Therapeutic Impact of Tocilizumab in the Setting of Severe COVID-19; an Updated and Comprehensive Review on Current Evidence.

Introduction: The COVID-19 pandemic caused by SARS-CoV-2 has been the major health concern in 2019 globally. Considering the severity and phase of the disease, various pharmacotherapy schedules were proposed. Here, we set out to provide close-up insights on the clinical utility of Tocilizumab (TCZ), a biologic monoclonal antibody in this regard. Methods: In this comprehensive review, various databases, including Scopus, PubMed Central, Medline, Embase, Google Scholar, and preprint publishers (med/bioRxiv) were searched until January 30, 2024, according to the keywords and search criteria. Results: Besides the pros and cons, compelling evidence purported the safety and efficacy of TCZ and indicated that it exhibits great potential to reduce short-term and all-cause (28-30-day) mortality. TCZ significantly drops the adverse events if administered in the right time course (in the inflammatory phase) during critical/severe COVID-19 pneumonia. Despite contradictory results, the benefits of TCZ appear significant, especially in combination with add-on therapies, such as corticosteroids. Although the safety of TCZ is acceptable, solid data is lacking as to its benefits during pregnancy. There are limited data on TCZ combination therapies, such as hemoperfusion, intravenous immunoglobulin (IVIG), simple O2 therapy, vasopressor support, convalescent plasma therapy, and even in vaccinated patients and COVID-19 reinfection, especially in elderly persons. In addition, the impact of TCZ therapy on the long-lasting COVID-19 is unclear. Conclusion: Personalized medicine based on individual characteristics and pertinent clinical conditions must be considered in the clinicians' decision-making policy. Finally, to mitigate the risk-to-benefit ratio of TCZ, a treatment algorithm, based on available literature and updated national institute of health (NIH) and Infectious Diseases Society of America (IDSA) guidelines, is also proposed.

Methanol Induced Optic Neuropathy: Molecular Mysteries, Public Health Perspective, Clinical Insights and Treatment Strategies.

Methanol-induced optic neuropathy (MION) represents a critical public health issue, particularly prevalent in lower socioeconomic populations and regions with restricted alcohol access. MION, characterized by irreversible visual impairment, arises from the toxic metabolization of methanol into formaldehyde and formic acid, leading to mitochondrial oxidative phosphorylation inhibition, oxidative stress, and subsequent neurotoxicity. The pathogenesis involves axonal and glial cell degeneration within the optic nerve and potential retinal damage. Despite advancements in therapeutic interventions, a significant proportion of affected individuals endure persistent visual sequelae. The study comprehensively investigates the pathophysiology of MION, encompassing the absorption and metabolism of methanol, subsequent systemic effects, and ocular impacts. Histopathological changes, including alterations in retinal layers and proteins, Müller cell dysfunction, and visual symptoms, are meticulously examined to provide insights into the disease mechanism. Furthermore, preventive measures and public health perspectives are discussed to highlight the importance of awareness and intervention strategies. Therapeutic approaches, such as decontamination procedures, ethanol and fomepizole administration, hemodialysis, intravenous fluids, electrolyte balance management, nutritional therapy, corticosteroid therapy, and erythropoietin (EPO) treatment, are evaluated for their efficacy in managing MION. This comprehensive review underscores the need for increased awareness, improved diagnostic strategies, and more effective treatments to mitigate the impact of MION on global health.

Evaluation of circulating levels of miR-135a and miR-193 in patients with sepsis.

