Venkata Ramireddy Narala

Introduction: Sepsis-induced Acute Lung Injury (ALI) is a life-threatening complication marked by intense inflammation, oxidative stress, and respiratory failure, with no effective targeted treatments available. This study aims to explore the protective effects of andrographolide (AGL) against sepsis-induced ALI and uncover its underlying mechanisms, focusing on the modulation of peroxisome Proliferator-Activated Receptor Gamma (PPARγ) as a potential therapeutic pathway. Methods: A murine model of ALI was established using Cecal Ligation and Puncture (CLP). AGL was administered to evaluate its effects on pulmonary inflammation and oxidative stress. Neutrophil and macrophage infiltration, pulmonary edema, and levels of malondialdehyde and nitrite were measured in Bronchoalveolar Lavage (BAL) fluid and lung tissue, along with the expression of PPARγ and the activities of antioxidant enzymes Superoxide Dismutase (SOD) and catalase. The involvement of PPARγ was further confirmed using GW9662, a selective PPARγ antagonist. Results: AGL treatment significantly attenuated neutrophil and macrophage infiltration, reduced pulmonary edema and inflammation, and decreased malondialdehyde and nitrite levels in bronchoalveolar lavage fluid. Additionally, AGL upregulated PPARγ expression and enhanced SOD and catalase activity. These protective effects were significantly reversed by co-administration of GW9662, indicating a PPARγ-dependent mechanism. Discussion: The present study demonstrated that AGL exerts significant protective effects against CLP-induced ALI, primarily through modulation of inflammatory and oxidative pathways. Conclusion: AGL’s ability to upregulate PPARγ and enhance SOD and catalase activity further supports its mechanistic role in mitigating lung damage. The reversal of AGL protective effects by GW9662 confirms its PPARγ-dependent mechanism, highlighting its potential as a targeted protective treatment for sepsis-induced ALI.

The therapeutic targeting of peroxisome proliferator-activated receptor gamma (PPARγ) for type 2 diabetes (T2D) remains a double-edged sword: while thiazolidinediones are efficacious, their severe side effects necessitate the discovery of safer modulators. We propose a novel nutrient-centred hypothesis that thiamine (vitamin B1), an essential micronutrient, may act as a natural ligand for PPARγ. To investigate this, we adopted a translational approach. Molecular docking and dynamics simulations established that thiamine forms a stable, high-affinity interaction with the PPARγ ligand-binding domain. Functionally, in 3T3-L1 adipocytes, thiamine induced adipogenesis and PPARγ-response element binding with a potency analogous to rosiglitazone, suggesting direct agonistic activity. Corroborating these mechanistic insights at the clinical level, a new meta-analysis of randomized controlled trials demonstrates that high-dose benfotiamine, a synthetic thiamine derivative, significantly improves neuropathic and vascular outcomes in T2D patients. While the contribution of thiamine’s established antioxidant effects to these clinical benefits cannot be ruled out, the synergy of computational, cellular, and human evidence provides a compelling foundation for our hypothesis. This study suggests that thiamine could act as a PPARγ ligand and serve as a safer treatment option for metabolic disorders, which needs to be tested in vivo .

Mitochondria play a significant and varied role in inflammatory lung disorders. Mitochondria, known as the powerhouse of the cell because of their role in producing energy, are now recognized as crucial regulators of inflammation and immunological responses. Asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome are characterized by complex interactions between immune cells, inflammatory substances, and tissue damage. Dysfunctional mitochondria can increase the generation of reactive oxygen species (ROS), triggering inflammatory pathways. Moreover, mitochondrial failure impacts cellular signaling, which in turn affects the expression of molecules that promote inflammation. In addition, mitochondria have a crucial role in controlling the behavior of immune cells, such as their activation and differentiation, which is essential in the development of inflammatory lung diseases. Their dynamic behavior, encompassing fusion, fission, and mitophagy, also impacts cellular responses to inflammation and oxidative stress. Gaining a comprehensive understanding of the intricate correlation between mitochondria and lung inflammation is essential in order to develop accurate treatment strategies. Targeting ROS generation, dynamics, and mitochondrial function may offer novel approaches to treating inflammatory lung diseases while minimizing tissue damage. Additional investigation into the precise contributions of mitochondria to lung inflammation will provide significant knowledge regarding disease mechanisms and potential therapeutic approaches. This review will focus on how mitochondria in the lung regulate these processes and their involvement in acute and chronic lung diseases.

