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The dopaminergic system is involved in the regulation of immune responses in various homeostatic and disease conditions. For conditions such as Parkinson’s disease and multiple sclerosis (MS), pharmacological modulation of dopamine (DA) system activity is thought to have therapeutic relevance, providing the basis for using dopaminergic agents as a treatment of relevant states. In particular, it was proposed that restoration of DA levels may inhibit neuroinflammation. We have recently reported a new class of dopamine transporter (DAT) inhibitors with high selectivity to the DAT over other G-protein coupled receptors tested. Here, we continue their evaluation as monoamine transporter inhibitors. Furthermore, we show that the urea-like DAT inhibitor (compound 5) has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors in the experimental autoimmune encephalomyelitis model mimicking clinical signs of MS. To the best of our knowledge, this is the first study reporting the beneficial effects of DAT inhibitor-based treatment in animals with induced autoimmune encephalomyelitis, and the observed results provide additional support to the model of DA-related neuroinflammation.

Transplantation of stem cells for treating neurodegenerative disorders is a promising future therapeutic approach. However, the molecular mechanism underlying the neuronal differentiation of mesenchymal stem cells remains inadequately explored. Therefore, the current study aims to define the regulatory role of KLF2 (Kruppel-like factor 2) during the neural differentiation (ND) of dental pulp-derived stem cells (DPSC). Herein, we showed that the expression level of KLF2, autophagy and mitophagy-associated markers were significantly elevated during ND of DPSC. We next validated our results using the chemical-mediated loss- and gain-of-function approaches. We found that the KLF2 inhibitor, GGPP (geranylgeranyl pyrophosphate) significantly reduces the ND of DPSC. Inversely, KLF2 overexpression was accomplished by using the KLF2 inducer, GGTI-298 (geranylgeranyl transferase inhibitor-298) which accelerated the molecular phenomenon of DPSC’s commitment towards ND, indicating the crucial function of KLF2 in neurogenesis. Moreover, we found that the KLF2 positively regulated autophagy, mitophagy, and the Wnt5a signaling pathway during neurogenesis. Furthermore, we measured the oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR) during ND in the presence of a KLF2 inducer or KLF2 inhibitor using the Xeflux analyzer. We found that most of the ECAR and OCR parameters were significantly increased during ND and inhibition of KLF2 marginally reversed them towards DPSC’s cellular bioenergetics. However, KLF2 overexpression shifted the cellular energy metabolism towards quiescent. Cumulatively, our findings provide the first evidence that the KLF2 critically regulates the neurogenesis of DPSC by inducing autophagy and mitophagy.

Astrocytes have been implicated in the onset and complication of various central nervous system (CNS) injuries and disorders. Uncontrolled astrogliosis (gliosis), while a necessary process for recovery after CNS trauma, also causes impairments in CNS performance and functions. The ability to preserve astrocyte health and better regulate the gliosis process could play a major role in controlling damage in the aftermath of acute insults and during chronic dysfunction. Here in, we demonstrate the ability of dental pulp-derived stem cells (DPSCs) in protecting the health of astrocytes during induced gliosis. First of all, we have characterized the expression of genes in primary astrocytes that are relevant to the pathological conditions of CNS by inducing gliosis. Subsequently, we found that astrocytes co-cultured with DPSCs reduced ROS production, NRF2 and GCLM expressions, mitochondrial membrane potential, and mitochondrial functions compared to the astrocytes that were not co-cultured with DPSCs in gliosis condition. In addition, hyperactive autophagy was also decreased in astrocytes that were co-cultured with DPSCs compared to the astrocytes that were not co-cultured with DPSCs during gliosis. This reversal and mitigation of gliosis in astrocytes were partly due to induction of neurogenesis in DPSCs through enhanced expressions of the neuronal genes like GFAP, NeuN, and Synapsin in DPSCs and by secretion of higher amounts of neurotropic factors, such as BDNF, GDNF, and TIMP-2. Protein-Protein docking analysis suggested that BDNF and GDNF can bind with CSPG4 and block the downstream signaling. Together these findings demonstrate novel functions of DPSCs to preserve astrocyte health during gliosis.

