Effect of Black Seed Thymoquinone on Rheumatoid Arthritis

Thymoquinone (2-isoprpyl-5-methyl-1,4-benzoquinone) is the most active component of Black cumin (Nigella sativa) seed oil. It is widely used in traditional medicine to treat a wide range of illnesses.

According to various research findings, thymoquinone exert important health-beneficial effects including antioxidant, anti-inflammatory and anti-cancer effects. As an antioxidant agent, thymoquinone normalizes glutathione levels and increases the activity of antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase.

 

Black Cumin Tea Contains Thymoquinone

Black cumin seed is made into a tea and served as an antioxidant agent. Since it contains thymoquinone and other biologically active phytochemicals, black cumin seed tea should be recommended for patients who suffer rheumatoid arthritis. It can also be served to cancer patients who are undergoing chemotherapy.

How To Prepare Black Cumin Seed Tea

  • To prepare black cumin seed tea, assemble 2 cups of water, 2 tea spoonful of raw black cumin seeds and honey. Then follow the steps as follows:
  • Add the 2 cups of water and black cumin seeds in a pot and heat till it boils.
  • Remove from heat once it boiled.
  • Cover the pot and allow it to steep for about 10 minutes.
  • Strain the water into a cup using a mesh. You may add the seed to enjoy the whole benefits if you so wish.
  • Add two spoonful of honey and stir
  • Serve and enjoy your tea

 

Benefits of Thymoquinone and Black Cumin Seed Tea in Treatment of Rheumatoid Arthritis

The uncontrolled inflammation associated with rheumatoid arthritis arises as a result of the uncontrolled production and activity of various inflammatory cytokines, TNFα, IL-1, IL-17, IL-6 and the resulting inflammation is responsible for the pain, tenderness, swelling, redness and stiffness of joints.

Black cumin seeds and especially thymoquinone has been shown to be beneficial against rheumatoid arthritis and autoimmune diseases.

 

Thymoquinone Inhibits NF-kB Signaling In Rheumatoid Arthritis

NF-kB regulates the expression of many genes, enzymes, cytokines, cell cycle regulatory molecules as well as angiogenic factors. It induces inflammation by influencing the expression several pro-inflammatory cytokines, chemokines , acute phase proteins and growth factors.

Thymoquinone inhibits NF-kB induced inflammatory response in rheumatoid arthritis patients by inhibiting its translocation into the nucleus. Thymoquinone also inhibits NF-kB activities by suppressing TNF-induced-NF-kB activation. This is done by inhibiting TNF-induced IKBα phosphorylation and degradation as well as p65 phosphorylation and nuclear translocation.

 

Thymoquinone Inhibits Prostaglandins and COX-2 in Rheumatoid Arthritis

Prostaglandins (PGs) are arachidonic acid metabolites. They are found at elevated levels in synovial fluid and also in synovial membrane, where they function in the development of vasodilation, fluid extravasation and pain in synovial tissues. Aside these functions, Prostaglandin E2 (PGE2) and COX are upregulated in synovial tissues in rheumatoid arthritis patients, where PGE2 synergizes with IL-23 to stimulate Th17 cell proliferation.

Th17 in turn stimulates the release of pro-inflammatory cytokines and promotes bone resorption. PGE2 also mediates complex interactions that lead to the development of articular cartilage erosions and juxta-articular bone.

Cyclooxygenase enzymes (COX), especially COX-2 are involved in inflammatory responses. COX-2 is induced by pro-inflammatory cytokines, mainly IL-1.

Thymoquinone suppresses the expression of COX-2 protein by inhibiting NF-kB signaling pathway activation and induces the expression of cytoprotective enzymes.

Effect of Thymoquinone on PI3k/Akt Signaling Pathway

Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway is an intracellular regulatory signal transduction pathway that is activated by toxic substances or cellular stimuli that regulate many cellular processes including cell growth, survival and apoptosis.

