Landscape of Differentiation Potentials as a "Hallmark" in Oral-derived MSCs.

Background: Mesenchymal stem cells (MSCs) offer clinical promise for use in cell therapy approaches for regenerative medicine. A therapeutic challenge is that MSCs from different tissues are phenotypically and functionally distinct. Therefore, this study aims to molecularly characterize oral-derived MSCs by defining one of the three hallmarks of MSCs, differentiation potential, to discern their true molecular identities. Methods: Three different populations of oral tissue MSCs (from alveolar bone-aBMSCs; from dental pulp-DPSCs; and from gingiva-GMSCs) from three different patients were isolated and cultured. These MSCs were characterized for their stemness by flow cytometry and multi-differentiation potential, and their RNA was also isolated and analyzed quantitatively with RNA sequencing. Total mRNA-seq was performed and differentially expressed genes (DEGs) were identified in pairwise (DPSCs vs. aBMSCs, GMSCs vs. aBMSCs, and GMSCs vs. DPSCs) and tissue-specific comparisons (aBMSCs vs. Others, DPSCs vs. Others, GMSCs vs. Others) (FDR, p<0.05 ). Further, these DEGs, either common between MSC populations or unique to a specific MSC population, were evaluated for pathways and biological processes. Results: aBMSCs, DPSCs, and GMSCs were successfully isolated and characterized. The tissue-specific comparison revealed that DEGs were most numerous in DPSCs (693 genes) as compared to aBMSCs (103 genes) or DPSCs (232 genes). Statistically significant DEGs through pairwise comparisons present higher numbers in GMSCs vs. DPSCs (627) as compared to either DPSCs vs aBMSCs (286) or GMSCs vs. aBMSCs (82). Further analysis found that RUNX2, IBSP, SOX6, ACAN, and VCAM1 were significantly upregulated in aBMSCs. In DPSCs, BMP4 and IL6 were significantly downregulated, whereas AXL and NES were significantly upregulated. In GMSCs, AGPT1, SEMA4D, and PGDFA were significantly downregulated. Additionally, MAPK, PI3-AKT, and RAS signaling pathways were significantly regulated in GMSCs. Interestingly, aBMSCs and DPSCs revealed positive regulation of osteoblast differentiation, whereas GMSCs revealed negative regulation of osteoblast differentiation. DPSCs also revealed negative regulation of angiogenesis. Conclusions: Oral-derived MSCs have an inherent "landscape" of differentiation defined by their tissue of origin; yet this differentiation potential can be modulated by their microenvironment.

Consensus Statement from India on the Renal Benefits of ARNi, SGLT-2i, and Bisoprolol in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in India. CKD often coexists with heart failure (HF), diabetes, and hypertension. All these comorbidities are risk factors for renal impairment. HF and CKD are pathophysiologically intertwined, and the deterioration of one can worsen the prognosis of the other. There is a need for safe renal pharmacological therapies that target both CKD and HF and are also useful in hypertension and diabetes. Neurohormonal activation achieved through the activation of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and the natriuretic peptide system (NPS) is fundamental in the pathogenesis and progression of CKD and HF. Angiotensin receptor neprilysin inhibitor (ARNi), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and selective ß1-blocker (B1B) bisoprolol suppress this neurohormonal activation. They also have many other cardiorenal benefits across a wide range of CKD patients with or without concomitant HF, diabetes, or hypertension. This consensus statement from India explores the place of ARNi, SGLT-2i, and bisoprolol in the management of CKD patients with or without HF and other comorbidities.

Current Place of SGLT2i in the Management of Heart Failure: An Expert Opinion from India.

Heart failure (HF) is a global health concern that is prevalent in India as well. HF is reported at a younger age in Indian patients with comorbidity of type 2 diabetes (T2DM) in approximately 50% of patients. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), originally approved for T2DM, are new guideline-recommended and approved treatment strategies for HF. Extensive evidence highlights that SGLT2i exhibits profound cardiovascular (CV) benefits beyond glycemic control. SGLT2i, in conjunction with other guideline-directed medical therapies (GMDT), has additive effects in improving heart function and reducing adverse HF outcomes. The benefits of SGLT2i are across a spectrum of patients, with and without diabetes, suggesting their potential place in broader HF populations irrespective of ejection fraction (EF). This consensus builds on the updated evidence of the efficacy and safety of SGLT2i in HF and recommends its place in therapy with a focus on Indian patients with HF.

Injectable Tissue-Specific Hydrogel System for Pulp-Dentin Regeneration.

