AbdelMassih, A., and A. Ashraf, "Effect of pioglitazone, as antidiabetic agent, on atheroma regression in type 2 diabetic patients: a systematic review and meta-analysis", Beni-Suef University Journal of Basic and Applied Sciences, 2021.
AbdelMassih, A. F., R. Menshawey, J. H. Ismail, R. J. Husseiny, Y. M. Husseiny, S. Yacoub, A. Kamel, R. Hozaien, E. Yacoub, EsraaMenshawey, et al., "PPAR agonists as effective adjuvants for COVID-19 vaccines, by modifying immunogenetics: a review of literature.", Journal, genetic engineering & biotechnology, vol. 19, issue 1, pp. 82, 2021. Abstract

BACKGROUND: Several coronavirus vaccine have been fast-tracked to halt the pandemic, the usage of immune adjuvants that can boost immunological memory has come up to the surface. This is particularly of importance in view of the rates of failure of seroconversion and re-infection after COVID-19 infection, which could make the vaccine role and response debatable. Peroxisome proliferator-activated receptors (PPARs) have an established immune-modulatory role, but their effects as adjuvants to vaccination have not been explored to date. It is increasingly recognized that PPAR agonists can upregulate the levels of anti-apoptotic factors such as MCL-1. Such effect can improve the results of vaccination by enhancing the longevity of long-lived plasma cells (LLPCs). The interaction between PPAR agonists and the immune system does not halt here, as T cell memory is also stimulated through enhanced T regulatory cells, antagonizing PD-L1 and switching the metabolism of T cells to fatty acid oxidation, which has a remarkable effect on the persistence of T memory cells. What is even of a more significant value is the effect of PPAR gamma on ensuring a profound secretion of antibodies upon re-exposure to the offending antigen through upregulating lipoxin B4, therefore potentially assisting the vaccine response and deterring re-infection.

SHORT CONCLUSION: In view of the above, we suggest the use of PPAR as adjuvants to vaccines in general especially the emerging COVID-19 vaccine due to their role in enhancing immunologic memory through DNA-dependent mechanisms.

Menshawey, R., EsraaMenshawey, A. H. K. Alserr, and A. F. AbdelMassih, "JAK out of the Box; The Rationale behind Janus Kinase Inhibitors in the COVID-19 setting, and their potential in obese and diabetic populations.", Cardiovascular endocrinology & metabolism, vol. 10, issue 2, pp. 80-88, 2021. Abstract

The adaptive use of Janus kinase (JAK)-inhibitors has been suggested by rheumatology experts in the management of COVID-19. We recount the rationale behind their use in this setting, and the current evidence for and against their use in this review. JAK-inhibitors role in COVID-19 infection appears to be multifaceted, including preventing viral endocytosis and dampening the effect of excessive chemokines. This drug class may be able to achieve these effects at already preapproved dosages. Concerns arise regarding reactivation of latent viral infections and the feasibility of their use in those with severe disease. Most interestingly, JAK-Inhibitors may also have an additional advantage for diabetic and obese populations, where the dysregulation of JAK-signal transducer and activator of transcription pathway may be responsible for their increased risk of poor outcomes. Targeting this pathway may provide a therapeutic advantage for these patient groups.

, "The microvascular hypothesis underlying neurologic manifestations of long COVID-19 and possible therapeutic strategies.", Cardiovascular endocrinology & metabolism, vol. 10, issue 4, pp. 193-203, 2021. Abstract

With the ongoing distribution of the coronavirus disease (COVID) vaccines, the pandemic of our age is ending, leaving the world to deal with its well-documented aftereffects. Long COVID comprises a variety of symptoms, of which the neurological component prevails. The most permeating theory on the genesis of these symptoms builds upon the development of microvascular dysfunction similar to that seen in numerous vascular diseases such as diabetes. This can occur through the peripheral activation of angiotensin-converting enzyme 2 receptors, or through exacerbations of pro-inflammatory cytokines that can remain in circulation even after the infection diminishes. Several drugs have been identified to act on the neurovascular unit to promote repair, such as gliptins, and others. They also succeeded in improving neurologic outcome in diabetic patients. The repurposing of such drugs for treatment of long COVID-19 can possibly shorten the time to recovery of long COVID-19 syndrome.