When abnormally activated, PI3K/Akt signaling pathway is involved in the pathogenesis of many diseases including diabetes mellitus, cancer, and rheumatoid arthritis. In RA, PI3K/Akt signaling pathway play important role through the expression of different types of pro-inflammatory mediators that degrade IKβ and activate NF-kB signaling pathway.

Thymoquinone induces apoptosis by blocking PI3K/Akt signaling pathway in DU-145 cell line. It also deactivate PI3K/Akt and NF-kB signaling pathway and regulate various gene products such as p65 and COX-2.

 

REFERENCES

J.K. Kundu, L. Liu, J.-W. Shin, Y.-J. Surh., Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo Biochem. Biophys. Res. Commun., 438 (4) (2013), pp. 721-727

 

Umar, J. Zargan, K. Umar, S. Ahmad, C.K. Katiyar, H.A. Khan Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats Chem. Biol. Interact., 197 (1) (2012), pp. 40-46

 

Vaillancourt, P. Silva, Q. Shi, H. Fahmi, J.C. Fernandes, M. Benderdour

Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis J. Cell. Biochem., 112 (1) (2011), pp. 107-117

 

Thymoquinone inhibits IL-1β-induced inflammation in human osteoarthritis chondrocytes by suppressing NF-κB and MAPKs signaling pathway Inflammation, 38 (6) (2015), pp. 2235-2241

 

Khan, A. Sureda, T. Belwal, S. Çetinkaya, İ. Süntar, S. Tejada, H.P. Devkota, H. Ullah, M. Aschner. Polyphenols in the treatment of autoimmune diseases. Autoimmun. Rev., 18 (7) (2019), pp. 647-657

 

Stańczyk J, Kowalski ML. Rola cyklooksygenaz oraz prostaglandyn w patogenezie reumatoidalnego zapalenia stawów [The role of cyclooxygenase and prostaglandins in the pathogenesis of rheumatoid arthritis]. Pol Merkur Lekarski. 2001 Nov;11(65):438-43.

 

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is an autoimmune disease, which is characterized by chronic inflammation at the skeletal joints. Most times, the bone and cartilage of the joints affected are destroyed, and tendons and ligaments weakened. As the disease progresses, it eventually affects the skin, eye, heart, kidneys and lungs.

According to reports, RA affects more females than males, and is predominantly observed in the elderly. The prevalence rate of RA reported in 2002 ranged from 0.5% to 1% of the population. It also has regional variation. It primarily affects the lining of the synovial joints and can cause progressive disability, premature death, as well as socioeconomic burdens.

 

Symptoms of Rheumatoid Arthritis (RA)

Common symptoms of RA include:

  • Stiffness at affected joints, especially in the morning
  • Fatigue
  • Fever
  • Weight loss
  • Tender, swollen and warm joints
  • Rheumatoid nodules under the skin

Early stage of Rheumatoid arthritis tends to affect the smaller joints, particularly the joints that join the fingers to the hands and toes to the feet. As the disease progresses, the symptoms may progress to the wrists, knees, ankles, elbows, shoulders and hips.

 

Pathogenic Roles of Immune Cells in Rheumatoid Arthritis (RA)

As an autoimmune disorder, immune cells such as B-cells, T-cells and macrophages play important roles in RA pathogenesis. They can either reside in synovium or circulate in peripheral blood.

 

Roles of B-Lymphocytes in RA Pathogenesis

B-cells secrete physiologically important proteins such as rheumatoid factors (RFs), anti-citrullinated protein antibodies (ACPA) and pro-inflammatory cytokines in supporting RA.

Auto-reactive B-cells are B-cells that identify host antigens and go on to destroy such cell or tissue. Normally, auto-reactive B-cells are eliminated by repair mechanisms either at the time when it is still immature B-cells in the bone marrow, or before the B-cells become mature naïve B-cells. Both processes of repair mechanisms are highly regulated by two immune checkpoints; they are

  • The central B-cell tolerance checkpoint and,
  • The peripheral B-cell tolerance checkpoint.