Osteoclasts (OCs) differentiate from the monocyte/macrophage lineage, critically regulate bone resorption and remodelling in both homeostasis and pathology. Various immune and non‐immune cells help initiating activation of myeloid cells for differentiation, whereas hyper‐activation leads to pathogenesis, and mechanisms are yet to be completely understood. Herein, we show the efficacy of dental pulp–derived stem cells (DPSCs) in limiting RAW 264.7 cell differentiation and underlying molecular mechanism, which has the potential for future therapeutic application in bone‐related disorders. We found that DPSCs inhibit induced OC differentiation of RAW 264.7 cells when co‐cultured in a contact‐free system. DPSCs reduced expression of key OC markers, such as NFATc1, cathepsin K, TRAP, RANK and MMP‐9 assessed by quantitative RT‐PCR, Western blotting and immunofluorescence detection methods. Furthermore, quantitative RT‐PCR analysis revealed that DPSCs mediated M2 polarization of RAW 264.7 cells. To define molecular mechanisms, we found that osteoprotegerin (OPG), an OC inhibitory factor, was up‐regulated in RAW 264.7 cells in the presence of DPSCs. Moreover, DPSCs also constitutively secrete OPG that contributed in limiting OC differentiation. Finally, the addition of recombinant OPG inhibited OC differentiation in a dose‐dependent manner by reducing the expression of OC differentiation markers, NFATc1, cathepsin K, TRAP, RANK and MMP9 in RAW 264.7 cells. RNAKL and M‐CSF phosphorylate AKT and activate PI3K‐AKT signalling pathway during osteoclast differentiation. We further confirmed that OPG‐mediated inhibition of the downstream activation of PI3K‐AKT signalling pathway was similar to the DPSC co‐culture–mediated inhibition of OC differentiation. This study provides novel evidence of DPSC‐mediated inhibition of osteoclastogenesis mechanisms.

To define the role of SETD2 in the WNT5a signaling in the context of osteoclastogenesis, we exploited two different models: in vitro osteoclast differentiation, and K/BxN serum-induced arthritis model. We found that SETD2 and WNT5a were upregulated during osteoclast differentiation and after induction of arthritis. Using gain- and loss-of-function approaches in the myeloid cell, we confirmed that SETD2 regulated the osteoclast markers, and WNT5a via modulating active histone marks by enriching H3K36me3, and by reducing repressive H3K27me3 mark. Additionally, during osteoclastic differentiation, the transcription of Wnt5a was also associated with the active histone H3K9 and H4K8 acetylations. Mechanistically, SETD2 directed induction of NF-κβ expression facilitated the recruitment of H3K9Ac and H4K8Ac around the TSS region of the Wnt5a gene, thereby, assisting osteoclast differentiation. Together these findings for the first time revealed that SETD2 mediated epigenetic regulation of Wnt5a plays a critical role in osteoclastogenesis and induced arthritis. Graphic abstract Model for the Role of SETD2 dependent regulation of osteoclastic differentiation. A In monocyte cells SETD2-dependent H3K36 trimethylation help to create open chromatin region along with active enhancer mark, H3K27Ac. This chromatin state facilitated the loss of a suppressive H3K27me3 mark. B Additionally, SETD2 mediated induction of NF-κβ expression leads to the recruitment of histone acetyl transferases, P300/PCAF, to the Wnt5a gene and establish H3K9Ac and H4K8Ac marks. Along with other activation marks, these acetylation marks help in Wnt5a transcription which leads to osteoclastogenesis.