AbdelMassih, A., M. Gadalla, E. Hussein, M. Elahmady, N. Zahra, M. A. Eid, M. Hussein, A. A. Hassan, A. S. Abou-Zeid, A. Hassan, et al., "The forgotten oral microbial transplantation for improving the outcomes of COVID-19.", New microbes and new infections, vol. 43, pp. 100923, 2021. Abstract

Ever since the uncovering of the severe discrepancy of COVID-19 manifestations, irrespective of viral load, scientists have raced to locate and manage factors contributing to the genesis of a critical state. Recent evidence delineates the role of oral dysbiosis in the development of low-grade inflammation, characterized by the increase of inflammatory cytokines common to those fundamental to the development of severe COVID. Furthermore, high periodontopathic bacteria were recorded in severe acute respiratory syndrome in COVID patients, as well as its common provoking comorbidities such as diabetes and hypertension. This can be explained by the immigration and elimination of oral bacteria into the airways, which, in the context of an injured lung, allows for their preferential overgrowth familiar to that, causing the progression to advanced lung diseases. This is why we indicate the promising usage of oral microbiome transplantation as a treatment of oral microbial dysbiosis, not only associated with the worst outcomes of COVID-19 but also in other disorders of low-grade inflammation.

AbdelMassih, A., R. Hozaien, M. El Shershaby, A. Kamel, H. - A. Ismail, and R. Fouda, "Is the heparin-induced thrombocytopenia-like syndrome associated with ChAdOx vaccine related to the vaccine itself or to an autoimmune reaction to severe acute respiratory syndrome 2 coronavirus: insights and implications from previous ", New microbes and new infections, vol. 41, pp. 100884, 2021. Abstract

Prothrombotic states, similar to heparin-induced thrombocytopenia (HIT) in recipients of the ChAdOx vaccine, sounded alarm bells internationally. Equivalent episodes of HIT were detailed in several case reports of coronavirus disease 2019. This suggests a common pathogenesis and warrants a shift in the management of implicated cases.

AbdelMassih, A. F., R. Menshawey, R. Hozaien, A. Kamel, F. Mishriky, R. J. Husseiny, A. M. Hanoura, E. Yacoub, N. AlShehry, EsraaMenshawey, et al., "The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology.", Medical hypotheses, vol. 148, pp. 110520, 2021. Abstract

Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.

AbdelMassih, A., A. A. Hassan, A. S. Abou-Zeid, A. Hassan, E. Hussein, M. Gadalla, M. Hussein, M. A. Eid, M. Elahmady, N. El Nahhas, et al., "Salivary markers and coronavirus disease 2019: insights from cross-talk between the oral microbiome and pulmonary and systemic low-grade inflammation and implications for vascular complications.", Cardiovascular endocrinology & metabolism, vol. 10, issue 3, pp. 162-167, 2021. Abstract

To date, coronavirus disease 2019 (COVID-19) has affected over 6.2 million individuals worldwide, including 1.46 million deaths. COVID-19 complications are mainly induced by low-grade inflammation-causing vascular degeneration. There is an increasing body of evidence that suggests that oral dysbiotic taxa are associated with worse prognosis in COVID-19 patients, especially the Prevotella genus, which was retrieved from nasopharyngeal and bronchoalveolar lavage samples in affected patients. Oral dysbiosis may act by increasing the likelihood of vascular complications through low-grade inflammation, as well as impairing respiratory mucosal barrier mechanisms against SARS-CoV-2. Salivary markers can be used to reflect this oral dysbiosis and its subsequent damaging effects on and the lungs and vasculature. Salivary sampling can be self-collected, and is less costly and less invasive, and thus may be a superior option to serum markers in risk stratification of COVID-19 patients. Prospective studies are needed to confirm such hypothesis. Video Abstract: http://links.lww.com/CAEN/A28.

