Observational research on the effect of an Ayurvedic treatment protocol in patients of hereditary pancreatitis.

BACKGROUND: Hereditary pancreatitis (HP) is a chronic and recurrent inflammatory disorder caused by genetic abnormalities, often accompanied by severe symptoms and complications. Conventional treatments offer limited relief but fail to halt disease progression. An Ayurvedic Treatment Protocol has been reported to be effective in treating various types of pancreatitis. OBJECTIVES: This observational clinical study is aimed at assessing the efficacy of a year long Ayurvedic treatment protocol (ATP) in mitigating attack frequency and intensity in Hereditary Pancreatitis patients. MATERIALS & METHODS: The study enrolled 151 patients across diverse age groups and genders, subjecting them to a comprehensive Ayurvedic treatment protocol at a specialized center. The protocol incorporated Metal-Based Ayurvedic Formulation (MBAF) named Amar, alongside supportive Ayurvedic compounds and dietary adjustments. Patients underwent pre- and post-treatment evaluations involving interviews, medical records, blood tests, radiological imaging, and symptom assessments. Notably, pancreatic enzyme use was discontinued prior to initiating Ayurvedic treatment. RESULTS: Among 151 patients, 88 completed the year long ATP, resulting in significant enhancement of their quality of life. There was a marked 98.7% reduction in emergency hospitalizations and a notable 92.8% decrease in attack frequency (p < 0.0001). Radiological assessments indicated pancreatic health stabilization, while no adverse effects were reported, highlighting the intervention's safety and tolerability. CONCLUSION: The study furnishes promising evidence supporting the efficacy and safety of ATP, especially the MBAF, in managing Hereditary Pancreatitis. The observed decline in attack frequency, absence of adverse effects, and stabilization of pancreatic health underscore the potential of Ayurvedic medicine. Subsequent research, including randomized controlled trials, is warranted to substantiate these findings and elucidate underlying mechanisms.

Immunomodulatory Effects of a Herbo-Mineral Ayurvedic Formulation in Experimental Models.

BACKGROUND: Ayurveda, an ancient Indian system of medicine, encapsulates comprehensive principles and formulations for disease prevention and treatment. A herbo-mineral Ayurvedic formulation, IMMBO, comprising Mandoor Bhasma and 18 herbs has shown promising results in treating allergic rhinitis in clinical studies. OBJECTIVE: This discussed series of experimental studies were conducted to explore the immuno-modulatory potential of IMMBO. METHODOLOGY: A series of experimental studies were carried out in immunosuppressed rats to explore the immune-modulatory effects of IMMBO. RESULTS: IMMBO was effective in reinstating neutrophil activation, stimulating cellular and humoral immunity, and counteracting immunosuppression at the molecular level. The modulation of key signalling molecules, including tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-1 beta (IL-1ß), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and nuclear factor-kappa B (NF-κb), showcased the formulation's multifaceted impact. Additionally, its ability to block histamine release suggests potential in controlling allergic states, positioning it as a promising therapeutic candidate for immune-related disorders. However, the precise mode of action remains elusive, warranting further in-depth pharmacological studies. CONCLUSION: This research substantiates the ancient Ayurvedic wisdom using modern scientific parameters, endorsing IMMBO's potential as an immune-modulatory agent.

Improved Protein Dynamics and Hydration in the Martini3 Coarse-Grain Model.

The Martini coarse-grain force-field has emerged as an important framework to probe cellular processes at experimentally relevant time- and length-scales. However, the recently developed version, the Martini3 force-field with the implemented Go̅ model (Martini3Go̅), as well as previous variants of the Martini model have not been benchmarked and rigorously tested for globular proteins. In this study, we consider three globular proteins, ubiquitin, lysozyme, and cofilin, and compare protein dynamics and hydration with observables from experiments and all-atom simulations. We show that the Martini3Go̅ model is able to accurately model the structural and dynamic features of small globular proteins. Overall, the structural integrity of the proteins is maintained, as validated by contact maps, radii of gyration (Rg), and SAXS profiles. The chemical shifts predicted from the ensemble sampled in the simulations are consistent with the experimental data. Further, a good match is observed in the protein-water interaction energetics, and the hydration levels of the residues are similar to atomistic simulations. However, the protein-water interaction dynamics is not accurately represented and appears to depend on the protein structural complexity, residue specificity, and water dynamics. Our work is a step toward testing and assessing the Martini3Go̅ model and provides insights into future efforts to refine Martini models with improved solvation effects and better correspondence to the underlying all-atom systems.

Proof of Efficacy Study to Evaluate an Ayurvedic Formulation in the Treatment of Allergic Rhinitis: An Open Label Randomized Controlled Clinical Trial.