Sloan W Rush,1,2 Jennifer Chain,3 Hiranmoy Das2 1Panhandle Eye Group, Amarillo, TX, 79106, USA; 2Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA; 3Oklahoma Blood Institute, Oklahoma City, OK, 73104, USACorrespondence: Sloan W RushPanhandle Eye Group, 7400 Fleming Ave, Amarillo, TX, 79106, USATel +1 806 353-0125Email sloan.rush@paneye.comPurpose: To report the subjective assessment of topical self-administered, cadaver-derived corneal epithelial stem cell supernatant for treatment of severe dry eye disease (DED).Methods: Thirty-four eyes of 17 patients with advanced DED as defined by Standardized Patient Evaluation of Eye Dryness (SPEEDTM) questionnaire ≥ 14, Ocular Surface Disease Index (OSDI©) score ≥ 40 and documented attempt of at least six conventional dry eye therapies were enrolled into a prospective clinical trial at a single private practice institution. Treatment consisted of patient self-administered topical instillation of the corneal epithelial stem cell-derived product four times daily in both eyes for 12 weeks. Patient-reported outcome measures (PROMs) were taken with the SPEEDTM questionnaire (the main outcome variable), OSDI© score and visual analog score (VAS; UNC Dry Eye Management Scale©), and objective clinical measurements were taken with best-corrected visual acuity (BCVA), corneal topographic index measurements and tear film osmolarity. These measurements were compared at baseline versus the endpoint at completion of the 12-week treatment.Results: All 34 eyes tolerated the treatment without any adverse events or significant side effects. Compared with baseline, both the SPEEDTM questionnaire and the VAS significantly improved at the conclusion of the 12-week treatment (p = 0.0054 and p = 0.0202, respectively). The OSDI© improved by an average of 10.9 points after the treatment but was not statistically significant (p = 0.1409). There were no significant changes in any of the objective clinical measurements. None of the study subjects failed to complete the treatment course, experienced decrease in any of the PROMs or lost one or more lines of BCVA during the follow-up period.Conclusion: Topical corneal epithelial stem cell-derived supernatant that can be self-administered by the patient shows promise at improving patient symptoms and quality of life in the setting of severe DED that is unresponsive to conventional therapies.Keywords: dry eye disease, corneal epithelial stem cells, conjunctival goblet cells, supernatant, chronic ocular surface disease, glycocalyx, galectin-3, mucins

Despite advances in diabetic wound care, the significant number of amputations that occur every year demands more effective therapeutics. Herein, we offer an aminated polyethersulfone nanofiber-expanded human umbilical cord blood-derived CD34+ cells (henceforth CD34+ cells) effective therapy, tested in cutaneous wounds developed in streptozotocin-induced diabetic NOD/SCID mice. We show that systemic administration of CD34+ cells homed to the wound site and significantly accelerated wound closure. Wound closure was associated with improved re-epithelialization and increased neovascularization; and with decreased sustained pro-inflammatory activity of NF-κB and its downstream effector molecules TNF-α, IL-1β, and IL-6 at the wound bed. This finding was further supported by the observation of a decreased number of myeloperoxidase positive neutrophils, and concomitantly increased levels of IL-10. In addition, improved granulation tissue formation was observed along with higher collagen deposition and myofibroblasts and decreased expressions of MMP-1. Mechanistically, CD34+ cells reduced the level of MMP-1 expression by inhibiting recruitment of NF-κB to the MMP-1 promoter site in dermal fibroblasts. In summary, we provide evidence of a novel nanofiber-expanded CD34+ stem cell therapeutic development for treating diabetic wounds by defining their cellular and molecular mechanisms.

