الفهرس 
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Abstract
exposure-related mortality risks, with a little focus on its metal constituents. Surface-adsorbed heavy metals in PM2.5, according to recent scientific work, have a substantial effect on the development of elevated cardiovascular disease (CVD) mortality risk. However, there are few reports on Alexandria’s regional differences in PM2.5 cardiotoxic mechanism in-vivo.
Recently, PM2.5 modulation of endoplasmic reticulum stress has been related to an increased risk of cardiac complications. Although the PERK-eIF2α pathway is implicated in endoplasmic reticulum stress, its paramount contribution in the pathophysiology of PM2.5-induced cardiotoxicity is unknown. With the hypothesized ability of SERCA2a to modify endoplasmic reticulum stress via the PERK-eIF2α axis, the purpose of this work was to evaluate the potential cardioprotective effect of nano-emulsion curcumin (NEC), as a SERCA2a stimulator, against PM2.5-induced heart injury.
Based on these findings, the current study was carried out to investigate the following:
• characterize and quantify the main metals adsorbed on particulate matter (PM2.5) samples collected from Wadi El-Kamar and El-Kafoury sites in Alexandria governorate.
• investigate the toxicological mechanisms by which PM2.5 will affect the cardiac tissue.
• assess the correlation between the region of collected PM2.5 samples, concentration of their metal extract solutions and increasing the risk of cardiotoxicity.
• evaluate the possible antioxidant and anti-inflammatory properties of nano-emulsion curcumin (NEC) against the cardiotoxic effects induced by PM2.5 in rats.
• identify the mechanisms by which NEC will exert its pharmacological effects, if any.
In order to investigate these goals, a total of 60 male rats were used in two expeimental designs;
i. Cardiotoxicity rat model of PM2.5 collected from Wadi El-Kamar and El-Kafoury
A total of 30 male rats were used in this model and randomly arranged into five groups;
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each group consisted of 6 rats as follows:
1. Blank filter (BF); each rat received 1 mL BF extract/kg/day.
2. Industrial concentrated PM2.5 (ICS); each rat received 1 mL ICS extract/kg/day.
3. Industrial diluted PM2.5 (I10X); each rat received 1 mL I10X extract/kg/day.
4. Residential concentrated PM2.5 (RCS); each rat received 1 mL RCS extract/kg/day.
5. Residential diluted PM2.5 (R10X); each rat received 1 mL R10X extract/kg/day.
All extracts were intraperitoneally injected (i.p.) once every day for 25 days.
ii. Protective role of nano-emulsion curcumin (NEC) against PM2.5-induced cardiotoxicity
A total of 30 male rats were used in this model and randomly arranged into five groups; each group consisted of 6 rats as follows:
1. Vehicle (V); each rat received 0.5 mL vehicle/kg/day; 10 min before 1 mL saline/kg/day.
2. Blank filter (BF); each rat received 1 mL BF extract/kg/day.
3. Nano-emulsion curcumin (NEC); each rat received 0.5 mL NEC equivalent to 50 mg curcumin/kg/day; 10 min before 1 mL saline/kg/day.
4. Particulate Matter (PM); each rat received 1 mL PM extract/kg/day.
5. NEC+PM; each rat received 0.5 mL NEC/kg/day; 10 min before 1 mL PM extract/kg/day.
All treatments were given once daily over 25 days, where both vehicle and NEC were taken orally, while saline as well as BF and PM extract solutions were injected i.p.
The animals were slain by cervical dislocation one day after the experiment ended, and their blood was gathered. One heart from each group was separated, fixed with a formalin/glutaraldehyde solution (4:1), and prepared for transmission electron microscopy (TEM) examination. To remove any blood residues, the hearts of the other rats were immersed for 30 seconds in cold phosphate buffered saline (PBS). Each left ventricle was removed and preserved for histological analysis in 10% neutral buffered formalin (pH 7.4) while the remaining heart tissues were kept frozen in liquid nitrogen until further processing.
