The development of this protocol followed the recommendations proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols 2015 (PRISMA-P 2015)  (Additional File 1). The preparation of this systematic review will follow the steps described in this protocol; if eventual changes are necessary, they will be properly reported and justified. This systematic review protocol is registered in the International Prospective Register of Systematic Review (PROSPERO) with registration number CRD42021229294. Registration related information can be accessed at http://www.crd.york.ac.uk/PROSPERO.
Is the use of curcumin able to improve CFTR function and clinical outcomes in CF?
Type os study
Observational, experimental (in vitro), and/or interventional (in vivo) original articles will be included, without date and language restrictions. Case reports, letters to the editor and narrative reviews will be excluded.
The studies should characterize the participants as follows: 1) humans with CF, regardless of gender and age; 2) animal models transfected with any type of CF mutation and 3) cell cultures (in vitro) originating from individuals homozygous or heterozygous for any CF mutation.
Studies that used curcumin (alone or in combination) will be included, regardless of the formulations presented (extract, capsule, or powder), in order to promote better expression of CFTR in different gene mutations that compromise its functions.
Studies should demonstrate that comparisons have been made between the therapeutic effect of curcumin with other bioactive compounds or placebo.
Outcomes that demonstrate changes in CFTR maturation, expression, and function after exposure to curcumin, with the consequent restoration of chloride transport across the cell membrane will be considered.
Two researchers will search the studies in the following databases: PubMed–MEDLINE (www.ncbi.nlm.nih.gov/pubmed/), EMBASE (www.embase.com), Cochrane Library (www.cochranelibrary.com), PROSPERO (www.crd.york.ac.uk), SCOPUS (https://www.scopus.com). As a search strategy, descriptors suitable for the research question will be identified from the controlled vocabularies of the Medical Subjects Heading (MeSH) and between terms. The descriptors will be combined using Boolean operators and used to identify the studies of interest. Figure 1 exemplifies the search strategy used in the PubMed database – MEDLINE, which will be replicated in the other databases (Additional File 2).
Selections of studies
The Mendeley reference manager software will be used to tabulate studies and select duplicates. Two independent reviewers (IZA and GMA) will select the studies found by the two-phase search strategy:
Phase 1: screening of titles and abstracts
Reviewers will assess whether selected titles and abstracts meet predetermined eligibility criteria.
Phase 2: screening of articles after reading the full text
The articles selected after reading the titles and abstracts will be read in full and re-analyzed for eligibility criteria. In case of disagreement between reviewers, a third reviewer will be consulted (PSSC).
The selected studies will submit qualitative assessment and data extraction. For a better visualization of the steps related to the selection of studies, the diagram proposed by PRISMA (Preferential Reporting Items for Systematic Reviews and Meta-analyses) will be presented .
Extraction of data
A table will be created in Microsoft Word® (Microsoft Corporation), specifically for the purpose of this review, where the following data will be extracted and tabulated: (1) author, country and year of publication; (2) study design and population characteristics – age, type of genetic mutation, cell lineage; (3) study objectives; (4) intervention – doses of curcumin used, time of exposure to treatment and/or incubation; (5) outcomes - changes in chloride efflux and transport, movement of CFTR towards the plasma membrane, restoration of CFTR expression, change in chloride channel opening time and its functionality, and correction of the nasal potential difference defect.
Assessment of methodological quality
Risk of bias
The risk of bias analysis will be performed using the checklist for Quasi-Experimental Studies, prepared by the Joana Briggs Institute, and recommended by Tran et al., 2021 . The objective of this tool will be to assess the methodological quality of the studies, determining whether the possibility of bias in their design, conduct, and analysis was addressed . This tool contains nine criteria to be judged among: "yes", when the item was correctly reported, "no", when the item was not reported, "not clear", when it is not clear whether the item was reported, and "no applicable”, When is not applicable report the information requested in the item (Additional File 3). The final score will be the number of “yes” scored divided by the maximum score (9) and multiplied by 100.
Assessment of the quality of evidence – GRADE Cochrane
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool will be applied to grade the analysis of the quality of evidence and the strength of the recommendations. Five criteria will be evaluated: 1. methodological limitations (risk of bias); 2. inconsistency (heterogeneity); 3. indirect evidence; 4. imprecision; and 5. publication bias. For each item, a category should be applied: (a) high - we are very confident that the true effect is close to the effect estimate; (b) moderate - we are moderately confident in the effect estimate, and the true effect will likely be close to the effect estimate, but there is a possibility that it will be substantially different; (c) low - our confidence in the effect estimate is limited and the true effect may be substantially different from the effect estimate and (d) very low - we have very little confidence in the effect estimate and the true effect .
The methodological evaluation and quality of evidence will be analyzed independently by two researchers (IZA and PMF). If there is disagreement, a third reviewer will be consulted (PSSC).
A qualitative summary of the evaluation of variables, interventions, outcomes, and any other information relevant to the objectives proposed by the review will be reported in the form of tables or narratives. If appropriate, the characteristics of the variables will be submitted to statistical analysis.