INTRODUCTION:

The new Corona virus or severe acute syndrome (SARS-Cov-2) has spread rapidly from Wuhan, Hubei Province, China, to all parts of the world¹. The rapid and continuous spread of Covid-19 poses a serious threat to human health in particular and to the global economy in general ². The virus has spread to all countries and continents around the world, recording 453 million cases and 6.03 deaths³, most patients suffer from high temperature, shortness of breath, cough and pneumonia , and in severe cases it develops into respiratory failure or organ failure⁴.

Virus detection and diagnosis through the polymerase chain reaction test via nasopharyngeal smear, some laboratory tests and computerized tomography⁵, as they showed low lymphocytosis and high CRP, Ferritin, D. dimer predicting the severity and severity of infection with the virus⁶. ACE2 is the entry point of the virus into the human body, which is expressed in lung cells, renal tubules, and vascular endothelium⁷ . The spike of COVID-19 formed a trimer and interacted with angiotensin-converting enzyme 2 (ACE2), initiating the viral infection. The E-protein could create an ion channel, which facilitated the viral material to enter into the host cell, and an N protein initiated the binding of the host protein to host DNA, while the M protein was important in viral morphogenesis. Accessory proteins included 3a, 6, 7a,7b, 8 and 9b, which were suggested to regulate the immunity of host ⁸⁹ as shown in Figure 1.

Figure 1. Transmission and life cycle of SARS-CoV-2 causing COVID-19. SARS-CoV-2 is transmitted via respiratory droplets of infected cases to oral and respiratory mucosal cells ¹⁰.

The vaccine against COVID-19 is our main hope in tackling the coronavirus pandemic and returning to everyday life ¹¹¹², scientists have begun to develop a special vaccine based on live cells mRNA, as a message from the coronavirus is copied and used to make a spike protein that works to enter the human cell because it combines with ACE2 and causes Covid-19 infection ¹³^,¹⁴. The protein does not cause infection, but it stimulates the body to recognize the virus and form immune bodies. Vaccines have proven effective by 95% ¹⁵^,¹⁶. So, the aim of the study is to measure the gene expression of ACE2 and compare it with the studied groups, measure biochemical indicators and compare them between males and females in the groups, and know the extent of the effect of the vaccine’s efficacy.

ATERIALS AND METHODS:

1-Sample Collection:

In the period from November 2021 to February 2022, all samples were collected in the private Central Al-Tamyaz Laboratory for pathological analyzes, Ramadi Teaching Hospital, and the Al-Anbar health department. Their ages ranged between (17-75) years, 5ml of blood was withdrawn for 80 samples divided into four groups, each groups includes 20 samples divided into 10 males and 10 females, (Healthy Groups ) ، (Patient Groups ) , (Healthy Vaccine Recipient Groups)، (Patient Vaccine Recipient Groups). In this analysis, according to the ethics of scientific research.

2-Assessment of biomarker levels:

Both of D-dimer ,and ferritin levels are tested using automated Mini-Vidas system (Biomerieux, France). Reference range of less than 500 ng/ml for D-dimer and 28 -390 ng/ml for ferritin. On other hand , CRP were evaluated using a specific automated protein analyzer (PA120) provided by (Shenzhen Genius Electronics Co., Ltd. China 2019). Serum samples for each of the patients and healthy persons were applied to the instrument then the concentrations of CRP is calculated automatically.

3-Assessment of renal function test:

The serum separated from the blood by centrifligation was used, in duplicates, for the estimation of urea and creatinine according to the manufacturer's instructions.

4- Extraction RNA and real time-PCR (qRT-PCR):

500 µL of blood sample was used and 100 µL of Trizol reagent was added to extract the RNA. The RNA was converted into cDNA using a special kit supplied by the Korean company BIONEER according to the company’s instructions. Then real-time quantitative reverse transcription (Real-Time q RT-PCR) technology was used to quantify the gene expression of the study gene ACE2 and the titration gene β-actin as shown in )Table 1). the data were partially calculated using the Livak equation and according to the method ¹⁷.

Table 1: shows the primers used in the molecular study.

