Can Coenzyme Q₁₀ Improve Clinical and Molecular Parameters in Fibromyalgia?

Lee S.K., Lee J.O., Kim J.H., Kim N., You G.Y., Moon J.W., Sha J., Kim S.J., Lee Y.W., Kang H.J., Park S.H., Kim H.S.

Coenzyme Q10(CoQ10) is a known anti-adipogenic factor. However, the mechanism by which CoQ10 acts is unclear. In this study, we found that CoQ10 increased the phosphorylation of AMP-activated protein kinase (AMPK) in 3T3-L1preadipocytes. CoQ10 induced an increase in cytoplasmic calcium concentrations, which is reflected by increased Fluo-3 intensity under confocal microscopy recording. Either inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) or knock-down CaMKK blocked CoQ10-induced AMPK phosphorylation, suggesting the involvement of calcium in CoQ10-mediated AMPK signaling. CoQ10 also increased the expression of peroxisome proliferator-activated receptor alpha (PPARα) at both the mRNA and protein levels. Knock down of AMPK with siRNA or inhibition of AMPK using an AMPK inhibitor compound C blocked CoQ10-induced expression of PPARα, indicating that AMPK plays a critical role in PPARα induction. In addition, CoQ10 increased fatty acid oxidation in 3T3-L1preadipocytes. The promoter activity of PPARα was increased by CoQ10 in an AMPK-dependent fashion. Moreover, the induction of acyl-CoA oxidase (ACO), a target gene of PPARα, was blocked under the PPARα knock down condition. Furthermore, treatment with CoQ10 blocked differentiation-induced adipogenesis. This blockade was not observed under the PPARα knock-down condition. Collectively, these results demonstrate that CoQ10 induces PPARα expression via the calcium-mediated AMPK signal pathway and suppresses differentiation-induced adipogenesis.

Cordero M.D., Díaz-Parrado E., Carrión A.M., Alfonsi S., Sánchez-Alcazar J.A., Bullón P., Battino M., de Miguel M.

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress, and inflammation in FM. We studied 30 women diagnosed with FM and 20 healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of coenzyme Q₁₀ (CoQ₁₀) and mtDNA contents and high level of mitochondrial reactive oxygen species (ROS) and serum tumor necrosis factor (TNF)-alpha and transcript levels. A significant negative correlation between CoQ₁₀ and TNF-alpha levels (r=-0.588; p

Hardie D.G., Ross F.A., Hawley S.A.

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.

Tsai K., Chen L., Chiou S., Chiou G., Chen Y., Chou H., Chen L., Chen H., Chiu T., Tsai C., Ou H., Kao C.

The lectin-like oxidized low-density lipoprotein receptor (LOX-1) is one pivot receptor for oxidized low-density lipoprotein (oxLDL) in human endothelial cells. Co-enzyme Q10 (Co Q10) has been widely used in clinical intervention. However, the molecular mechanisms underlying its protective effects against oxidative stress in endothelial cells are still largely unknown. This study was designed to test the hypothesis that Co Q10 mitigates oxLDL-induced endothelial oxidative injuries via modulation of LOX-1-mediated reactive oxygen species (ROS) generation and explored the role of AMP-activated protein kinase (AMPK), a negative regulator of NADPH oxidase.Human umbilical vein endothelial cells (HUVECs) were pretreated with Co Q10 and then incubated with oxLDL for 24 h. Co Q10 attenuated oxLDL-elicited LOX-1 expression and ROS generation by suppression of NADPH oxidase activation. Co Q10 rescued dephosphorylation of AMPK caused by oxLDL that in turn led to an activation of NADPH oxidase by PKC. The results were confirmed using AMPK siRNA. Moreover, oxLDL-suppressed Akt/eNOS and enhanced p38 phosphorylation, which in turn activated NF-κB pathway. These detrimental events were ameliorated by Co Q10.These results provide new highlight onto the possible molecular mechanisms of how Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway.

Colombo S., Moncada S.

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKα1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKα1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, γ-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKα1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKα1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKα1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.

Bazzichi L., Giannaccini G., Betti L., Fabbrini L., Schmid L., Palego L., Giacomelli C., Rossi A., Giusti L., De Feo F., Giuliano T., Mascia G., Bombardieri S., Lucacchini A.