BACKGROUND: Allergic rhinitis is largely treated by using antihistamines and nasal sprays, either alone or in combination. However, these measures ease out the symptoms but do not address causative factors, and have their share of side effects and limitations. An Ayurvedic herbo-mineral formulation, IMMBO, has been reported to be effective in treating allergic rhinitis. OBJECTIVE: The present study was carried out to evaluate the efficacy, safety, and tolerability of the Ayurvedic herbo-mineral formulation in comparison with a fixed-dose combination of levocetirizine and montelukast. METHOD: This was a randomized, comparative, clinical study carried out on 250 patients at a medical college in India. The patients were enrolled according to the eligibility criteria of the study and randomized into two groups, to receive either Ayurvedic herbo-mineral formulation, IMMBO, or a combination of levocetirizine and montelukast for 28 days. Total nasal symptom score (TNSS) and Immunoglobulin E (IgE) were calculated for evaluation of efficacy parameters.  Result: At the end of therapy both IMMBO and levocetirizine and montelukast combination showed significant improvement in TNSS in both treated population and per protocol population. The IMMBO group had a statistically higher reduction in TNSSs compared to the levocetirizine + montelukast group (-5.70 vs. -3.31; p<0.01). There was a statistically significant difference in the reduction of IgE levels between the groups (-351.54 vs. -208.79; p<0.05).  Conclusion: The findings of this study establish prima facie evidence about the efficacy and safety of Ayurvedic formulation. However, the said Ayurvedic formulation needs to be further developed scientifically.

Ayurvedic Treatment Protocol for Hereditary Pancreatitis: A Case Report Demonstrating Disease Arrestation.

The case report presented here highlights the use of an Ayurvedic treatment protocol (ATP) in managing hereditary pancreatitis (HP) in a 14-year-old boy. HP is a rare form of pancreatitis caused by specific gene mutations that are inherited within families. It is known to be aggressive and can lead to pancreatic cancer in later stages. The boy, in this case, experienced multiple episodes of pancreatitis and required several hospitalizations despite following a conventional treatment approach, which included a dairy-free, protein and fat-restricted diet, and pancreatic enzyme supplementation. However, after starting the ATP in February 2022, which involved a modified diet and the use of herbo-mineral Ayurvedic formulations, the boy reported significant improvement in his general well-being and was able to lead a normal life without experiencing any discomfort. The ATP included a customized diet comprising dairy products with moderate amounts of fat and protein, along with specific herbo-mineral formulations and the withdrawal of pancreatic enzymes. The boy also received vitamin D3 supplementation. After approximately one year of following the ATP, the disease progression was arrested, as indicated by follow-up images and investigations. The size of the pancreatic duct decreased from 8 mm to 2.8 mm. This case report suggests that the ATP may have potential efficacy in managing hereditary pancreatitis and halting disease progression. However, it is important to note that this is a single case report, and further research and clinical studies are needed to validate the long-term benefits and understand the underlying mechanisms of Ayurvedic interventions in hereditary pancreatitis.

Differential membrane curvature induced by distinct protein conformers.

Membrane topology changes are associated with various cellular processes and are modulated by synergistic effects between lipid composition and membrane-associated proteins. However, how protein shape or conformational dynamics couples to membrane molecular properties remains unclear. In this work, we aim to investigate this coupling behavior using the curvature-inducing protein caveolin-1. We considered distinct protein conformers of the helical hairpin protein corresponding to different protein shapes, such as the wedge and the banana-shaped conformers. The different protein conformers were simulated in a coarse-grain representation in the presence of cholesterol-sphingomyelin rich membrane. We observed that membrane curvature is dependent on protein shape and is the lowest for the wedge conformer and maximal for the banana conformer. The differences in the net stress between the two membrane leaflets, calculated from the lateral pressure profile distributions in lipid bilayers for different protein conformers, show a similar trend. In conjunction, we show that cholesterol and sphingomyelin clustering in the membrane is modulated by protein shape. Overall, our results provide molecular-level insights into the coupling between membrane topology, protein shape and lipid clustering in cell membranes.

Cofilin-Membrane Interactions: Electrostatic Effects in Phosphoinositide Lipid Binding.