BACKGROUND: Sepsis is a life-threatening condition where early diagnosis and prognostic awareness provide guidance for selecting the appropriate treatment strategies. A wide variety of biomarker-based studies in clinical medicine provide new insights into personalized medicine for sepsis patients. MiRNAs are endogenous non-coding RNA molecules that have been acting as great potential diagnostic, prognostic and therapeutic biomarkers in various diseases. METHODS AND RESULTS: In the present study, the expression levels of two selected miRNAs, including miR-135a and miR-193, were evaluated for their prognostic potential in patients with sepsis. The circulating levels of miRNAs were quantified by quantitative PCR (qPCR) in patients with sepsis (n = 100) and age- and sex-matched healthy controls (n = 100). Statistical findings confirmed the valuable prognostic potential of miR-135a in patients with sepsis, while no significant difference was found between the miR-193 expression level in the patients with sepsis and the controls. CONCLUSIONS: Circulating levels of miRNA-135a can serve a the prognostic biomarker for patients with sepsis. These findings highlight the importance of miRNAs as signatures in the personalized managements of sepsis.

Berberine-induced glucagon-like peptide-1 and its mechanism for controlling type 2 diabetes mellitus: a comprehensive pathway review.

Introduction: A growing number of studies have thus far showed the association between type 2 diabetes mellitus (DM) and the intestinal microbiome homoeostasis. As reported, the gut microflora can be significantly different in patients with type 2 DM (T2DM) compared to those in healthy individuals.Methods: The authors collected the relevant articles published until 2022 and these are carefully selected from three scientific databases based on keywords.Discussion: This review highlights research on the anti-diabetic properties of berberine (BBR)-induced glucagon-like peptide-1 (GLP-1), as a glucose-lowering factor and a balance regulator in the microbial flora of the intestines, which plays an important role in adjusting the signalling pathways affecting insulin secretion.Results: Considering the anti-diabetic characteristics of the BBR-induced GLP-1, BBR makes a promising complementary treatment for reducing the clinical symptoms of DM by reducing the hyperglycaemia. Berberin might be a safe and effective drug for T2DM with little or no adverse effects.HighlightsBerberine induces GLP-1 insulin secretion by PLC2 pathway in the intestinalBerberine-induced GLP-1 decreases mitochondrial stress and relocates cytochrome c out of the mitochondria.Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptomsBerberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell.Preventing mitochondrial damage, reducing adipose tissue fat, and reducing oxidative stress are thus among the results of BBR-induced GLP-1.The lower costs of BBR, and its limited side effects and higher availability, make it a promising supplementary medicine for DM.

T Lymphocyte Characteristic Changes Under Serum Cytokine Deviations and Prognostic Factors of COVID-19 in Pregnant Women.

Physiological changes during pregnancy make the individuals more susceptible to severe respiratory diseases. Hence, pregnant women with coronavirus disease 2019 (COVID-19) are likely at a higher risk. We investigated the effects of COVID-19 on T cell response and serum cytokine profile in pregnant patients. Peripheral blood mononuclear cells (PBMCs) of women with COVID-19 were collected during the first trimester of pregnancy, and the percentage of total lymphocytes, as well as CD4 + and CD8 + T cells, was assessed using flow cytometry. The expression of the programmed death-1 (PD-1) marker for exhausted T cells was evaluated. Additionally, the serum samples were provided to evaluate the levels of antiviral and proinflammatory cytokines, as well as laboratory serological tests. Pregnant women with COVID-19 presented lymphopenia with diminished CD4 + and CD8 + T cells. Besides, high expression levels of the PD-1 gene and protein were observed on PBMCs and T cells, respectively, when compared with normal pregnant individuals. Moreover, serum levels of TNF-α, IL-6, IL-1ß, and IL-2 receptor were notably enhanced, while IFN-I α/ß values were significantly decreased in the patients when compared with controls. Furthermore, hyperlipidemia, hyperglycemia, and hypertension were directly correlated with the disease although serum albumin and vitamin D3 levels adversely affected the viral infection. Our study showed extreme lymphopenia and poor T cell response while elevated values of serum inflammatory cytokines in infected pregnant women. Moreover, a hypertension background or metabolic changes, including hyperlipidemia, hyperglycemia, and vitamin D3 or albumin deficiency, might be promising prognostic factors in pregnant women with COVID-19.

Prognostic potential of circulating cell free mitochondrial DNA levels in COVID-19 patients.