To evaluate the intracellular levels of the high energy adenosine triphosphate nucleotide ATP and essential divalent cations, calcium and magnesium, in platelets of patients affected by primary fibromyalgia syndrome (FMs).Platelet ATP and cation concentrations were measured in 25 patients affected by FMs and 25 healthy volunteers through a chemiluminescent and a fluorimetric assay, respectively.Significant lower ATP levels were observed inside platelets of FM patients (fmol ATP/plt: 0.0169+/-0.0012 vs. healthy controls, fmol ATP/plt: 0.0306+/-0.0023, mean+/-SEM) (*** P

Lister R.

An open, uncontrolled study was undertaken to measure the subjective effects of coenzyme Q10 combined with a Ginkgo biloba extract in volunteer subjects with clinically diagnosed fibromyalgia syndrome. Anecdotal reports from patients with fibromyalgia syndrome have claimed benefits from the use of these supplements. The aim of this study was to determine if these reports could be substantiated in a pilot clinical trial. Patient questioning had determined that poor quality of life was a major factor in the condition and a quality-of-life questionnaire was used to measure potential benefit. Subjects were given oral doses of 200 mg coenzyme Q10 and 200 mg Ginkgo biloba extract daily for 84 days. Quality of life was measured, using the well-validated Dartmouth Primary Care Cooperative Information Project/World Organization of Family Doctors (COOP/WONCA) questionnaire that measures seven different subjective responses, at 0-, 4-, 8- and 12-week intervals. The subjects were asked for an overall self-rating at the end of the study. A progressive improvement in the quality-of-life scores was observed over the study period and at the end, the scores showed a significant difference from those at the start. This was matched by an improvement in self-rating with 64% claiming to be better and only 9% claiming to feel worse. Adverse effects were minor. A controlled study is now planned.

Bradford M.

Pan S., Luo L.

Xie S., Marques-Vidal P., Kraege V.

Abstract Purpose The consumption of vitamin/mineral supplements (VMS) and vitamin/mineral and/or dietary supplements (VMDS) is popular among the general population. However, the association of VMS/VMDS with fatigue remains sparse and conclusions are mixed. We aimed to understand the association between VMS/VMDS and fatigue. Methods Prospective study in the city of Lausanne, Switzerland, including 1361 participants (50.3% female, mean age 61.0 ± 9.4 years). Participants were divided into VMS/VMDS users and non-users. Fatigue levels were assessed using the Fatigue Severity Scale (FSS) and the 14-item version of the Chalder Fatigue Scale (CFS). Statistical analyses included multivariable logistic regression for categorical outcomes and analysis of variance for continuous outcomes, adjusting for relevant covariates. Results No association was found between VMS consumption and changes in FSS (mean ± standard error 0.05 ± 0.03 vs. -0.06 ± 0.14 for non-consumers and consumers, respectively, p = 0.440) and CFS (-0.05 ± 0.06 vs. 0.22 ± 0.28, p = 0.388). Similarly, no effect of VMS consumption was found on incidence odds ratio and 95% confidence interval: 1.75 (0.82–3.74), p = 0.149 or remission 1.36 (0.49–3.74), p = 0.550 of clinical fatigue. Similar findings were obtained for VMDS: FSS 0.06 ± 0.04 vs. 0 ± 0.08, p = 0.577; CFS − 0.07 ± 0.08 vs. 0.04 ± 0.15, p = 0.545 for non-consumers and consumers, respectively. OR 1.96 (1.20–3.20), p = 0.008 and 1.14 (0.57–2.31), p = 0.712 for incidence and remission of fatigue. Alternate or persistent VMS/ VMDS consumers had a higher incidence of clinical fatigue and a higher increase in FSS compared with never consumers. Conclusion In this population-based sample, we found no consistent association between VMS or VMDS consumption and remission of fatigue. Conversely, VMDS users tended to develop greater fatigue.

Wang R., Liu Y., Jiang Y., Zhang Y., Zhang Y., Wang B., Lu H., Su H., Liao W., Liu L., Li F., Zhang W., Ma S.

Mantle D., Hargreaves I.P.

Some 90 autoimmune disorders have been described in medical literature, affecting most of the tissues within the body. Autoimmune disorders may be difficult to treat, and there is a need to develop novel therapeutic strategies for these disorders. Autoimmune disorders are characterised by mitochondrial dysfunction, oxidative stress, and inflammation; there is therefore a rationale for a role for coenzyme Q10 in the management of these disorders, on the basis of its key role in normal mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. In this article, we have therefore reviewed the potential role of CoQ10, in terms of both deficiency and/or supplementation, in a range of autoimmune disorders.