Macroautophagy/autophagy is involved in myeloid cellular repair, destruction, and osteoclast differentiation; conversely, KLF2 (kruppel-like factor 2 [lung]) regulates myeloid cell activation and differentiation. To investigate the specific role of KLF2 in autophagy, osteoclastic differentiation was induced in monocytes in presence or absence of the autophagy inhibitor 3-methyladenine (3-MA), KLF2 inducer geranylgeranyl transferase inhibitor (GGTI298), and adenoviral overexpression of KLF2. We found that the number of autophagic cells and multinucleated osteoclasts were significantly decreased in presence of 3-MA, GGTI298, and KLF2 overexpressed cells indicating involvement of KLF2 in these processes. In addition, autophagy-related protein molecules were significantly decreased after induction of KLF2 during the course of osteoclastic differentiation. Furthermore, induction of arthritis in mice reduced the level of Klf2 in monocytes, and enhanced autophagy during osteoclastic differentiation. Mechanistically, knocking down of KLF2 increased the level of Beclin1 (BECN1) expression, and conversely, KLF2 over-expression reduced the level of BECN1 in monocytes. Moreover, 3-MA and GGTI298 both reduced myeloid cell proliferation concomitantly upregulating senescence-related molecules (CDKN1A/p21 and CDKN1B/p27(kip1)). We further confirmed epigenetic regulation of Becn1 by modulating Klf2; knocking down of Klf2 increased the levels of histone activation marks H3K9 and H4K8 acetylation in the promoter region of Becn1; and overexpression of Klf2 decreased the levels of H4K8 and H3K9 acetylation. In addition, osteoclastic differentiation also increased levels of H3K9 and H4K8 acetylation in the promoter region of Becn1. Together these findings for the first time revealed that Klf2 critically regulates Becn1-mediated autophagy process during osteoclastogenesis. Abbreviations: ACP5/TRAP: acid phosphatase 5, tartrate resistant; Ad-KLF2: adenoviral construct of KLF2; ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1, autophagy related; C57BL/6: inbred mouse strain C57 black 6; ChIP: chromatin immunoprecipitation; CSF1/MCSF: colony stimulating factor 1 (macrophage); CTSK: cathepsin K; EV: empty vector; GGTI298: geranylgeranyl transferase inhibitor; H3K9Ac: histone H3 lysine 9 acetylation; H4K8Ac: histone H4 lysine 8 acetylation; K/BxN mice: T cell receptor (TCR) transgene KRN and the MHC class II molecule A(g7) generates K/BxN mice; KLF2: kruppel-like factor 2 (lung); 3MA: 3-methyladenine; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MDC: monodansylcadaverine; NFATc1: nuclear factor of activated T cells 1; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; p21/CDKN1A: cyclin dependent kinase inhibitor 1A; p27(kip1)/CDKN1B: cyclin-dependent kinase inhibitor 1B; PCR: polymerase chain reaction; PtdIns3K: phosphoinositide 3-kinase; RA: rheumatoid arthritis; siKlf2: small interfering KLF2 ribonucleic acid; NS: non-specific; RAW 264.7: abelson murine leukemia virus transformed macrophage cell line; TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11; TSS: transcriptional start site; UCSC: University of California, Santa Cruz.

Long-term sustainability concerns are growing in agriculture owing to over and under application of fertilizers and poor management of available resources which are resulting into soil health deterioration and declining crop productivity. Balanced and integrated use of organic and inorganic fertilizers is the most logical concept for managing and sustaining long term soil health and crop productivity. Hence, a long-term field experiment was conducted from 2012 to 2017 to develop integrated nutrient management (INM) practices for sustaining crop productivity and maintaining soil health under maize (Zea mays L.) chickpea (Cicer arietinum L.) cropping system in Vertisols of central India. Twelve treatments that comprised of various combinations of general recommended dose (GRD) of NPK, farmyard manure (FYM), poultry manure (poultry manure), urban compost (UC), maize residue (MR), glyricidia loppings (GL) and soil test crop response (STCR) based NPK with target yield 5.0 and 1.50 Mg ha1 in maize and chickpea, respectively were tested. The experiment was conducted following a Randomized Complete Block Design (RCBD) set up with three replications and Simple Random Sampling (SRS) technique of sampling. The results indicated that the grain yield and system yield were observed to be significantly higher with 75% NPK of STCR + FYM at 5 Mg ha1 treatment and recorded an increase of 20.9% and 13.08% in mean grain yield of maize and chickpea, respectively over GRD. The combined analysis results illustrated significant (P

The climate change, as evidenced by changes in temperature rise and increased CO2 concentration, is a major concern. According to the Intergovernmental Panel on Climate Change (IPCC), global temperature is anticipated to upsurge between 1.1 and 6.4 °C during the twenty-first century followed by alteration in precipitation patterns. Soils are directly linked to the climate system through the carbon, nitrogen, and hydrologic cycles. Because of this, the altered climate will have an effect on soil processes and properties. In the recent past, there are numerous studies conducted to study the impact of climate change on crop performance and soil properties. These studies indicated that climate change has a negative impact on soil health by increasing soil degradation through the loss of soil organic carbon, soil erosion, salinization, sodification, acidification, etc. Reversing these downward spirals implies the implementation of best-proven technologies, such as conservation agriculture, integrated nutrient management, precision agriculture, and use of biochar. Bringing back degraded soils under cultivation and sustaining soil health by the adoption of climate-smart agricultural practices is the only way to combat the negative imprints of climate change on soil health and fulfilling the food demands of the ever-growing population.