The central B-cell tolerance checkpoint is controlled by B-cell growth factors that regulate B-cell receptor (BCR) and toll-like receptor (TLR) signaling. But the peripheral B-cell tolerance checkpoint involves extrinsic B-cell factors such as regulatory T-cells (Treg) and serum B-cell activating factor (BAFF).

In patients with RA, both checkpoints are defective, which leads to the larger production of auto-reactive mature naïve B-cells. Such defect is usually caused by a mutation in PTPN22 gene that disrupts the BCR signaling pathway in central B-cell tolerance checkpoint. This impairment is irreversible and cannot be treated effectively with anti-inflammatory drugs.

In impaired peripheral tolerance checkpoint, mature naïve B-cell levels are elevated. The elevated mature naïve B-cell expresses both poly-reactive and human epithelia (HEP-2) reactive antibodies in RA patients. This dysfunction in peripheral checkpoint results in defective Tregs and in B-cell resistance to suppression and apoptosis.

Also, in patients with RA, BAFF is increased in the presence of cytokines and chemokines, as well as through TLRs activation. The increased BAFF expression further prolongs the survival and maturation of auto-reactive B-cells, exacerbate autoimmune conditions.

 

Roles of T-Lymphocytes in RA Pathogenesis

The chronic immune response of RA is contributed by CD4+ T-cells. During activation of T-cells, CD4+T-cells interact with human leukocyte antigen (HLA) or major histocompatibility complex class II (MHC-II) molecules and also co-stimulate molecules such as CD28, that are expressed on the surface of APC. This leads to the onset of downstream PI3K signaling pathway, which leads to the maturation of CD4+ cells. Subsequently, the interaction leads to the antigenic activation of naive CD8+ T-cells, which promote inflammation.

CD4+ T-cells also associate with particular MHC-II alleles, HLA-DR4, which contains similar amino acid motifs in the third hyper-variable region of DRB-chain. This interaction then leads to a more aggressive form of RA. The systemic morbidity associated with RA such as vasculitis and acute coronary syndrome is correlated with CD4+CD28 null.

In addition to cell-to-cell interaction, CD4+ T-helper (Th) cells contribute to the pathogenesis of RA through the secretion of cytokines and chemokines, which are important immune modulators in cell-mediated immunity.

Type 1 T-helper (Th1) cells, which are highly activated in RA, secrete pro-inflammatory cytokines such as IFNϒ, IL-2, and TNF-α. Th1 cells also activate macrophages to act as an APC to present MHC-II molecules to the T-cells. Meanwhile, CD4+ Th2 cells on the other hand secrete anti-inflammatory cytokines such as IL-4 and IL-5 and play central roles in B-cell activation and in immunoglobulin (Ig) class switching to IgE. A T-cell subset, Th17 cells secrete Il-17 which stimulates production of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases (MMps).

 

Roles of Macrophages in RA Pathogenesis

Macrophages are found in synovial tissue where most of it resides within the tissue in a resting state under normal conditions. But in an inflamed joint, they regulate the secretion of pro-inflammatory cytokines and damaging enzymes, which are associated with inflammatory responses and subsequently, joint destruction. They also mediate the recruitment of lymphocytes, cartilage damage, joint erosion, angiogenesis and fibroblast proliferation. Macrophages act as APC and are found to highly express HLA-DR and leukocyte adhesion molecules, which allow macrophages to participate in T-cell activation alongside B-cells.

The macrophage-mediated T-cell activation results in the production of effectors T-cells as well as expression of resulting pro-inflammatory mediators like IL-1α, IL-1β, and MMPs, which support RA pathogenesis.

 

The Role of Cytokines in RA pathogenesis

Cytokines are proteins that function as mediators in cell signaling; they comprise monokines, lymphocytes, ILs, IFNs, colony stimulating factors (CFS) and chemokines. Pro-inflammatory cytokines play pivotal roles in the pathogenesis of RA.