Carvalho J.F., Skare T.

Summary Coenzyme Q10 (CoQ10) is a potent antioxidant and anti-inflammatory substance used to treat some rheumatic diseases. Our objective was to review the use of CoQ10 in rheumatic diseases. PubMed/Medline, Embase, Scopus, and Web of Science databases were searched for articles on CoQ10 and rheumatic diseases between 1966 and April 2023. Twenty articles were found, including 483 patients. The investigated conditions were Fibromyalgia (FM) with 15 studies, Rheumatoid Arthritis (RA) with 3 studies, and Antiphospholipid Syndrome (APS) with 2 studies. After CoQ10 supplementation, RA patients observed improvements in disease activity index, inflammatory biomarkers (erythrocyte sedimentation rate), cytokine levels, and a decrease in malondialdehyde. In APS, CoQ10 improved endothelial function and decreased prothrombotic and proinflammatory mediators. Regarding FM, in most of the studies, the patients observed improvements in pain, fatigue, sleep, tender points count, mood disorders, and scores on the Fibromyalgia Impact Questionnaire (FIQ). The drug was well tolerated, with reports of minor side effects in two studies. CoQ10 supplementation seems to be efficacious as a complementary treatment for RA and FM. Upcoming studies with larger samples and including other rheumatic diseases are welcome.

Mantle D., Hargreaves I.P., Domingo J.C., Castro-Marrero J.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown causes characterised by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS); fibromyalgia (FM); and more recently post-COVID-19 condition (long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. The accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and long COVID. To address this issue, this article aims to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, it aims to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Napiórkowska-Baran K., Schmidt O., Szymczak B., Lubański J., Doligalska A., Bartuzi Z.

A strong relationship exists between immune dysfunction and cardiovascular disease. Immune dysregulation can promote the development of cardiovascular diseases as well as exacerbate their course. The disorders may occur due to the presence of primary immune defects (currently known as inborn errors of immunity) and the more common secondary immune deficiencies. Secondary immune deficiencies can be caused by certain chronic conditions (such as diabetes, chronic kidney disease, obesity, autoimmune diseases, or cancer), nutritional deficiencies (including both lack of nutrients and bioactive non-nutrient compounds), and medical treatments and addictive substances. This article unravels the molecular linkage between the aforementioned immune system disorders and atherosclerosis.

Hou S., Tian Z., Zhao D., Liang Y., Dai S., Ji Q., Fan Z., Liu Z., Liu M., Yang Y.

ScopeCoenzyme Q10 (CoQ10) has become a popular nutritional supplement due to its wide range of beneficial biological effects. Previous meta‐analyses show that the attenuation of CoQ10 on inflammatory biomarkers remains controversial. This meta‐analysis aims to assess the efficacy and optimal dose of CoQ10 supplementation on inflammatory indicators in the general population.Methods and resultsDatabases are searched up to December 2022 resulting in 6713 articles, of which 31 are retrieved for full‐text assessment and included 1517 subjects. Double‐blind randomized controlled trials (RCTs) of CoQ10 supplementation are eligible if they contain C reactive protein (CRP), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). CoQ10 supplementation can significantly reduce the levels of circulating CRP (SMD: −0.40, 95% CI: [−0.67 to −0.13], p = 0.003), IL‐6 (SMD: −0.67, 95% CI: [−1.01 to −0.33], p < 0.001), and TNF‐α (SMD: −1.06, 95% CI: [−1.59 to −0.52], p < 0.001) and increase the concentration of circulating CoQ10.ConclusionThis meta‐analysis provides evidence for CoQ10 supplementation to reduce the level of inflammatory mediators in the general population and proposes that daily supplementation of 300–400 mg CoQ10 show superior inhibition of inflammatory factors.

Barnish M., Sheikh M., Scholey A.