To define the regulatory role of Kruppel-like factor 2 (KLF2) during osteoblast (OB) differentiation of dental pulp-derived stem cell (DPSC)s, herein, we show that the levels of KLF2 and autophagy-related molecules were significantly increased in differentiated cells. Gain-of-function and loss-of-function approaches of KLF2 confirmed that KLF2 modulated autophagic and OB differentiation-related molecules. In addition, knockdown of the autophagic molecule (ATG7 or BECN1) in DPSCs resulted in reduced levels of KLF2 and OB differentiation-related molecules. Conversely, the induction of autophagy increased levels of KLF2 and OB differentiation-related molecules. Moreover, OB differentiation induced mitophagy and mitochondrial membrane potential-related molecules. In addition, OB differentiation reduced the generation of total and mitochondrial ROS productions and induced intracellular Ca2+ production. Measurements of glycolysis and oxidative phosphorylation simultaneously in live cells revealed that OB differentiation decreased the oxygen consumption rate, which is an indicator of mitochondrial respiration and reduced the level of ATP production. Furthermore, flux analysis also revealed that OB differentiation increased the extracellular acidification rate (ECAR) in the non-glycolytic acidification, and the glycolytic capacity conditions, increasing the lactate production and reducing the metabolic activity of the cells. Thus, a metabolic shift from mitochondrial respiration to the glycolytic pathway was observed during OB differentiation. Finally, chromatin immunoprecipitation (ChIP) analysis confirmed that the KLF2 and active epigenetic marks (H3K27Ac and H3K4me3) were upregulated in the promoter region of ATG7 during OB differentiation. These results provide evidence that the mitophagy process is important during OB differentiation, and KLF2 critically regulates it., Graphical abstract Image 1, Highlights • Osteoblast (OB) differentiation increased KLF2 and autophagy-related molecules. • Gain- and loss-of-function of KLF2 confirmed regulation of autophagic and OB differentiation. • OB differentiation induced mitophagy, mitochondrial membrane potential, and intracellular Ca2+; and reduced ROS, oxygen consumption, and ATP production. • A metabolic shift from mitochondrial respiration to glycolysis during OB differentiation. • KLF2 and active epigenetic marks were upregulated on ATG7 promoter during OB differentiation.

Myocardial ischemia is a common manifestation of cardiovascular diseases (CVD) that affects the health and lives of millions of people worldwide. While numerous treatment options exist that address cardiac damage after ischemic injury, none of these can repair damaged cardiac tissue. Stem cell-mediated therapy is an emerging approach for cardiac tissue regeneration that has shown promise in preclinical models and in clinical studies. However, much more research in this field must be carried out to bring effective stem cell therapies to clinical settings. This protocol discusses the methods for generation of an animal model of myocardial ischemia in a preclinical setting, expansion of viable hematopoietic stem cells on a nanofiber scaffold, and administration of cells into the ischemic animal to verify therapeutic efficacy.

Chronic nonhealing wounds impact nearly 15% of Medicare beneficiaries (8.2 million) in the United States costing $28-$32 billion annually. Despite advancement in wound management, approximately 8% of diabetic Medicare beneficiaries have a foot ulcer and 1.8% will have an amputation. The development of a regenerative approach is warranted to save these before-mentioned amputations. To this extent, herein, we describe the detailed methods in generating a type 1 diabetes mellitus (T1DM) condition in immunocompromised mice, inducing cutaneous wound, and application of dental pulp stem cell-derived secretory products for therapeutic assessment. This model helps in evaluating the efficacy of stem cell-based therapy and helps with the investigation of involved mechanisms in impaired cutaneous wound healing caused by hyperglycemic stress due to type 1 diabetes.