BACKGROUND: In viral infections, mitochondria act as one of the main hubs of the pathogenesis. Recent findings present new insights into the potential role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in COVID-19 pathogenesis by the induction of immune response and aggressive cytokine storm in SARS-CoV-2 infection. METHODS AND RESULTS: The levels of ccf-mtDNA were investigated in 102 hospitalized patients with COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong association between the levels of ccf-mtDNA and and mortality, ICU admission, and intubation. Also, our findings highlighted the pivotal role of comorbidities as a risk factor for COVID-19 mortality and severity. CONCLUSION: Higher levels of ccf-mtDNA can serve as a potential early indicator for progress and poor prognosis of COVID-19.

Lipid Profile as a Predictive Marker for Organ Dysfunction after Thoracoabdominal Surgery: A Cross-sectional Study.

Background: Plasma total cholesterol is considered a negative acute phase reactant. In various pathological conditions, such as trauma, sepsis, burns, and liver dysfunction, as well as post-surgery, serum cholesterol level decreases. This study aimed to investigate the role of lipid profiles in determining the probability of organ dysfunction after surgery. Methods: This cross-sectional study included patients who underwent thoracoabdominal surgery and were admitted to the intensive care unit of Imam Reza Hospital in Tabriz, Iran, between October 2016 and September 2018. During the first two days of admission, blood samples were taken, and serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), Low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and albumin were measured. The relation between the changes in these laboratory markers and six organ functions including cardiovascular, respiratory, renal, central nervous system, hepatic, and hematologic, length of stay in the hospital and intensive care unit, mechanical ventilation duration, and vasopressor use were investigated. The independent t test was used to compare continuous variables. The association between different variables and organ dysfunction and mortality was evaluated by using logistic regression. Results: The serum TC increased the risk of mortality (OR=1.09, 95%CI=1.06-1.11, P<0.001), renal dysfunction (OR=1.09, 95%CI=1.06-1.12; P<0.001), liver dysfunction (OR=1.07, 95%CI=1.03-1.10; P<0.001), respiratory dysfunction (OR=1.08, 95%CI=1.05-1.13; P<0.001). Moreover, LDL, HDL, and TG were found to be inversely related to mortality, organ dysfunction, length of stay in the hospital and intensive care unit, mechanical ventilation duration, and vasopressor use. Conclusion: TC could be considered a risk factor for mortality, organ dysfunction, and clinical outcomes. On the other hand, LDL, HDL, and TG played a protective role in the patients' mortality, organ dysfunction, and clinical outcomes.

A comprehensive insight into the molecular and cellular mechanisms of action of resveratrol on complications of sepsis a systematic review.

Sepsis and septic shock are still one of the most important medical challenges. Sepsis is an extreme and uncontrolled response of the innate immune system to invading pathogenesis. Resveratrol (3,5,4'-trihydroxytrans-stilbene), is a phenolic and non-flavonoid compound naturally produced by some plants and fruits. The object of the current study is to systematically review the impacts of resveratrol and its mechanisms of function in the management of sepsis and its related complications. The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements were applied to perform the study (PROSPERO: CRD42021289357). We searched Embase, Web of Science, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus databases up to January 2023 by using the relevant keywords. Study criteria were met by 72 out of 1415 articles screened. The results of this systematic review depict that resveratrol can reduces the complications of sepsis by affecting inflammatory pathways, oxidative stress, and modulating immune responses. Future human randomized clinical trials are necessary due to the promising therapeutic effects of resveratrol on sepsis complications and the lack of clinical trials in this regard.

SARS-CoV2 infection induce miR-155 expression and skewed Th17/Treg balance by changing SOCS1 level: A clinical study.