The actin cytoskeleton interacts with the cell membrane primarily through the indirect interactions of actin-binding proteins such as cofilin-1. The molecular mechanisms underlying the specific interactions of cofilin-1 with membrane lipids are still unclear. Here, we performed coarse-grain molecular dynamics simulations of cofilin-1 with complex lipid bilayers to analyze the specificity of protein-lipid interactions. We observed the maximal interactions with phosphoinositide (PIP) lipids, especially PIP2 and PIP3 lipids. A good match was observed between the residues predicted to interact and previous experimental studies. The clustering of PIP lipids around the membrane bound protein leads to an overall lipid demixing and gives rise to persistent membrane curvature. Further, through a series of control simulations, we observe that both electrostatics and geometry are critical for specificity of lipid binding. Our current study is a step towards understanding the physico-chemical basis of cofilin-PIP lipid interactions.

Molecular Mechanisms Underlying Caveolin-1 Mediated Membrane Curvature.

Caveolin-1 is one of the main protein components of caveolae that acts as a mechanosensor at the cell membrane. The interactions of caveolin-1 with membranes have been shown to lead to complex effects such as curvature and the clustering of specific lipids. Here, we review the emerging concepts on the molecular interactions of caveolin-1, with a focus on insights from coarse-grain molecular dynamics simulations. Consensus structural models of caveolin-1 report a helix-turn-helix core motif with flanking domains of higher disorder that could be membrane composition dependent. Caveolin-1 appears to be mainly surface-bound and does not embed very deep in the membrane to which it is bound. The most interesting aspect of caveolin-1 membrane binding is the interplay of cholesterol clustering and membrane curvature. Although cholesterol has been reported to cluster in the vicinity of caveolin-1 by several approaches, simulations show that the clustering is maximal in membrane leaflet opposing the surface-bound caveolin-1. The intrinsic negative curvature of cholesterol appears to stabilize the negative curvature in the opposing leaflet. In fact, the simulations show that blocking cholesterol clustering (through artificial position restraints) blocks membrane curvature, and vice versa. Concomitant with cholesterol clustering is sphingomyelin clustering, again in the opposing leaflet, but in a concentration-dependent manner. The differential stress due to caveolin-1 binding and the inherent asymmetry of the membrane leaflets could be the determinant for membrane curvature and needs to be further probed. The review is an important step to reconcile the molecular level details emerging from simulations with the mesoscopic details provided by state of the art experimental approaches.

Caveolin induced membrane curvature and lipid clustering: two sides of the same coin?

Caveolin-1 (cav-1) is a multi-domain membrane protein that is a key player in cell signaling, endocytosis and mechanoprotection. It is the principle component of cholesterol-rich caveolar domains and has been reported to induce membrane curvature. The molecular mechanisms underlying the interactions of cav-1 with complex membranes, leading to modulation of membrane topology and the formation of cholesterol-rich domains, remain elusive. In this study, we aim to understand the effect of lipid composition by analyzing the interactions of cav-1 with complex membrane bilayers comprised of about sixty lipid types. We have performed a series of coarse-grain molecular dynamics simulations using the Martini force-field with a cav-1 protein construct (residue 82-136) that includes the membrane binding domains and a palmitoyl tail. We observe that cav-1 induces curvature in this complex membrane, though it is restricted to a nanometer length scale. Concurrently, we observe a clustering of cholesterol, sphingolipids and other lipid molecules leading to the formation of nanodomains. Direct microsecond timescale interactions are observed for specific lipids such as cholesterol, phosphatidylserine and phosphatidylethanolamine lipid types. The results indicate that there is an interplay between membrane topology and lipid species. Our work is a step toward understanding how lipid composition and organization regulate the formation of caveolae, in the context of endocytosis and cell signaling.

Sphingomyelin Effects in Caveolin-1 Mediated Membrane Curvature.

The caveolin-1 (cav-1) protein is an integral component of caveolae and has been reported to colocalize with cholesterol and sphingomyelin-rich curved membrane domains. Here, we analyze the molecular interactions between cav-1 and sphingomyelin containing bilayers using a series of coarse-grain simulations, focusing on lipid clustering and membrane curvature. We considered a palmitoylated-cav-1 construct interacting with phospholipid/cholesterol membranes with asymmetrically distributed sphingomyelin, varying between 5 and 15% in total. We observe that cav-1 binds to the intracellular leaflet and induces a small positive curvature in the leaflet to which it is bound and an opposing negative curvature in the extracellular leaflet. Both cholesterol and sphingomyelin are observed to cluster in cav-1 bound membranes, mainly in the extracellular leaflet. Due to their negative spontaneous curvature, clustering of cholesterol and sphingomyelin facilitates membrane curvature such that the extent of either cholesterol or sphingomyelin clustering is dependent on the curvature induced. Our results suggest that cav-1 binding induces concentration-dependent curvature effects in sphingomyelin-rich membranes. Overall, our work is an important step in understanding the molecular basis of curvature and lipid clustering in cav-1 bound cellular membranes.