AbdelMassih, A. F., F. Al Zahraa Hassan, A. El-Gammal, M. Tawfik, and D. Nabil, "The overlooked left ventricle in persistent pulmonary hypertension of the newborn.", The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, vol. 34, issue 1, pp. 72-76, 2021. Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a rapidly increasing condition among neonates. It represents failure of adaptation of pulmonary circulation to the extrauterine environment causing severe hypoxemia in affected newborns. Few data have weighed the relationship of ventricular dysfunction in the context of PPHN and the outcome in involved patients. The aim of this paper is to study ventricular functions in newborns with PPHN and to determine whether short-term outcome is closely related or not to ventricular dysfunction occurring in PPHN. Thirty full-term neonates with PPHN were screened with conventional echocardiography and tissue Doppler imaging (TDI) for the assessment of ventricular functions at the start of treatment for PPHN, demographic data and Arterial blood gazes were performed as well. The echocardiographic data were compared to healthy age-matched controls. The sensitivity and specificity of relevant echocardiographic data to predict the short-term (Day 3) outcome of patients were measured. Patients with PPHN had both left ventricular (LV) and right ventricular (RV) dysfunction when compared to controls, RV Tei (Cases: 0.39 ± 0.1 versus controls: 0.29 ± 0.08,  < .01) LV Tei (Cases: 0.3 ± 0.04 versus controls: 0.25 ± 0.02,  < .01), LV functions were found of greatest prediction of negative outcome in cases with PPHN than RV Tei. The aforementioned findings are sight opening towards the importance of LV dysfunction in PPHN, LV dysfunction might occur in PPHN as a result of RV-LV interactions and the observed involvement might be an important aggravating factor of PPHN.

AbdelMassih, A., E. Yacoub, R. J. Husseiny, A. Kamel, R. Hozaien, M. El Shershaby, M. Rajab, S. Yacoub, M. A. Eid, M. Elahmady, et al., "Hypoxia-inducible factor (HIF): The link between obesity and COVID-19.", Obesity medicine, vol. 22, pp. 100317, 2021. Abstract

The COVID-19 death toll has involved to date more than 1 million confirmed deaths. The death rate is even higher in the obese COVID-19 patients, as a result of hypoxia, due to the interplay between adipose tissue hypoxia and obstructive sleep apnea. The discrepancy of manifestations seen in COVID-19 seems to be mediated by a differential immune response rather than a differential viral load. One of the key players of the immune response is HIF. HIF-1β is a stable constitutively expressed protein in the nucleus; and under hypoxic changes, its activity is unaffected, whereas the HIF-α subunit has a short half-life and because of its degradation by an enzyme known as propyl hydroxylase; under hypoxic conditions, propyl hydroxylase gets deactivated thus leading to the stabilization of HIF-1α. As mentioned before, HIF-1α expression is triggered by hypoxic states, this crippling condition will aggravate the pro-inflammatory characteristics of HIF-1α. The vast majority of decompensated COVID19 cases manifest with drastic lung injury and severe viral pneumonia, the infection-induced hypoxia will the existing hypoxia in obesity. This will additionally augment HIF-1α levels that will provoke the already existing cytokines' storm to fulminant. Consequently, this will directly correlate the effect of a hypoxic environment with the increase of HIF-1α level. HIFɑ exists in two main isoforms HIF-1α and HIF-2α. HIF-1α and HIF-2α act in distinct ways in how they work on different target genes. For example, HIF-2α may act on hemopoietin genes (heme-regulating genes); while HIF-1α acts on EPO. HIF-1α release seems to be markedly augmented in obesity due to adipose tissue hypoxia and obstructive sleep apnea resulting in cyclic hypoxia. HIF-1α can also be secreted by direct viral proteolytic effects. Whereas, HIF-2α is stimulated by chronic hypoxia. HIF-1α exerts detrimental effects on the immune system, characterized by unopposed pro-inflammation at the macrophages, dendritic cells, T cells, and complement levels resulting in cytokines' storm, which is linked to the poor outcomes of COVID-19. On the other hand, HIF-2α role is regulatory and largely opposes the actions mediated by HIF-1α. In view of this, inhibiting HIF-1α release or switching its production to HIF-2α by natural products such as resveratrol or by synthetic drugs, offer a good therapeutic strategy that can prevent COVID-19 worst outcome in infected patients. The approach of breaking the vicious circle between lung damage-induced hypoxia and HIF-1α pro-inflammatory stimulant through drugs is considered to be extremely promising as a therapeutic manner to combat further deterioration of COVID19 cases.