BACKGROUND: One of the regulators in severe acute respiratory syndrome coronavirus2 (SARS-CoV2) infection is miRNAs. In COVID-19 patients, immunological responses to SARS-CoV2 infection may be impacted by miR-155, a miRNA associated to inflammation. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) of 50 confirmed COVID-19 patients /Healthy Controls (HCs) was isolated by Ficoll. The frequency of T helper 17 and regulatory T cells was analyzed by flowcytometry. The RNA was extracted from each sample and after synthesis of c-DNA, the relative expression of miR-155, suppressor of cytokine signaling (SOCS-1), Signal transducer and activator of transcription 3(STAT3), and Fork Head Box Protein 3 (FoxP3) was evaluated by real-time PCR. The protein level of STAT3, FoxP3 and RORγT in the isolated PBMCs measured by western blotting. The serum level of IL-10, TGF-ß, IL-17 and IL21 was assessed by ELISA method. RESULTS: The population of Th17 cells showed a significant rise, whereas Treg cells reduced in COVID-19 cases. The master transcription factor of Treg (FoxP3) and Th17 (RORγT) relative expression showed the same pattern as flowcytometry. STAT3 level of expression at RNA and protein level increased in COVID-19 cases. FOXP3 and SOCS-1 proteins were down-regulated. The relative expression of miR-155, up-regulated in PBMC of COVID-19 patients and revealed a negative correlation with SOCS-1. The serum cytokine profile showed a reduction in TGF-ß, on the other hand an increase was seen in IL-17, IL-21 and IL-10 in COVID-19 cases toward control group. CONCLUSION: Based on the studies conducted in this field, it can be suggested that Th17/Treg in covid-19 patients can be affected by miR-155 and it can be considered a valuable diagnostic and prognostic factor in this disease.

Association between leukocyte telomere length and COVID-19 severity.

Background: Inter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases. Result: In this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity. Conclusions: These findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s43042-023-00415-z.

Efficient dispersive solid-phase extraction of methylprednisolone from exhaled breath of COVID-19 patients.

In the current study, bismuth ferrite nano-sorbent was synthesized and utilized as a sorbent for the dispersive solid-phase extraction of methylprednisolone from exhaled breath samples. The size and morphology of the nano-sorbent were characterized by X-ray diffraction analysis and scanning electron microscopy. Following its desorption with acetonitrile, methylprednisolone was quantified by a high-performance liquid chromatography-ultraviolet detector. Factors affecting the extraction of methylprednisolone were optimized. Under optimized experimental conditions, a linear relationship between the analytical signals and methylprednisolone concentration was obtained in the range of 0.001-0.2 µg mL-1 for exhaled breath condensate samples and 0.002-0.4 µg per filter for filter samples. A pre-concentration factor of 6.4-fold, corresponding to an extraction recovery of 96.0%, was achieved. The validated method was applied for the determination of methylprednisolone in real samples taken from the exhaled breath of COVID-19 patients under mechanical ventilation.

Diagnostic value of an increase in central venous pressure during SBT for prediction of weaning failure in mechanically ventilated patients: A cross-sectional study.

Background: Timely and successful extubation is an essential step forward in clinical practice to minimize complications of mechanical ventilation and unsuccessful weaning processes. Thus, research into predictive factors of weaning outcome to optimize spontaneous breathing trial (SBT) precision before extubation is critical in intensive care practices. In this study, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients. Methods: In this cross-sectional study, 159 mechanically ventilated patients who were eligible for SBT were enrolled. Of these patients, 140 had successful extubation, whereas the remainder failed. Each patient's PaCO2 and PaO2 levels, respiratory rate (RR), SpO2, mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) values at the start of SBT, 3 min later, and at the end of SBT were measured. These values, along with the patients' clinical characteristics, were then investigated to determine if there was any correlation between these variables and the weaning outcome. Results: Our analysis revealed that increase in CVP, independent of hemoglobin (Hb) concentration, PaO2, SpO2, duration of mechanical ventilation (MV), length of intensive care unit (ICU) stay, and SBT process, as well as underlying disease, was positively correlated with extubation/weaning failure. While age, gender, vital signs (MAP, RR, and HR), sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation (APACHE) scores had no significant correlation with patients' extubation outcomes. Conclusion: According to our findings, integrating CVP assessment into SBT besides routine indices measurement and monitoring can be considered for the prediction of weaning outcome in critically ill mechanically ventilated patients.