Comparison of Serum Apolipoproteins and Traditional Lipids in Eyes with Diabetic Retinopathy in Indian Population: A Case Series.

PURPOSE: To review the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy (DR). MATERIALS AND METHODS: This was a cross-sectional study of patients of DR. DR was graded according to modified Airlie House Classification system. Traditional serum lipids (total, low-density lipoprotein [LDL], and high-density lipoprotein [HDL] cholesterol and triglycerides [TGs]), apolipoprotein AI (apoAI), apolipoprotein B (apoB), and apoB-to-apoAI ratios were assessed. The analysis of variance test was applied. P < 0.05 was considered statistically significant, and P < 0.001 was considered highly significant. RESULTS: Twenty-four patients with DR were evaluated. Serum apoAI was statistically significantly associated with a reduced likelihood of having more severe DR levels (P < 0.001). Increasing levels of apoB (P < 0.001) and apoB-to-apoAI ratio (P < 0.001) were statistically significantly associated with increasing DR severity levels. The association of total (P > 0.05) and LDL cholesterol (P > 0.05) with severity of DR was not statistically significant. HDL cholesterol levels were inversely associated with the severity of DR (P < 0.05). TGs were also statistically significantly associated with the severity of DR (P < 0.05). CONCLUSION: Serum apolipoprotein levels may be stronger biomarkers of DR than traditional lipids.

Fluctuations in the DNA double helix: A critical review.

A critical overview of the extensive literature on fluctuations in the DNA double helix is presented. Both theory and experiment are comprehensively reviewed and analyzed. Fluctuations, which open up the DNA double helix making bases accessible for hydrogen exchange and chemical modification, are the main focus of the review. Theoretical descriptions of the DNA fluctuations are discussed with special emphasis on most popular among them: the nonlinear-dynamic Peyrard-Bishop-Dauxois (PBD) model and the empirical two-state (or helix-coil) model. The experimental data on the issue are comprehensibly overviewed in the historical retrospective with main emphasis on the hydrogen exchange data and formaldehyde kinetics. The theoretical descriptions are critically evaluated from the viewpoint of their applicability to describe DNA in water environment and from the viewpoint of agreement of their predictions with the reliable experimental data. The presented analysis makes it possible to conclude that, while the two-state model is most adequate from theoretical viewpoint and its predictions, based on an empirical parametrization, agree with experimental data very well, the PBD model is inapplicable to DNA in water from theoretical viewpoint on one hand and it makes predictions totally incompatible with reliable experimental data on the other. In particular, it is argued that any oscillation movements of nucleotides, assumed by the PBD model, are severely damped in water, that no "bubbles", which the PBD model predicts, exist in reality in linear DNA well below the melting range and the lifetime of an open state in DNA is actually 5 orders of magnitude longer than the value predicted by the PBD model.

Shear unzipping of double-stranded DNA.

We use a simple nonlinear scaler displacement model to calculate the distribution of effects created by a shear stress on a double-stranded DNA (dsDNA) molecule and the value of shear force F(c) that is required to separate the two strands of a molecule at a given temperature. It is shown that for molecules of base pairs fewer than than 21, the entire single strand moves in the direction of applied force, whereas for molecules having base pairs more than 21, part of the strand moves in the opposite direction under the influence of force acting on the other strand. This result as well as the calculated values of F(c) as a function of length of dsDNA molecules are in very good agreement with the experimental values of Hatch et al. [Phys. Rev. E 78, 011920 (2008)].

Visual outcome and electron microscopic features of indocyanine green-assisted internal limiting membrane peeling from macular hole of various aetiologies.

PURPOSE: To describe the visual outcome of internal limiting membrane (ILM) peeling for macular hole of various aetiologies and ultrastructural features of the ILM. MATERIALS AND METHODS: The study was conducted on 40 eyes of 38 patients. Thirty eyes with full thickness macular hole were treated with vitrectomy and removal of ILM. Ten eyes with retinal detachment served as negative controls and these patients underwent vitrectomy and ILM removal. The surgical specimens were examined by transmission electron microscopy. RESULTS: The anatomical success rate of the first operation was 90% in idiopathic and myopic groups, whereas it was 100% in traumatic macular hole group. Visual improvement of (3) two lines was noted in 80% of the cases. Electron microscopy revealed the presence of ILM in all surgical specimens. Proliferation of astrocytes and synthesis of new collagen along the inner surface of ILM was noted in the surgical specimens. CONCLUSION: Our findings suggest that the ILM removal helps in closure of the macular hole and retinal reattachment. Vitrectomy with ILM peeling is a reasonable surgical approach to treat macular holes of idiopathic, myopic and traumatic aetiology.