In early pathogenesis, the predominant cytokines that are secreted from T-cells and stroma cells are IL-13, IL-14 and IL-15. These cytokines cause the inflammatory response and contribute to chronic inflammation. In RA patients, pro-inflammatory cytokines such as TNF-α, IL-1 and IL-17 usually outweigh the protective effects of the anti-inflammatory cytokines such as IL-4, IL-11 and IL-13, which results in the cytokine-mediated inflammation.

In RA, B-cells and macrophages, which are APCs, present arthritis-associated antigens to T-cells and activate the signaling cascades to secrete cytokines. The cytokines so activated stimulate the activation of chondrocytes and osteoclasts and produce MMPs, which degrades the matrix of articular cartilage leading to bone resorption.

 

Role of NF-kB in RA Pathogenesis

NF-kB activation plays a pivotal role at the stage of initiation and also at the stage of perpetuation of chronic inflammation in RA. The NF-kB activation is triggered in T cells by the engagement of the T cell receptor and the CD28 receptor with their ligands, MHC-II and the co-stimulatory molecule CD80 and CD86 presented by APCs. The T cell receptor CD28 work in synergy in induction for T cells activation and proliferation, such as IL-2, IL-2 receptor (IL-2R), and IFNϒ. In turn, activated T cells elicit NF-kB activation in APCs.

The suppression of NF-kB inhibited expression of many proinflammatory molecules, including IL-1, TNFα, IL-6, IL-8, ICAM-1 and VCAM-1 but had no effect on the expression of anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. It thus suggests that NF-kB activation facilitates the impaired balance of proinflammatory and anti-inflammatory molecules in the arthritic joint.

 

Treatment of Rheumatoid Arthritis (RA)

There is presently no cure for rheumatoid arthritis. However, symptoms of RA can be abated when treated with disease-modifying antirheumatic drugs (DMARDs). Some of the medications for Rheumatoid Arthritis include:

Steroids. Corticosteroid medications reduce inflammation and slow joint damage.

NSAIDS. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation. E.g. includes Ibuprofen and Naproxen sodium.

DMARDs. Conventional DMARDs can slow the progress of rheumatoid arthritis and prevent the joints and other tissues from permanent damage.

 

Nuclear Factor-Kappa B (NF-kB)

Nuclear factor-kappa B (NF-kB) is a transcription factor that plays critical functional roles in inflammation, immunity, cell proliferation, differentiation, and survival. It exists in an inactive state in the cytosol and can be stimulated by molecules such as TNFα, and other cell stressors.

NF-kB is found in almost all cellular cell types and is identified as a regulator of kB light chain expression in mature B and plasma cells.

Because NF-kB has the ability to influence the expression of numerous genes, its activity is tightly regulated at multiple levels. The primary mechanism for regulating NF-kB is through inhibitory IkB proteins and the IKK complex, which phosphorylates IkBs.

Nuclear Factor-kappa B (NF-kB) Activation

NF-kB activation is initiated by TNFα. When TNFα binds to TNF receptors and activate them, IkB kinase (IKK) is ultimately triggered, which leads to the phosphorylation of IkB. The phosphorylation of IkB results in ubiquitination and degradation of IkB. When this happens, the remaining NF-kB dimmer (e.g., p65/p50 or p50/p50 subunits) translocates to the nucleus, where it then binds to a DNA consensus sequence of target genes.

 

Nuclear Factor-kappa B (NF-kB) Structure-Function relationship

NF-kB is a multiple-gene family of proteins that can form stable homo- and heterodimeric complexes, which vary in their DNA binding specificity and transcriptional activation potential.