Prognostic values of modified NUTRIC score to assess outcomes in critically ill patients admitted to the intensive care units: prospective observational study.

PURPOSE: Modified Nutrition Risk in the Critically Ill (NUTRIC) score (mNUTRIC score) have been validated as screening tool for quantifying risk of adverse outcome critically ill patients admitted to the intensive care units (ICUs). The aim of this study was to evaluate the prognostic value of mNUTRIC score to assess outcomes in this population. MATERIALS AND METHODS: This prospective, observational study was conducted on adult patients admitted to the general ICUs of two university affiliated hospital in northwest of Iran. The association between the mNUTRIC score and outcomes was assessed using the univariate and multivariate binary logistic regression. The performance of mNUTRIC score to predict outcomes was assessed using the receiver operating characteristic (ROC)-curve. RESULTS: In total 445 ICU patients were enrolled. Based on mNUTRIC score, 62 (13.9%) and 383 (86.1%) individuals were identified at high and low nutritional risk, respectively. The area under the curve (AUC) for predicting ICU mortality, using vasopressor, duration of vasopressor, and mechanical ventilation (MV) duration were (AUC: 0.973, 95% CI: 0.954-0.986, P < 0.001), (AUC: 0.807, 95% CI: 0.767-0.843, P < 0.001), (AUC: 0.726, 95% CI: 0.680-0.769, P < 0.001) and (AUC: 0.710, 95% CI: 0.666-0.752, P < 0.001), respectively. CONCLUSIONS: An excellent and good predictive performance of the mNUTRIC score was found regarding ICU mortality and using vasopressor, respectively. However, this predictive was fair for MV and vasopressor duration and poor for ICU and hospital length of stay.

Sirolimus- and cyclosporine-loaded nanostructured lipid carriers: Development, characterization, and in vitro evaluation in T-cell profiles of patients with a history of recurrent pregnancy loss.

Purpose: The authors developed nanostructured lipid carriers (NLCs) loaded with sirolimus (SRL) and cyclosporine (CsA) to improve their therapeutic efficacy in recurrent pregnancy loss (RPL) patients. Methods: Mono-delivery and co-delivery of SRL and CsA by NLCs (S-NLCs, C-NLCs, and S-C-NLCs) were developed. The MTT assay was used to study the optimum dose of formulations. PCR, Western blotting, and ELISA were also conducted. Results: Well-designed nanodrugs with a suitable size, zeta potential, desirable encapsulation efficiency drug loading, and cellular uptake confirmed optimum formulations. Based on cell viability, the amounts of SRL and CsA could be reduced greatly due to the co-delivery by NLCs. Following S-NLCs and C-NLCs interventions in T cells of patients with RPL and immune abnormality, a significant difference was observed in transcription factors and cytokine levels of Th1, Th17, and Tregs compared with healthy samples. Thus, a higher level of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17, and IL-21) and their regulators (T-bet and RORγt), as well as a lower level of an anti-inflammatory cytokine (IL-10) and its regulatory (Foxp3), were observed. However, no significant difference was found following the S-C-NLCs intervention. Conclusions: S-C-NLCs effectively balance the immune responses in peripheral T cells in RPL patients to induce maternal immune tolerance.

Taurine in Septic Critically Ill Patients: Plasma versus Blood.