Human Gene	Sequence 5’ – 3’	bp	NCBI Reference
β-actin	5´-CTGGAACGGTGAAGGTGACA-3´
β-actin	5´- AAGGGACTTCCTGTAACAATGCA-3´	146	NM_001101.5
ACE2	5´-TTCAAGGAGGCCGAGAAGTTC-3´	100	AB046569.1
ACE2	5´-TCTGAACATTTCCTGGGTCCG-3´	100	AB046569.1

5-Statistical analysis

The results were statistically analyzed using the SPSS program (Spss, 2011) and using the Analysis of Variance (ANOVA Table) to calculate the variance, covariance, correlation and test the averages using the least significant difference test L.S.D at the probability level of 0.05. The averages were also compared using the standard error in addition to Duncan's Multiple Range Test at the level of significance (P ≤ 0.01, P ≤ 0.05). The Correlation Matrix Person's Correlation Matrix was used between the biochemical analyzes and the molecular tests using the equation ¹⁸.

RESULTS AND DISCUSSION:

Molecular Biology:

The results show in (Fig.1.A) there are significant differences between G2M and between G3M , G4M at the level (P≤ 0.05) ، there are no significant differences between the G2M and G1M at the same level. there were significant differences between the G2F and all groups، there was also a significant difference between the G4F and the G3F at the level of significance (P≤ 0.01). (Fig .1.B) It showed that there was a significant difference in the G2M at the level (P≤ 0.05), as well as the presence of a significant and apparent difference at the level (P≤ 0.05) in G3F and betweenG3M , and there was a significant difference between G4M. And between the G4F , the results showed that there was a significant and high phenotypic difference among the G2F compared with the studied groups and males at the level (P≤ 0.05), as well as the presence of a significant difference among the G3F compared with the males and other groups at the level (P≤ 0.05) , and there was also a seemingly low significant difference among G4F and between males and other groups at the level of significance (P≤ 0.05).

(Fig.1.A) shows the ACE2 gene expression in males and females in the groups studied for COVID-19. G1M healthy males , G2M Patient males, G3M healthy males vaccine recipients, G4M Patient males vaccine recipients, G1F healthy females , G2F Patient females , G3F healthy females vaccine recipients, G4f Patient females vaccine recipients, lowercase letters indicate significant differences at the level (P ≤ 0.05, P ≤ 0.01).

(Fig. 1.B) shows the gene expression of ACE2 gene and the interactions between groups, G1M healthy males , G2M Patient males, G3M healthy males vaccine recipients, G4M males Patient vaccine recipients, G1F healthy females , G2F Patient females , G3F healthy females and vaccine recipients, G4f Patient females vaccine recipients, lowercase letters indicate significant differences at the level (P ≤ 0.05, P ≤ 0.01).

There were no sex-related differences in the activity of ACE2 enzyme in the blood in healthy individuals ¹⁹, However, ACE2 enzyme activity in serum was observed to be higher in women older than 55 years compared to women younger than 55 years, with no difference in ACE2 activity in the serum of older and young men. [19] confirmed that there was no difference in ACE2 enzyme level in the serum of men compared to women. Viral respiratory infections are the most common cause of acute asthma exacerbations in children and adults, ACE2 expression was lower in those with high levels of allergic sensitization and asthma compared to healthy people ²¹. Studies show that the high frequency of Covid-19 in patients receiving ACE inhibitors or angiotensin receptor blockers is not due to these drugs, but because the patients were often older or suffering from high blood pressure or diabetes ²². It is known that high blood pressure significantly reduces ACE2 expression, so patients with high blood pressure are more likely to have ACE2 levels below a certain threshold, making them more susceptible to severe lung disease ²³.

Inactivated or attenuated vaccines that contain the S protein expressed in pseudo viruses or virus-like particles can bind to the available ACE2, and the mACE2 complex can bind to ACE2 resulting in an overall decrease of ACE2 resulting in elevated (Ang II) in the same way that the original virus does it dangerously for sick individuals and the elderly, healthy individuals can overcome the vaccine-induced Ang II elevation ²⁴. The official US report found that the death rate for men is 55%, while women are 45% from a biological and immune point of view. Women usually have a stronger and faster immune response than men, while some researchers discovered that estrogen and testosterone may affect the response to the new Corona virus ²⁵ as estrogen regulates ACE2 which has been suggested as a protective mechanism against organ damage by SARS-COV-2 ²⁶. Studies have shown the difference between the sexes in the response to vaccines, where women give a response to the vaccine and the formation of higher antibodies to vaccination against most vaccines, diseases such as seasonal influenza, etc. than men ²⁷, Immunity depends on the production of antibodies to achieve self-protection from infectious diseases that require antibodies for resistance. Women tend to show fewer cases and weaker disease cycles when compared to men, and the effect of vaccination to produce protective antibodies to prevent infectious diseases is often better in women compared to men ²⁸ The results of the statistical analysis in (Fig .2) There is a significant difference at the level of (P ≤ 0.05) for D.dimer between males and females in the healthy group, and the presence of a significant difference for ferritin at the level of (P ≤ 0.05 ) in the healthy group.