The quest for finding a suitable scaffold system that supports cell survival and function and, ultimately, the regeneration of the pulp-dentin complex remains challenging. Herein, we hypothesized that dental pulp stem cells (DPSCs) encapsulated in a collagen-based hydrogel with varying stiffness would regenerate functional dental pulp and dentin when concentrically injected into the tooth slices. Collagen hydrogels with concentrations of 3 mg/mL (Col3) and 10 mg/mL (Col10) were prepared, and their stiffness and microstructure were assessed using a rheometer and scanning electron microscopy, respectively. DPSCs were then encapsulated in the hydrogels, and their viability and differentiation capacity toward endothelial and odontogenic lineages were evaluated using live/dead assay and quantitative real-time polymerase chain reaction. For in vivo experiments, DPSC-encapsulated collagen hydrogels with different stiffness, with or without growth factors, were injected into pulp chambers of dentin tooth slices and implanted subcutaneously in severe combined immunodeficient (SCID) mice. Specifically, vascular endothelial growth factor (VEGF [50 ng/mL]) was loaded into Col3 and bone morphogenetic protein (BMP2 [50 ng/mL]) into Col10. Pulp-dentin regeneration was evaluated by histological and immunofluorescence staining. Data were analyzed using 1-way or 2-way analysis of variance accordingly (α = 0.05). Rheology and microscopy data revealed that Col10 had a stiffness of 8,142 Pa with a more condensed and less porous structure, whereas Col3 had a stiffness of 735 Pa with a loose microstructure. Furthermore, both Col3 and Col10 supported DPSCs' survival. Quantitative polymerase chain reaction showed Col3 promoted significantly higher von Willebrand factor (VWF) and CD31 expression after 7 and 14 d under endothelial differentiation conditions (P < 0.05), whereas Col10 enhanced the expression of dentin sialophosphoprotein (DSPP), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and collagen 1 (Col1) after 7, 14, and 21 d of odontogenic differentiation (P < 0.05). Hematoxylin and eosin and immunofluorescence (CD31 and vWF) staining revealed Col10+Col3+DPSCs+GFs enhanced pulp-dentin tissue regeneration. In conclusion, the collagen-based concentric construct modified by growth factors guided the specific lineage differentiation of DPSCs and promoted pulp-dentin tissue regeneration in vivo.

The Power and Promise of Angiotensin Receptor Neprilysin Inhibitor (ARNI) in Heart Failure Management: National Consensus Statement.

;Heart failure (HF) is a huge global public health task due to morbidity, mortality, disturbed quality of life, and major economic burden. It is an area of active research and newer treatment strategies are evolving. Recently angiotensin receptor-neprilysin inhibitor (ARNI), a class of drugs (the first agent in this class, Sacubitril-Valsartan), reduces cardiovascular mortality and morbidity in chronic HF patients with reduced left ventricular ejection fraction (LVEF). Positive therapeutic effects have led to a decrease in cardiovascular mortality and HF hospitalizations (HFH), with a favorable safety profile, and have been documented in several clinical studies with an unquestionable survival benefit with ARNI, Sacubitril-Valsartan. This consensus statement of the Indian group of experts in cardiology, nephrology, and diabetes provides a comprehensive review of the power and promise of ARNI in HF management and an evidence-based appraisal of the use of ARNI as an essential treatment strategy for HF patients in clinical practice. Consensus in this review favors an early utility of Sacubitril-Valsartan in patients with HF with reduced EF (HFrEF), regardless of the previous therapy being given. A lower rate of hospitalizations for HF with Sacubitril-Valsartan in HF patients with preserved EF who are phenotypically heterogeneous suggests possible benefits of ARNI in patients having 40-50% of LVEF, frequent subtle systolic dysfunction, and higher hospitalization risk.

Role of Iron Therapy in Heart Failure: A Consensus Statement from India.

Iron deficiency (ID) with or without anemia is frequently observed in patients with heart failure (HF). Uncorrected ID is associated with higher hospitalization and mortality in patients with acute HF (AHF) and chronic HF (CHF). Hence, in addition to chronic renal insufficiency, anemia, and diabetes, ID appears as a novel comorbidity and a treatment target of CHF. Intravenous (IV) ferric carboxymaltose (FCM) reduces the hospitalization risk due to HF worsening and improves functional capacity and quality of life (QOL) in HF patients. The current consensus document provides criteria, an expert opinion on the diagnosis of ID in HF, patient profiles for IV FCM, and correct administration and monitoring of such patients.

Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India.

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), ß-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Role of Bisoprolol in Heart Failure Management: A Consensus Statement from India.