Purpose: Sepsis and systemic inflammatory response syndrome (SIRS) encompass various problems throughout the body, and two of its major problems are the creation of oxidative substances in the body and decrease of the body's antioxidant capacity to deal with the stress and organ damage. Optimal enteral nutrition fortified with antioxidant or immunomodulator amino acid is a hot topic concerning sepsis in the critical care setting. Taurine plays a protective role as an antioxidant in cells that is likely to have a protective role in inflammation and cytotoxicity. Methods: In the present study, 20 septic patients and 20 healthy volunteers were enrolled. The blood and plasma taurine levels of the patients on days 1, 3 and 7 were measured. Blood and plasma taurine level and the correlation between them, organ failure, and severity of the disease were assessed. Results: Taurine concentrations in the plasma of the septic patients were significantly lower than control group, and the whole blood concentrations were significantly higher than those of the control group (P<0.001). There was not a significant correlation between the blood and plasma taurine levels in control and septic patients. In addition, there was not any correlation between the severity of the disease, organ failure, mortality, and plasma as well as the blood concentration of taurine. Conclusion: In septic patients, taurine concentration in plasma and blood are low and high, respectively. These concentrations are not linked to each other and not associated with the patients' outcome, and the disease severity, and organ failure.

Upper lip bite test compared to modified Mallampati test in predicting difficult airway in obstetrics: A prospective observational study.

Difficult airway and intubation can have dangerous sequela for patients if not managed promptly. This issue is even more challenging among obstetric patients. Several studies have aimed to determine whether the test to predict a difficult airway or difficult intubation, is higher in accuracy. This study aims to compare the upper lip bite test with the modified Mallampati test in predicting difficult airway among obstetric patients. During this prospective observational study, 184 adult pregnant women, with ASA physical status of II, were enrolled. Difficult intubations of Cormack-Lehane grade III and IV were defined as difficult airways and difficult intubation in this study. Upper lip bite test, modified Mallampati test, thyromental distance and sternomental distance were noted for all patients. Modified Mallampati test, upper lip bite test and sternomental distance had highest specificity. Based on regression analysis, body mass index and Cormack-Lehane grade have a significant association. Modified Mallampati test was the most accurate test for predicting difficult airway. The best cut-off points of thyromental distance and sternomental distance in our study were 5cm and 15cm, respectively, by receiver operating characteristic curve analysis. Based on the results of the present study, it can be concluded that in the obstetric population, modified Mallampati test is practically the best test for predicting difficult airway. However, combining this test with upper lip bite test, thyromental distance and sternomental distance might result in better diagnostic accuracy.

Vitamin D in respiratory viral infections: a key immune modulator?

Respiratory viral infections are common respiratory diseases. Influenza viruses, RSV and SARS-COV2 have the potential to cause severe respiratory infections. Numerous studies have shown that unregulated immune response to these viruses can cause excessive inflammation and tissue damage. Therefore, regulating the antiviral immune response in the respiratory tract is of importance. In this regard, recent years studies have emphasized the importance of vitamin D in respiratory viral infections. Although, the most well-known role of vitamin D is to regulate the metabolism of phosphorus and calcium, it has been shown that this vitamin has other important functions. One of these functions is immune regulation. Vitamin D can regulate the antiviral immune response in the respiratory tract in order to provide an effective defense against respiratory viral infections and prevention from excessive inflammatory response and tissue damage. In addition, this vitamin has preventive effects against respiratory viral infections. Some studies during the COVID-19 pandemic have shown that vitamin D deficiency may be associated with a higher risk of mortality and sever disease in patients with COVID-19. Since, more attention has recently been focused on vitamin D. In this article, after a brief overview of the antiviral immune response in the respiratory system, we will review the role of vitamin D in regulating the antiviral immune response comprehensively. Then we will discuss the importance of this vitamin in influenza, RSV, and COVID-19.

Mitochondrial transplantation protects against sepsis-induced myocardial dysfunction by modulating mitochondrial biogenesis and fission/fusion and inflammatory response.

BACKGROUND: Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis. METHODS: Male Wistar rats (n = 80, 12 weeks old, 250-300 g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1 h or 1 and 7 h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400 µl of mitochondrial suspension containing 7.5 × 106 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1ß, and IL-6) levels were evaluated. Survival was tested over 72 h post-operation. RESULTS: Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7 h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection. CONCLUSION: Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.