Despite significant advances in diabetic wound management, diabetic wounds remain a significant global problem that decreases patient's quality of life, and chronic wounds may lead to amputation and death to the patients. To develop a potential regenerative therapy, a xenogeneic transplantation compatible laboratory model needs to be developed. This procedure demonstrates how to isolate hematopoietic stem cells (CD133

Critical limb ischemia (CLI) is primarily associated with a high risk of major amputation, cardiovascular events, and death. The current therapy involves direct endovascular intervention and is associated with long-term recurrence. However, patients with significant comorbidities are not eligible for this therapy. Hind limb ischemia model via femoral artery excision has commonly been used to determine therapeutic potential and for investigating cellular and molecular mechanisms. This protocol describes the ischemic model development in NOD/SCID mice and the use of human umbilical cord blood-derived and nanofiber scaffold-expanded CD34

Chronic nonhealing wounds impact nearly 15% of Medicare beneficiaries (8.2 million) in the United States costing $28-$32 billion annually. Despite advancement in wound management, approximately 8% of diabetic Medicare beneficiaries have a foot ulcer and 1.8% will have an amputation. The development of a regenerative approach is warranted to save these before-mentioned amputations. To this extent, herein, we describe the detailed methods in generating a type 1 diabetes mellitus (T1DM) condition in immunocompromised mice, inducing cutaneous wound, and application of dental pulp stem cell-derived secretory products for therapeutic assessment. This model helps in evaluating the efficacy of stem cell-based therapy and helps with the investigation of involved mechanisms in impaired cutaneous wound healing caused by hyperglycemic stress due to type 1 diabetes.

Critical limb ischemia (CLI) is primarily associated with a high risk of major amputation, cardiovascular events, and death. The current therapy involves direct endovascular intervention and is associated with long-term recurrence. However, patients with significant comorbidities are not eligible for this therapy. Hind limb ischemia model via femoral artery excision has commonly been used to determine therapeutic potential and for investigating cellular and molecular mechanisms. This protocol describes the ischemic model development in NOD/SCID mice and the use of human umbilical cord blood-derived and nanofiber scaffold-expanded CD34+ stem cells to investigate the efficacy of regenerative therapy.

Myocardial ischemia is a common manifestation of cardiovascular diseases (CVD) that affects the health and lives of millions of people worldwide. While numerous treatment options exist that address cardiac damage after ischemic injury, none of these can repair damaged cardiac tissue. Stem cell-mediated therapy is an emerging approach for cardiac tissue regeneration that has shown promise in preclinical models and in clinical studies. However, much more research in this field must be carried out to bring effective stem cell therapies to clinical settings. This protocol discusses the methods for generation of an animal model of myocardial ischemia in a preclinical setting, expansion of viable hematopoietic stem cells on a nanofiber scaffold, and administration of cells into the ischemic animal to verify therapeutic efficacy.

Conventionally, non-judicious and blanket fertilizer nitrogen (N) used in rainfed maize lead to higher N losses, low N use efficiency (NUEs) and poor yields due to substandard agronomic management practices. To avoid such N losses, fertilizer additions are synchronized with plant uptake requirements. In this context, agronomic based management focused on optimizing N rates and biochar application is essential for improved NUEs and crop productivity. Keeping this in view, a field experiment was conducted during 2014, 2015 and 2016 in rainfed maize (Zea mays L.) grown in Vertisols of India. In this study, twelve treatments that comprised of N omission plot (N0), skipping of basal rate, multi-split topdressing at varying time as broadcast and band placement, soil test crop response (STCR) based NPK with target yield 6.0 t ha-1 in maize and biochar application (10 t ha−1) were investigated. The experiment was conducted following a Randomized Complete Block Design (RCBD) set up with three replications. Pooled analysis of three years data revealed that the application of N rates (120 kg Nha−1) in 2 equal splits (60 kg Nha−1) at knee high (V8) and tasseling (VT) stages with skipped basal N rate, achieved higher maize grain yield (5.29 t ha−1) ascribed to the greater growth parameters, yield components and N uptake compared to the recommended practices. Biochar application (10 t ha−1) as soil amendments along with multi top dressed N (120 kg N ha−1) into 3 splits also increased the grain yield. Delayed N application at V8 and VT growth stages, resulted in higher N uptake, agronomy efficiency (AE), partial factor productivity (PFP), physiology efficiency (PE) and recovery efficiency (RE). Biochar along with N fertilizer also improved the soil organic carbon (5.47g kg−1), ammonium-N (2.40 mg kg−1) and nitrate-N (0.52 mg kg−1) concentration in soil (P−1) significantly increased the concentration of ammonium (2.40 mg kg−1) and nitrate (0.52 mg kg−1) in soil (PR2=0.99 at p