Fig.2: The average values of biochemical traits for healthy males and females .

The results in (Fig.3) showed that there was a statistically significant difference at the level (P ≤ 0.05) for (Ferritin, D. dimer, LDH) between males and females in the Patient group.

Fig.3: The average values of biochemical traits for Patient males and females .

The results of the statistical analysis in (Fig 4) indicate that there are no statistically significant differences between males and females in the healthy group that received the vaccine.

Fig. 4: The average values of biochemical traits for healthy vaccine recipients males and females .

(Fig.5) showed that there was a statistically significant difference at the level (P ≤ 0.05) for (Ferritin, D.dimer, CRP) between males and females in the Patient vaccine recipients group.

Fig. 5: The average values of biochemical traits for Patient vaccine recipients males and females.

The results in (Fig.6) showed that there was a high significant difference for Urea in females compared to males in the two groups of healthy and Patient people at the level (P ≤ 0.05), while in the group of Patient people who received the vaccine, it showed a significant increase for males at the level (P ≤ 0.05) compared to females.

Fig. 6: Average urea values in males and females between groups.

(Fig.7) The results showed that there was a significant difference in Creatinine for males in the Patient group at the level (P ≤ 0.05) compared to females, as well as significant differences for females at the level (P ≤ 0.05) compared to males in the group of patients who received the vaccine, and no significant differences appeared in the other groups.

Fig. 7: Average Creatinine values in males and females between groups.

Table (2) showed highly significant relationships at the level (0.01) between D.dimer, Ferritin, Urea, LDH with ACE2 , as well as between D.dimer with (Urea, LDH, Ferritin) , also indicated that there is a relationship between Ferritin with ( LDH, Urea, Creatinine) , and also between Urea and Creatinine.

D. dimer is a biological indicator of fibrin formation, It is considered one of the important protein compounds that are produced in the event of blood clots in the body, and its levels are low in normal conditions and high levels within the body indicate the occurrence of pathological conditions and works to break down blood clots ²⁹. Several studies have confirmed that the level of D. dimer in healthy people is lower in males compared to females, Associated with Covid-19 infection with a high level of D. dimer, high levels of D. dimer cause venous thromboembolism, which contributes to respiratory deterioration associated with Covid-19 infection, female sex was a major risk factor for the development of high D. dimer, a study was conducted in more than 20 countries on people who received the vaccine, where high D. dimer was observed in the majority of women aged 55 years or less ³⁰³¹³². The value of Ferritin was also shown , which is a protein for storing iron inside cells and is a sign of iron storage in the blood. Its normal levels in the blood vary its average in males and females before menopause is ˃300 µg/L and ˃200 µg/L in premenopausal women. It is of unlimited value and is released from damaged liver cells and its levels are raised in inflammatory disorders, liver disease, excessive alcohol consumption and malignant diseases. The concentration of ferritin in males is twice its concentration in females, and in a study conducted on people infected with COVID-19, it was noted that all infected individuals, especially severe infections, showed a higher level of ferritin in their blood compared with healthy people ³³³⁴. That patients who recovered from COVID-19 disease had a clear decrease in their ferritin level, which confirms that the high level of ferritin in the blood is associated with infection with COVID-19. Therefore, ferritin is an important predictor of infection with COVID-19 ³⁵³⁶.

