckey, Lythgoe, Stephanou and Ioannou [112] in ischemia-reperfusion animal models.
T405 22030-22147 Sentence denotes The pharmacological preconditioning with HCQ seems to be a good strategy to protect from ischemia-reperfusion injury.
T406 22148-22252 Sentence denotes The pretreatment with daily gavage of 200 mg/kg of HCQ, indeed, reduced the cardiac infarct size by 47%.
T407 22253-22383 Sentence denotes The mechanism underlying this effect is linked to the inhibition of apoptosis and total cell death in neonatal rat cardiomyocytes.
T408 22384-22464 Sentence denotes The atherosclerotic process contributes to increasing the risk of heart failure.
T409 22465-22515 Sentence denotes The etiology of this condition is still not clear.
T410 22516-22711 Sentence denotes A hypothesis supposes that the accumulation of lipids in vessels caused the formation of atherosclerotic plaques that are responsible for vessel narrowing, shear stress, and platelet aggregation.
T411 22712-22845 Sentence denotes HCQ decreased free-fatty acids, triglycerides, total cholesterol, and LDL levels in diabetic rats under doses of 200 mg/kg/day [106].
T412 22846-23040 Sentence denotes Moreover, HCQ (10 mg/kg/day) was demonstrated to exhibit functional and structural protection in 40 high-fat diet mice, by reducing atherosclerotic area by 60% with respect to the control [114].
T413 23041-23181 Sentence denotes These favorable effects at the metabolic level might be due to its anti-inflammatory power that influences many other biological activities.
T414 23182-23372 Sentence denotes In gastrointestinal inflammations, mainly in inflammatory bowel disease, HCQ suppressed pro-inflammatory cytokines and enhanced the expression of ILs involved in anti-inflammatory processes.
T415 23373-23626 Sentence denotes In mouse models of colitis, the HCQ methacryloylated form (30 mg/kg) avoided systemic absorption, accumulating in the gastrointestinal tract, where alterations in the immune homeostasis of the intestinal mucosa had a positive impact on the disease [74].
T416 23627-23732 Sentence denotes Inflammation, together with alterations in the immune system, are at the basis of pulmonary hypertension.
T417 23733-24029 Sentence denotes The ability of HCQ to interfere with the production of pro-inflammatory cytokines from monocytes and lymphocytes might underlie the observed improvements in systolic pressure and ventricular hypertrophy, in rats with pulmonary hypertension treated with 50 mg/kg/day i.p. of HCQ for 20 days [115].
T418 24030-24193 Sentence denotes Likewise, in endometriosis, the abnormal presence of endometrium in other organs leads to a chronic inflammatory status that could be affected by HCQ intervention.
T419 24194-24388 Sentence denotes Ruiz, Rockfield, Taran, Haller, Engelman, Flores, Panina-Bordignon and Nanjundan [116] observed an increment of peritoneal macrophages in mouse models of endometriosis under HCQ (60 mg/kg i.p.).
T420 24389-24539 Sentence denotes In their role of scavengers, abnormalities in these cell populations may lead to an accumulation of endometrial cells, with impairment of the disease.
T421 24540-24710 Sentence denotes Moreover, histopathologic improvement of lesions was observed, probably due to the inhibition of autophagy by HCQ that alters anoikis response of endometrial cells [116].