Dysregulation of osteoclastic differentiation and its activity is a hallmark of various musculoskeletal disease states. In this review, the complex molecular factors underlying osteoclastic differentiation and function are evaluated. The emerging role of KLF2 in regulation of osteoclastic differentiation is examined, specifically in the context of rheumatoid arthritis in which it has been most extensively studied among the musculoskeletal diseases. The therapies that exist to manage diseases associated with osteoclastogenesis are numerous and diverse. They are varied in their mechanisms of action and in the outcomes they produce. For this review, therapies targeting osteoclasts will be emphasized, though it should be noted that many therapies exist which bolster the action of osteoblasts. A new targeted molecular approach is under investigation for the future potential therapeutic development of rheumatoid arthritis.

Attempts were made to ameliorate sodic black calcareous soils by using different crop residues (composted cotton stalk and biomulch 5 t ha−1, respectively) and green manures (in-situ Crotalaria juncea, Sesbania aculeata, Vigna unguiculata, Vigna radiata, and ex-situ Leucaena leucocephala loppings 5 t ha−1) and gypsum 2.5 t ha−1. The organic amendments were outperformed with respect to improvement in soil microbial biomass carbon and dehydrogenase activity, not gypsum. The application of dhaincha significantly improved the mean weight diameter by 14% over control. The application of gypsum and dhaincha recorded a significant drop in pHs (0.1 and 0.07 units) and exchangeable sodium percentage (26.7% and 20.6%) over control. After 2 years of experiments, dhaincha (14.8%) and sunhemp (15.5%) also showed the commensurable potential of improving yields of chickpea as compared to gypsum (14.8%) over control. Hence, dhaincha and sunhemp can be a better alternative choice to gypsum in sodic soils.

Agriculture produces a large amount of greenhouse gases (GHGs), for instance overuse of synthetic fertilizer and pesticides in agriculture may lead to tremendous GHGs emission, which poses a serious threat to sustainability of agriculture, environmental quality and human health. Integrated nutrient management (INM) practices have been advised to farmers with the aim to boost agricultural productivity and soil quality. A long-term fertilizer experiment (LTFE) was undertaken from 2012 to 2020 to evaluate the energy budget, carbon footprint (CF) and economic audit under INM modules in maize–chickpea system over organic and inorganic modules for developing cleaner production technology. In this study, twelve organic, inorganic and INM modules that consisted of various combinations of soil test crop response (STCR) based NPK, general recommended dose (GRD) of NPK and organic manures (OM's) viz., farmyard manure (FYM), poultry manure (PM), urban compost (UC), maize residue mulch (MRM) and Gliricidia sepium mulch (GLM) were evaluated in maize–chickpea system. Uniqueness of this research work is that the effect of INM modules on GHGs emission was evaluated along with crop productivity, energy use efficiency (EUE) and carbon footprint (CF) jointly as environment friendly approach for sustainable and safe food grain production. Adoption of STCR based INM module (FYM+75%NPK of STCR) minimized the energy requirement by 14%, cost of cultivation by 6.5% and besides that CF on a spatial scale was 17% lower than GRD. Thus, STCR based INM module enhanced the EUE, energy productivity (EP) and energy profitability (EPF) by 28.5%, 31.5% and 31.8% respectively, over GRD. The CF (CO2-e) was greater in organic module (FYM 20 Mgha-1 every year) (2422 CO2-e kg ha−1) and GRD (2230 CO2-e kg ha−1) than STCR based INM module (2152 CO2-e kg ha−1). The saving of fossil fuels from judicious use of fertilizers/manures, lower input energy and higher crop yields under INM modules were significant. Nitrous oxide (N2O) emission was also increased by integration of OM's, and the higher quantity of organic inputs used, more was the emission. INM module (FYM+75%NPK of STCR) also increased system productivity by 17.0%, carbon efficiency (CE) by 19.3% and carbon sustainability index (CSI) by 21% than GRD. Thus, the study supports and suggests that the STCR based INM module is an economically viable, environmentally secure and clean production technology for improving crop yield and energy use, while decreasing the CFs and production cost of cereal–legume cropping system.