There are five proteins of the NF-kB family in mammalian cells; they are RelA (P65), C-Rel, RelB, and NF-kB1 (p50 and its precursor p105), and NF-kB2 (p52 and its precursor p100). NF-kB and Rel proteins share a highly conserved 300 amino acid N-terminal Rel homology domain (RHD), which is responsible for DNA binding, dimerization, and association with IkB inhibitory proteins.

The p50/p65 complex shows strong transcriptional activation, whereas p50/p50 and p52/p52 homodimers suppress transcription of NF-kB target genes.

 

Nuclear Factor-kappa B (NF-kB) Is Inhibited By IkB Family Proteins

NF-kB is inhibited by IkB family proteins through NF-kB/IkB complex formation. There are seven inhibitory protein members of IkB family. They are IkBα, IkBβ, IkBε, IkBϒ, Bcl3, NF-kB1 precursor and NFkB2 precursor.

The IkB family members have a common ankyrin repeat domain. They regulate the subcellular localization, and hence, the DNA binding and transcriptional activity of NF-kB proteins.

 

IkB Regulates NF-kB Translocation to the Nucleus.

NF-kB is localized in the cytoplasm in an NF-kB/IkB complex, which is inactive. The inactive NF-kB/IkB co2mplex is a result of masking of the nuclear localization signals (NLS) on the NF-kB subunits by the IkB proteins. Hence, the degradation of IkB would lead to unmasking of the NLS, allowing NF-kB to undergo translocation to the nucleus.

The IkB proteins show a preference for specific NF-kB/Rel complexes, which provides a means to regulate the activation of distinct Rel/NF-kB complexes.

After the binding and transcriptional activity of NF-kB on DNA, it induces the expression of IkBα, which enters the nucleus and remove NF-kB  from DNA by forming NF-kB/IkB complex with the released NF-kB. The complex is then expelled from the nucleus back to the cytoplasm as a result of potent nuclear export signals on IkB and p65.

 

IkB Degradation Is Mediated By Ubiquiti/Proteasome System

The activation of NF-kB is achieved through the signal induced proteolytic degradation of IkB. This degradation is initiated by the stimuli dependent phosphorylation of IkB at specific N-terminal residues (S32/S36 for IkBα, S19/S23 for IkBβ), and is mediated by the ubiquitin/proteasome system.

Phosphorylation of IkB however, is not enough to initiate degradation of IkB. Ubiquitination and subsequent degradation depends on the recognition of phosphorylated IkB by the β-TrCp, an F-box/WD containing component of the Skp1-cullin-F-box (SCF) class of E3 ubiquitin ligases.

 

IKKs Mediates The Phosphorylation Of IkB On Serine 32 and 36

Phosphorylation of IkBa on the Serine 32 and 36 is mediated by IkB kinases (IKKs), whose activity is induced by activators of the NF-kB pathway. IKK contains two subunits, IKK1 (IKKα) and IKK2 (IKKβ). It also contains a regulatory subunit, NEMO ( IKKy, IKKAPI, FIP3).

IKK1 and IKK2 are homologous kinases, and both contain an N-terminal kinase domain and a C-terminal region with two protein interaction motifs, a leucine zipper (LZ), and ahelix-loop-helix (HLH) motif.

The LZ domain is responsible for demerization of IKK1 and IKK2. It is also essential for IKK complex activity. The IKK1/2 complex associates with NEMO through a short interaction motif located at the C-terminus of either catalytic subunit. Short peptides derived from the interaction motif can be used to disrupt the IKK complex and prevent its activation. NEMO connects the IKK complex to upstream activators through its C-terminus, which contains a zinc finger motif. NEMO also undergoes stimulus dependent interaction with components of TNF receptor complex.

 

 

REFERENCES

 

Hacker H, Karin M. 2006. Regulation and function of IKK and IKK-related kinases. Sci STKE 2006: re13.

Harhaj EW, Maggirwar SB, Sun SC. 1996. Inhibition of p105 processing by NF-kB proteins in transiently transfected cells. Oncogene 12: 2385–2392.