CRP It is an inflammatory protein produced by the liver in acute injuries, and it is raised in several cases, such as inflammation, cardiovascular disease, viral and bacterial infections, Where CRP binds to pathogens and promotes their elimination by phagocytic cells that act as the host's first line of defense, in healthy subjects CRP is found in plasma and is usually less than 10 mg/L in males and females, Also CRP is considered an early sign of ICU admission as CRP level higher than 100mg/L was found to be associated with increased ICU and mortality ³⁷³⁸ . In a recent study, it was shown that the performance of CRP was better than other indicators in predicting Covid-19. In Covid-19 patients, the elevated LDH level is an expression of severe lung damage and shortness of breath as a result of the abnormal inflammatory state, the LDH concentration in males is higher compared to females, and the high level of LDH was also associated with the severity of covid-19 infection, organ dysfunction and coagulation, as well as with deaths in patients from severe acute respiratory syndrome SARS-Cov-2, and also indicate tissue injury and lack of oxygen, and these high levels are an important factor for predicting Covid-19 infection and an indicator of mortality in patients with septicemia diseases ³⁹⁴⁰. Where the level of LDH increased during acute pneumonia and indicates the extent of lung infection with the virus and shortness of breath, The respiratory system is not the only one that has been affected by the Corona virus, as well as complications resulting from kidney impairment, especially in patients with severe infection, for angiotensinogen ACE2 that is expressed in the renal tubular epithelium ⁴¹. Also, a study conducted by Xiang et al., 2021 showed that SARS-Cov-2 causes direct and dangerous injury to the kidneys through its binding to the ACE2 receptor and it is detected by analyzing urea and Creatinine.

Creatinine is present in the bloodstream in proportions it is the product of the metabolic breakdown of muscles and protein and is excreted in the event of muscle rupture, as it was used as an indicator of tissue and muscle damage and to determine the amount of damage through its level in the blood, through which the functions and effectiveness of the kidneys are measured. Kidney damage due to eating large quantities of proteins that are given to patients in intensive care, as well as the antidiuretic hormone (ADH) produced frequently, which led to a high uptake of urea by the renal marrow ⁴³.

Table (2) indicates that there are highly significant relationships at the level (0.01) between (Urea, D. dimer, and ferritin) each other and with the ACE2 gene in all study groups. ACE2 in cells and according to the results of our study, females have higher levels of D. dimer and Urea compared to males in normal cases and cases of infection with the virus , the presence of ACE2 in the kidneys and the association of blood pressure and kidney diseases with males and that high Blood pressure reduces the expression of ACE2 ⁴⁴, estrogen is known to up-regulate ACE2 and up regulation of ACE2 reduces inflammation and protects against cell injury. It acts as a protective mechanism against SARS-Cov-2 infection and estrogen also modulates pneumonia and lung damage. caused by the virus and that the level of estrogen in women is higher than in men, which gives women a higher immune and adaptive response to viral infection ⁴⁵, which confirms that women have a higher incidence of Covid-19 disease than men, but Due to the increased level of estrogen in women A gives it a higher resistance to the virus than males, so it will be less affected than males .

CONCLUSIONS:

The results show that ACE2 is an essential receptor for Covid-19, and also indicates that there is a significant difference between males and females in the level of gene expression of the ACE2 gene in the study groups. And a stronger and faster immune response to vaccines in females compared to males. The values of some vital indicators increased to predict infection and severity of the virus, and there were significant differences between males and females, as the values of )D. dimer, CRP) were higher when Patients with females than males . As for the value of (Ferritin, LDH) recorded a higher increase in males than females. The infection will not be limited to the respiratory system only. The virus caused weakness in the liver and kidneys in severe cases due to its association with ACE2 found in renal tubes, causing tissue and kidney damage in general due to the high level of both Creatinine urea , the value of Urea in females in all cases, except in the category of Patient and vaccine recipients, recorded a higher increase in males than females, and values of Creatinine level decreased in males when receiving the vaccine compared to females, There is a positive, high moral relationship between ACE and some vital indicators in cases of Covid-19.

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Received on 22.07.2022 Modified on 12.11.2022

Research J. Pharm. and Tech 2023; 16(8):3601-3607.

DOI: 10.52711/0974-360X.2023.00594

	2ΔΔCt	D-dimer	CRP	Ferritin	LDH	Urea	Creatinine
2ΔΔCt	1
D-dimer	0.9874**	1
CRP	0.2484	0.2484	1
Ferritin	0.5154**	0.5154**	0.3057	1
LDH	0.4991*	0.4991**	-0.0033	0.6088**	1
Urea	0.5157**	0.5157**	0.3922	0.7586**	0.4137	1
Creatinine	0.3373	0.3373	0.2638	0.7695**	0.2315	0.7169**	1