Fatigue, characterised by lack of energy, mental exhaustion and poor muscle endurance which do not recover following a period of rest, is a common characteristic symptom of several conditions and negatively impacts the quality of life of those affected. Fatigue is often a symptom of concern for people suffering from conditions such as fibromyalgia, chronic fatigue syndrome, cancer, and multiple sclerosis. Vitamins and minerals, playing essential roles in a variety of basic metabolic pathways that support fundamental cellular functions, may be important in mitigating physical and mental fatigue. Several studies have examined the potential benefits of nutrients on fatigue in various populations. The current review aimed to gather the existing literature exploring different nutrients’ effects on fatigue. From the searches of the literature conducted in PubMed, Ovid, Web of Science, and Google scholar, 60 articles met the inclusion criteria and were included in the review. Among the included studies, 50 showed significant beneficial effects (p < 0.05) of vitamin and mineral supplementation on fatigue. Altogether, the included studies investigated oral or parenteral administration of nutrients including Coenzyme Q10, L-carnitine, zinc, methionine, nicotinamide adenine dinucleotide (NAD), and vitamins C, D and B. In conclusion, the results of the literature review suggest that these nutrients have potentially significant benefits in reducing fatigue in healthy individuals as well as those with chronic illness, both when taken orally and parenterally. Further studies should explore these novel therapies, both as adjunctive treatments and as sole interventions.

Mantle D., Hargreaves I.P.

In this article we have reviewed the potential role of coenzyme Q10 (CoQ10) in the pathogenesis and treatment of a number of less common age-related disorders, for many of which effective therapies are not currently available. For most of these disorders, mitochondrial dysfunction, oxidative stress and inflammation have been implicated in the disease process, providing a rationale for the potential therapeutic use of CoQ10, because of its key roles in mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. Disorders reviewed in the article include multi system atrophy, progressive supranuclear palsy, sporadic adult onset ataxia, and pulmonary fibrosis, together with late onset versions of Huntington’s disease, Alexander disease, lupus, anti-phospholipid syndrome, lysosomal storage disorders, fibromyalgia, Machado-Joseph disease, acyl-CoA dehydrogenase deficiency, and Leber’s optic neuropathy.

Amini P., Sajedi F., Mirjalili M., Mohammadi Y., Mehrpooya M.

We hypothesized that the addition of coenzyme Q10 (CoQ10) to pregabalin might be helpful in improving symptoms in patients suffering from painful diabetic neuropathy (PDN). One hundred twelve patients with PDN were randomly allocated to receive CoQ10 + pregabalin (57 patients) or placebo + pregabalin (55 patients). Besides pregabalin (150 mg/day), the patients, upon their group assignment, received CoQ10 at a dosage of 100 mg every 8 h or matched placebo for 8 consecutive weeks. The primary efficacy measure was the changes in the pain intensity from baseline to endpoint measured on an 11-point NRS (numeric rating scale). Secondary efficacy measures included the changes in the pain-associated sleep interference score (SIS) as well as the patients’ global improvement with treatment measured on the Clinicians’ and Patients’ Global Impression of Change (CGIC/PGIC). On the intent‑to‑treat population (ITT) analysis, the CoQ10 + pregabalin regimen resulted in significantly greater pain relief than the placebo + pregabalin regimen. By the end of week 2, the decrease in the mean pain NRS score was similar in both groups, but at the end of weeks four and eight, the decrease in the mean pain NRS score was significantly greater in patients taking CoQ10 + pregabalin than in those taking placebo + pregabalin (p value = 0.01 and < 0.001, respectively). Likewise, at the end of week 8, the decrease in the pain-associated SIS was significantly greater in the patients supplemented with CoQ10 compared to placebo. Furthermore, the proportion of the responder patients (those having ≥ 50% decline in the mean pain NRS score) as well as the proportion of patients rated ‘‘very much’’ or ‘‘much improved’’ on the CGIC/PGIC scales were also significantly higher in the CoQ10 + pregabalin-treated patients than placebo + pregabalin-treated patients. Our data support the idea that diabetic patients suffering from PDN may benefit from using antioxidant and anti-inflammatory supplements like CoQ10. However, further studies are required before supplementation with CoQ10 can be recommended for treating PDN. Trial registration. The trial was registered at Iranian Registry of Clinical Trials (identifier code: IRCT20120215009014N385). Registration date: 2021–02-21.

Tippairote T., Bjørklund G., Gasmi A., Semenova Y., Peana M., Chirumbolo S., Hangan T.