In India, heart failure (HF) is an important health concern affecting younger age groups than the western population. A limited number of Indian patients receive guideline-directed medical therapy (GDMT). Selective ß-1 blockers (BB) are one of the GDMTs in HF and play an important role by decreasing the sympathetic overdrive. The BB reduces heart rate (HR) reverse the adverse cardiac (both ventricular and atrial), vascular, and renovascular remodeling seen in HF. Bisoprolol, a ß-1 blocker, has several advantages and can be used across a wide spectrum of HF presentations and in patients with HF and comorbid conditions such as coronary artery disease (CAD), atrial fibrillation (AF), post-myocardial infarction (MI), uncontrolled diabetes, uncontrolled hypertension, and renal impairment. Despite its advantages, bisoprolol is not optimally utilized for managing HF in India. This consensus builds on updated evidence on the efficacy and safety of bisoprolol in HF and recommends its place in therapy with a focus on Indian patients with HF.

HIF-1α Stabilization Boosts Pulp Regeneration by Modulating Cell Metabolism.

Stem cell-based therapeutics is a promising strategy in dental pulp regeneration. However, low cell viability after transplantation in vivo due to the ischemic microenvironment is still a critical challenge for future clinical application. With the aim of improving postimplantation cell survival and pulp tissue regeneration, stem cells from human exfoliated deciduous teeth (SHED) were preconditioned to a hypoxic condition by hypoxia-inducible factor 1α (HIF-1α) stabilization via knockdown of prolyl hydroxylase domain-containing protein 2 (PHD2) using lentiviral short hairpin RNA. HIF-1α-stabilized SHED were encapsulated in PuraMatrix hydrogel, injected into root canals of human tooth fragments, and implanted in the subcutaneous space of immunodeficient mice. After 28 d, enhanced dental pulp-like tissue formation was observed with a significantly higher level of vascularization, which could be attributed to both endothelial differentiation of SHED and recruitment of host blood vessels. Furthermore, dentin-like tissue formation in vivo and accelerated odontogenic/osteogenic differentiation both in vivo and in vitro were observed. At 7 d postimplantation, significantly less DNA damage and higher Ki67 expression were detected in the HIF-1α-stabilized SHED group compared with the control SHED. Accordingly, cell viability assay and staining for Ki67 and apoptotic cells in vitro showed that HIF-1α stabilization could decrease cell apoptosis and enhance cell survival significantly. We demonstrated that PI3K/AKT pathway activation had resulted in low caspase 3 expression in HIF-1α-stabilized SHED in hypoxic conditions. Furthermore, we found that HIF-1α-induced cell survival could also be attributed to the upregulated expression of PDK1, HK2, and Glut1, which contributes to the maintenance of reactive oxygen species homeostasis and metabolic adaptation in hypoxia. In addition, we identified Smad7 as 1 of the top 3 upregulated genes through RNA sequencing in HIF-1α-stabilized SHED and demonstrated its essential role in HK2 and Glut1 upregulation. Taken together, HIF-1α stabilization enhances cell survival of SHED through modulating various target genes and potential signaling pathways, as well as odontogenic tissue formation during dental pulp regeneration, which could benefit stem cell-based therapy in general.

COVID-Inflicted Coagulopathy: Expert Consensus on Management with Novel Oral Anticoagulants in India.

Coronavirus disease 2019 (COVID-19) is a highly hypercoagulable viral infection complicated as COVID-inflicted coagulopathy (CIC), that is associated with increased risk of morbidity and mortality. International guidelines recommend low molecular weight heparin (LMWH) to treat CIC in both in-hospital and in-home settings. However, in India, using subcutaneous LMWH may not be a feasible option for a vast majority of patients under home management. Additionally, while some evidence advocates the use of novel oral anticoagulants (NOACs), in hospitalized settings, most guidelines find no role of NOACs in hospital settings. On the other hand, the resource crunch faced in recent COVID-19 pandemic in India forced physicians to treat many patients in home settings. These patients had been usually prescribed NOACs for ease of administration and adherence. Therefore, there is a need to form a consensus on the use of NOACs to manage CIC in India.

Rheumatic Heart Disease in India in 2020: Advances in Diagnostic and Therapeutic Options.

Rheumatic Fever (RF)/ Rheumatic Heart Disease (RHD) is the result of autoimmune response triggered by group A Beta-haemolytic streptococcal pharyngitis leading to immune-inflammatory injury to cardiac valves. It is practically disappeared in developed countries. However, it continues to be a major cause of disease burden among children, adolescents, and young adults in low-income countries and even in high-income countries with socioeconomic inequalities. For decades, many cases of Acute Rheumatic Fever (ARF) and RHD were missed and were denied the secondary prophylaxis, as a result these patients used to end up with complications and untimely death. Advanced understanding of the echocardiography can prevent both under diagnosis and over diagnosis and thus help in management strategy. Another new advancement in recent past is the mitral valve repair, which is technically demanding, and the results are acceptable in experienced cardiac surgical units. Whenever feasible, valve repair should be preferred over valve replacement since it precludes the need for anticoagulation and future risks of prosthesis dysfunction.

Cardiological society of India document on safety measure during echo evaluation of cardiovascular disease in the time of COVID-19.