Environmental threat due to toxic heavy metals is of prime concern worldwide. Rapid urbanization, industrialization and other developmental activities including anthropogenic activities (e.g. mining, fossil fuel burning) are the major contributors of heavy metals above the prescribed permissible limit. High concentration of heavy metals has detrimental impact on soil, water and air as well as human and animal health. Heavy metals exert toxic effects on soil microorganism hence results in the change of the diversity, population size and overall activity of the soil microbial communities. Heavy metal toxicity influences all soil microbial activity that involves change in the microbial population, diversity, their size and growth. Loss of soil fertility results in reduced crop yield and imbalance nutrition due to presence of excess amount of metals. Lead is non-biodegradable highly toxic heavy metal present in the environment. Elevated Pb in soil causes to decrease of soil productivity and impair with various soil enzymatic activities. Lead contaminated soil created several chronic health implications (carcinogenic) or even to death of the living organisms via food chain contamination. Lead is considered as one of the potential carcinogens which can damage cardiovascular, kidney, brain, gastrointestinal tracts, low IQ, loss of hearing or multi-organ failure in humans. Lead toxicity causes several health hazards like everlasting brain injury, hearing loss, learning disabilities, behavioural abnormalities in children while in adults it comes with hypertension, blood pressure, heart disease, and so on. Lead pollution also has severe threat to the aquatic living organisms. In this chapter, a brief overview about the lead with its various active form, source of contamination and impact on agroecosystem, human and animals has been described in details.

Across the world, a major challenge is deteriorating environmental health by increasing growth of industries with the unscientific management of industrial waste. Soil contamination with organic and inorganic pollutant is a major task during the production of healthy food. In the last three decades, the concentration of heavy metals in soil has increased drastically, posing a risk to the whole environment, human, as well as animal health. Soil contamination is a threat to sustainable agricultural development and food security in developing countries. Nowadays protection and preservation of the environment from further deterioration have drawn increasing research attention. In the present context, use of modern and traditional technologies aims to maintain the health of natural resources from contamination at economic feasibility. Another major concern is remediation or minimization of toxic metal entry in the food chain contamination of different ecosystems without affecting their functionality. There is a need to make land resources free from metal contamination for healthy and safe agricultural production, to increase food security, and to maintain land use pattern. Advanced remediation techniques are more focusing on in situ environment-friendly practices. Several organic and inorganic remediation technologies to treat heavy metal-contaminated soils are discussed in this chapter.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease, and Kr&uuml, ppel-like factor 2 (KLF2) regulates immune cell activation and function. Herein, we show that in our experiments 50% global deficiency of KLF2 significantly elevated arthritic inflammation and pathogenesis, osteoclastic differentiation, matrix metalloproteinases (MMPs), and inflammatory cytokines in K/BxN serum-induced mice. The severities of RA pathogenesis, as well as the causative and resultant cellular and molecular factors, were further confirmed in monocyte-specific KLF2 deficient mice. In addition, induction of RA resulted in a decreased level of KLF2 in monocytes isolated from both mice and humans along with higher migration of activated monocytes to the RA sites in humans. Mechanistically, overexpression of KLF2 decreased the level of MMP9, conversely, knockdown of KLF2 increased MMP9 in monocytes along with enrichment of active histone marks and histone acetyltransferases on the MMP9 promoter region. These findings define the critical regulatory role of myeloid KLF2 in RA pathogenesis.