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All the saline extracts were subjected to determination of the metal constituents by inductively coupled plasma-mass spectrometry (ICP-MS), while the rats’ heart tissue included in this study were subjected to:
I. Detection of oxidative stress markers:
1. Measurement of total antioxidant capacity (TAC).
2. Measurement of Malondialdehyde concentration (MDA).
3. Measurement of Nuclear factor erythroid 2–related factor 2 (Nrf2)
4. Measurement of Hemeoxygenase-1 (HO-1)
II. Detection of Endoplasmic reticulumn stress markers:
5. Measurement of Protein kinase R-like endoplasmic reticulum kinase (PERK)
6. Measurement of Eukaryotic initiation factor-2α (eIF2α)
III. Detection of inflammatory markers:
7. Measurement of Tissue necrosis factor (TNF-α)
8. Measurement of Interleukin-1 beta (IL-1β)
IV. Detection of apoptotic axis biomarkers:
9. Measurement of Activating transcription factor 4 (ATF4)
10. Measurement of C/EBP homologous protein (CHOP)
11. Measurement of caspase-3 (CASP3)
12. Measurement of the cell lymphoma 2 (Bcl-2)
13. Measurement of Bcl-2 associated X protein (Bax)
I. Detection of autophagy axis:
14. Measurement of Phosphatidylinositol 3-kinase (PI3K)
15. Measurement of Protein kinase B (AKT)
16. Measurement of Mammalian target of rapamycin (mTOR)
V. Detection of cardiac damage markers:
17. Measurement of cardiac troponin I (cTnI)
18. Measurement of Pentraxin-3 (PTX3)
19. Measurement of Dwarf open reading frame (DWORF)
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VI. Detection of cardiac protein expession of:
20. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a)
21. Phospholamban (PLN)
VII. Histopathological examination of cardiac tissue
22. using H & E stain and Sirus red special stain
VIII. Transmission electron microscope (TEM) examination of cardiac tissue
The critical metal composition of PM2.5 collected from Wadi El-Kamar and El-Kafoury regions during Autumn can be summarized as follows;
- the average total mass of PM2.5 particles collected on filters for industrial and residential sites was 59.027 and 83.333 μg/m3, respectively.
- Metal analysis of PM2.5 extract solutions showed the presence of several heavy metals, main elements, and trace metals in both concentrated (CS) and diluted 10X solutions of Wadi El-Kamar (as an industrial site; ICS & I10X) and El-Kafoury (as a residential site; RCS & R10X).
- Various toxic metals such as Lead, Silver, Cadmium, Copper, Cobalt, Nickle, and Mercury were reported, but of low levels in all extract solutions except for that of ICS.
- The most prevailing toxic metals were Manganese, Iron, Zinc, and chrome, however, the ICS extract solution presented the highest conentrations.
- A strong correlation between the levels of Zn, Mn, and Fe soluble fractions of PM2.5 in both areas and all the cardiac dysfunction biomarkers.
The effect of PM2.5 collected from Wadi El-Kamar region (ICS & I10X) on assessed parameters compared to the blank filter (BF) group can be summarized as follows;
- An apparent decrease in the expressions of DWORF for both ICS & I10X group.
- A significant increase in cardiac PTX3 expression and serum cTnI for both ICS & I10X group.
- Significant reductions in HO-1 levels, and TAC with a marked rise in MDA level for both ICS & I10X group.
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- Significant increases in the levels of TNF-α and IL-1β for both ICS & I10X group.
- Strong immunopositive signals of Bax and caspase-3 with a weak signals of Bcl-2 for both ICS & I10X group.
- In ICS group, a sever widespread Zenker’s necrosis in multi-individual myocardial cells and in the myocardial cells around the blood vessels was recorded with a strong inflammation, while I10X group represented an obvious Zenker’s necrosi