An echocardiographic investigation is one of the key modalities of diagnosis in cardiology. There has been a rising presence of cardiological comorbidities in patients positive for COVID-19. Hence, it is becoming extremely essential to look into the correct safety precautions, healthcare professionals must take while conducting an echo investigation. The decision matrix formulated for conducting an echocardiographic evaluation is based on presence or absence of cardiological comorbidity vis-à-vis positive, suspected or negative for COVID-19. The safety measures have been constructed keeping in mind the current safety precautions by WHO, CDC and MoHFW, India.

Cardiological Society of India: Document on acute MI care during COVID-19.

The unprecedented and rapidly spreading Coronavirus Disease-19 (COVID-19) pandemic has challenged public health care systems globally. Based on worldwide experience, India has initiated a nationwide lockdown to prevent the exponential surge of cases. During COVID-19, management of cardiovascular emergencies like acute Myocardial Infarction (MI) may be compromised. Cardiological Society of India (CSI) has ventured in this moment of crisis to evolve a consensus document for care of acute MI. However, this care should be individualized, based on local expertise and governmental advisories.

Prevalence of hypertension among Indian adults: Results from the great India blood pressure survey.

OBJECTIVE: Hypertension is the most important risk factor for cardiovascular morbidity and mortality. There is limited data on hypertension prevalence in India. This study was conducted to estimate the prevalence of hypertension among Indian adults. METHODS: A national level survey was conducted with fixed one-day blood pressure measurement camps across 24 states and union territories of India. Hypertension was defined as systolic blood pressure (BP) ≥140 mmHg or a diastolic BP ≥90 mmHg or on treatment for hypertension. The prevalence was age- and gender-standardized according to the 2011 census population of India. RESULTS: Blood pressure was recorded for 180,335 participants (33.2% women; mean age 40.6 ± 14.9 years). Among them, 8,898 (4.9%), 99,791 (55.3%), 35,694 (11.9%), 23,084 (12.8%), 9,989 (5.5%), and 2,878 (1.6%) participants were of the age group 18-19, 20-44, 45-54, 55-64, 65-74, and ≥ 75 years, respectively. Overall prevalence of hypertension was 30.7% (95% confidence interval [CI]: 30.5, 30.9) and the prevalence among women was 23.7% (95% CI: 23.3, 24). Prevalence adjusted for 2011 census population and the WHO reference population was 29.7% and 32.8%, respectively. CONCLUSION: There is a high prevalence of hypertension, with almost one in every three Indian adult affected.

Insights into Endothelial Progenitor Cells: Origin, Classification, Potentials, and Prospects.

With the discovery of endothelial progenitor cells (EPCs) in the late 1990s, a paradigm shift in the concept of neoangiogenesis occurred. The identification of circulating EPCs in peripheral blood marked the beginning of a new era with enormous potential in the rapidly transforming regenerative field. Overwhelmed with the revelation, researchers across the globe focused on isolating, defining, and interpreting the role of EPCs in various physiological and pathological conditions. Consequently, controversies emerged regarding the isolation techniques and classification of EPCs. Nevertheless, the potential of using EPCs in tissue engineering as an angiogenic source has been extensively explored. Concomitantly, the impact of EPCs on various diseases, such as diabetes, cancer, and cardiovascular diseases, has been studied. Within the limitations of the current knowledge, this review attempts to delineate the concept of EPCs in a sequential manner from the speculative history to a definitive presence (origin, sources of EPCs, isolation, and identification) and significance of these EPCs. Additionally, this review is aimed at serving as a guide for investigators, identifying potential research gaps, and summarizing our current and future prospects regarding EPCs.

Acute effects of diets rich in almonds and walnuts on endothelial function.

OBJECTIVE: Omega-3 fatty acids, especially alpha-linolenic acid (ALA), which are present in nuts may reduce cardiovascular disease (CVD) risk, by changing vascular inflammation and improving endothelial dysfunction. The objective of the study was to evaluate the acute effects of two different diets, one containing walnuts and the other almonds on endothelial function. METHODS: Twenty-seven overweight volunteers underwent a randomized 2-period, crossover, controlled intervention study. The subjects were given either walnut or almond diets which varied in monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) content. The walnut diet provided 23.1% energy from PUFA and the almond diet provided 7.6% energy from PUFA. Endothelial function was assessed physiologically by flow-mediated dilation (FMD) and biochemically by sVCAM (soluble vascular cell adhesion molecules). RESULTS: The walnut diet significantly improved FMD (p=0.004) and decreased sVCAM (p=0.009) whereas the almond diet tended to improve FMD (p=0.06) and significantly decreased sVCAM (p=0.004). CONCLUSION: Both walnut and almond diets improved FMD and sVCAM and there was no significant difference in physiological and biochemical markers between the two diets.