Coenzyme Q10 (CoQ10) is a compound with a crucial role in mitochondrial bioenergetics and membrane antioxidant protection. Despite the ubiquitous endogenous biosynthesis, specific medical conditions are associated with low circulating CoQ10 levels. However, previous studies of oral CoQ10 supplementation yielded inconsistent outcomes. In this article, we reviewed previous CoQ10 trials, either single or in combination with other nutrients, and stratified the study participants according to their metabolic statuses and medical conditions. The CoQ10 supplementation trials in elders reported many favorable outcomes. However, the single intervention was less promising when the host metabolic statuses were worsening with the likelihood of multiple nutrient insufficiencies, as in patients with an established diagnosis of metabolic or immune-related disorders. On the contrary, the mixed CoQ10 supplementation with other interacting nutrients created more promising impacts in hosts with compromised nutrient reserves. Furthermore, the results of either single or combined intervention will be less promising in far-advanced conditions with established damage, such as neurodegenerative disorders or cancers. With the limited high-level evidence studies on each host metabolic category, we could only conclude that the considerations of whether to take supplementation varied by the individuals’ metabolic status and their nutrient reserves. Further studies are warranted.

Campisi L., La Motta C.

The coenzyme Q10 is a naturally occurring benzoquinone derivative widely prescribed as a food supplement for different physical conditions and pathologies. This review aims to sum up the key structural and functional characteristics of Q10, taking stock of its use in people affected by fibromyalgia. A thorough survey has been conducted, using Pubmed, Scifinder, and ClinicalTrials.gov as the reference research applications and registry database, respectively. Original articles, reviews, and editorials published within the last 15 years, as well as open clinical investigations in the field, if any, were analyzed to point out the lights and shadows of this kind of supplementation as they emerge from the literature.

Tsai I., Hsu C., Chang C., Tseng P., Chang K.

Coenzyme Q10 (CoQ10) is a popular nutritional supplement, an antioxidant and an essential component of the mitochondrial electron transport chain. Several clinical studies have suggested that fatigue can be reduced by antioxidant supplementation. However, the data on this topic has been sparse to date. Hence, we conducted this meta-analysis with the aim of investigating the effectiveness of fatigue reduction via CoQ10 supplementation. More specifically, we searched electronic databases for randomized controlled trials (RCTs) published from the database inception to January 2022. A random effects model was implemented to conduct the meta-analysis among 13 RCTs (with a total of 1,126 participants). As compared with the placebo groups evaluated in each RCT, the CoQ10 group showed a statistically significant reduction in fatigue scores (Hedges’ g = −0.398, 95% confidence interval = −0.641 to −0.155, p = 0.001). The directions of the treatment effects were consistent between the healthy and diseased participants. Compared with the placebo group, the effect of reducing fatigue was statistically significant in the subgroup using the CoQ10-only formulation but not in the subgroup using CoQ10 compounds. The results of our meta-regression demonstrate that increases in the daily dose (coefficient = −0.0017 per mg, p &lt; 0.001) and treatment duration (coefficient = −0.0042 per day, p = 0.007) of CoQ10 supplementation were correlated with greater fatigue reduction. There was only one adverse (gastrointestinal) event in the 602 participants who underwent the CoQ10 intervention. Based on the results of this meta-analysis, we conclude that CoQ10 is an effective and safe supplement for reducing fatigue symptoms.Systematic Review Registration:https://inplasy.com/inplasy-2022-1-0113/, identifier INPLASY202210113

Xu Lou I., Gil-García E., Cáceres-Matos R., Ali K., Molina E.

ObjectivesChronic pain (CP) is an unpleasant emotional and sensory experience that can be accompanied by tissue damage that persists for more than 3 months. Recent studies show that certain nutritional strategies can help to improve pain, so this study is aimed to systematically review scientific evidence to understand and map the effect of the use of nutritional strategies on the presence or intensity of chronic non-cancer pain (CNCP) and the association of these nutritional aspects with the presence or intensity of CNCP.Study designA systematic review.MethodsTwo independent researchers searched for randomized clinical trials (RCTs) and observational studies that explored the relationship between nutrition and CNCP in adults from 2010 to 2020 in PubMed, Web of Science, Scopus, and Cochrane Library databases. A total of 24 studies were included, of which 20 were RCTs and 4 were observational studies. They are classified into the administration of nutritional supplements, dietary modification, and incorporation of food.ResultsOf these studies, those that have a significant effect on pain are dietary modification and the use of nutritional supplements. On the other hand, the main results from the few observational studies included in this review point to the existence of an association relationship between less pain and a ketogenic or hypocaloric diet or adherence to the Mediterranean diet.ConclusionDietary modification seems to be one plausible therapeutic option to improve and relieve CNCP. However, more research is needed in this regard to obtain better conclusions.Systematic Review Registration[www.crd.york.ac.uk/prospero], identifier [CRD42021226431].