Background: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) plays a crucial role in regulating lipid and glucose metabolism, cancer, and inflammation, making it an attractive target for drug development. Meanwhile, β-Carotene, known for its antioxidant, anticancer and antiinflammatory properties, holds promise for modulating PPAR-γ activity. Understanding their interaction is crucial. Objective: This study aims to explore the therapeutic potential of β-carotene in modulating PPAR-γ activity by investigating their binding interactions. Methods: Screening of bioactive compounds from PubChem was conducted using GlideXP to identify potential PPAR-γ (PDB: 2PRG) ligands. During this screening, both protein and bioactive compounds were prepared following established protocols. Subsequently, the compounds were docked into the ligand binding domain (LBD) of the protein using XP docking. Rosiglitazone was used as an internal control. β-Carotene emerged as a lead based on Lipinski’s rule, docking score, free energy, and LBD interactions. Molinspiration analysis assessed its drug likeness. Molecular dynamics (MD) simulations utilizing Desmond with OPLS 2005 force field were employed to examine the dynamics and stability of the PPAR-γ/β-carotene complex. Results: β-carotene had strong hydrophobic interactions with specific residues within the ligandbinding domain of PPAR-γ. The calculated binding affinity (-9.07 kcal/mol) indicated a strong interaction between β-carotene and PPAR-γ, suggesting that β-carotene may modulate the activity of PPAR-γ. On a time scale of 100 ns, the MD simulations provided insights into the conformational changes, flexibility, and intermolecular interactions within the complex. Conclusion: In silico docking and dynamics simulation analyses show that PPAR-γ and β-carotene can form a stable complex, suggesting potential implications for metabolic modulation.

Background: There has been increasing evidence of the correlation between thiamine deficiency and type 2 diabetes (T2D). T2D is a condition in which an individual’s insulin sensitivity is highly compromised. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated transcription factor etiologically relevant to T2D. We hypothesized that thiamine could be a PPAR-γ ligand and thus activate PPAR-γ and ameliorate T2D. Objective: This study aims to establish thiamine as a PPAR-γ ligand via molecular docking and dynamics simulations (MDS) and thiamine’s ability to induce adipogenesis while upregulating PPAR-γ and AP-2 genes using in vitro assays. Methods: Thiamine/PPAR-γ binding was studied using Schrödinger’s Glide. The bound complex was simulated in the OPLS 2005 force field using Desmond. 3T3-L1 preadipocyte cells were differentiated in the presence of thiamine and rosiglitazone and stained with Oil Red O. Nuclear protein from the differentiated cells was used to study the binding of the PPAR-γ response element (PPRE) using an ELISA-based assay. mRNA from differentiated cells was used to study the expression of genes using quantitative RTPCR. Results: In silico docking shows that thiamine binds with PPAR-γ. MDS indicate that the interactions between thiamine and PPAR-γ are stable over a significant period. Thiamine induces the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner and enhances the PPRE-binding activity of PPAR-γ. Thiamine treatment significantly increases the mRNA levels of PPAR-γ and AP-2 genes. Conclusion: Our results show that thiamine is a PPAR-γ ligand. Animal studies and clinical trials are required to corroborate the results obtained.

The pandemic coronavirus disease 2019 outbreak’s causative agent was identified as severe acute respiratory syndrome coronavirus 2. It is a positive-sense single-stranded RNA virus with a ~30 kb size genome that belongs to the Nidovirales. Molecular analysis revealed that severe acute respiratory syndrome coronavirus 2 is a variant of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus with some sequence similarity. The confirmed cases and death toll are high in severe acute respiratory syndrome coronavirus 2 compared to severe acute respiratory syndrome coronavirus and the estimated R0 is >1. The data on pathological findings on severe acute respiratory syndrome coronavirus 2 are scarce and present treatment management is based on symptoms that are similar to severe acute respiratory syndrome coronavirus. In this review, we have discussed the transmission, viral replication, and cytokine storm and highlighted the recent pathological findings of coronavirus disease 2019. The reported severe acute respiratory syndrome coronavirus 2 pathological findings were similar to that of severe acute respiratory syndrome coronavirus. Though these findings help notify the clinical course of the disease, it warrants further in vivo and ex vivo studies with larger samples obtained from the coronavirus disease 2019 patients. Cite this article as: Panati K, Timmana LV, Reddy ATV, Saddala RR, Narala VR. Virology and molecular pathogenesis of coronavirus disease 2019: An update. Eurasian J Med., 2022;54(3):299-304.

: Recently, novel coronavirus infection (COVID-19) emerged in Wuhan, China has been declared as pandemic by WHO. Until now, no evidence is documented regarding its wild animal reservoir or intermediary host, but, human-to-human transmission, asymptomatic carriers were very much observed. The number of confirmed cases and death toll have been increased almost all over the world indicating its potential threat to public health. Though the phylogenetic analysis shows some similarity of SARS-CoV2 to bat betacoronaviruses, it exhibited significant variation in S1 domain of spike protein from bat-derived viruses. S1 domain plays an important role in receptor binding and it can be a target for the development of therapeutics and vaccines. In this review, we have discussed the updates on transmission, diagnosis, genome analysis and comparison, treatment options and clinical trials of COVID-19.