Hatakeyama S, Kitagawa M, Nakayama K, Shirane M, Matsumoto M, Hattori K, Higashi H, Nakano H, Okumura K, Onoe K, et al. 1999. Ubiquitin-dependent degradation of IkB is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. Proc Natl Acad Sci 96: 3859–3863.

Chen G , Cao P , Goeddel DV . TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 . Mol Cell 2002 ; 9 : 401 – 10.

Hu Y , Baud V , Delhase M , et al . Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase . Science 1999 ; 284 : 316 – 20 .

Li Q , Lu Q , Hwang JY , et al . IKK1-deficient mice exhibit abnormal development of skin and skeleton . Genes Dev 1999 ; 13 : 1322 – 8.

Li Q , Van Antwerp D , Mercurio F , et al . Severe liver degeneration in mice lacking the IkappaB kinase 2 gene . Science 1999 ; 284 : 321 – 5.

Takeda K , Takeuchi O , Tsujimura T , et al . Limb and skin abnormalities in mice lacking IKKalpha . Science 1999 ; 284 : 313 – 16.

Ghosh S , Karin M . Missing pieces in the NFkappaB puzzle . Cell 2002 ; 109 ( Suppl. ) : S81 – 96.

Yang J , Lin Y , Guo Z , et al . The essential role of MEKK3 in TNFinduced NFkappaB activation . Nat Immunol 2001 ; 2 : 620 – 4.

Li ZW , Chu W , Hu Y , et al . The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis . J Exp Med 1999 ; 189 : 1839 – 45.

 

 

 

 

 

The Functions of Zinc in Immune System

Zinc is an essential macronutrient, which play a crucial role in multiple cellular functions, including immune cell signaling. In zinc dyshomeostasis, which includes zinc deficiency, there are impairments in several cellular and organ function including overall immune function and increased susceptibility to infection. This shows that zinc cannot be overlooked in immune system and other cellular processes.

Some of the problems associated with zinc deficiency are growth retardation, neurological disorder, immune dysfunction and Acrodermatitis enteropathica, a metabolic disorder.

 

Zinc Transporters

Zinc coordinates its signaling through two families of zinc transporters and metallothiones. The two families of zinc transporters are:

The Solute-linked carrier 39 (SLC39A or ZIP) family of zinc transporters, which transport zinc into the cytosol and out of the intracellular organelles and,

The Solute-liked carrier 30 (SLC30A or ZnT) family of zinc transporters, which transport zinc out of the cytosol and into the intracellular organelles.

Both ZIP and ZnT transporters are expressed in a cell- or tissue-specific manner.

Metallothione (MT)

Metallothione is a zinc-binding protein that functions as a reservoir of intracellular zinc. It has the ability to bind up to seven zinc ions per MT molecule. It also plays a crucial role in the distribution, transport and maintenance of intracellular zinc ions.

The Function of Zinc in Pathogen Invasion

Zinc regulates complex signaling pathways in immune cells. As a result, when an invasion by a pathogen occurs, the pathogen creates a conflict in which Zn becomes a shared resource.

In this battle-like state, the pathogen strives to utilize Zn for its biological functions at the expense o the host, while the host cells seek to reserve Zn and render it inaccessible for pathogen uptake. This strategy of the host cell curtails the growth of some pathogens, but there are some pathogen which resist this cellular mechanism by possessing strong Zn acquisition machineries that effectively compete with the host for Zn.

Excess zinc however, can exert toxic effects on microbial survival. And the immune cells have taken advantage of this to localize and fuel excessive Zn concentrations that intoxicate the pathogen without impacting host cells.

 

Zinc Signals in Monocytes and Macrophages.

The immune system provides two layers of defense against pathogens; they are innate and adaptive immunity. Innate immunity, which is the frontier of host defense, involves the recognition of pathogen-associated molecular patterns (PAMPs), conserved structures of invading pathogens, and the immediate initiation of immune responses.

During invasion, mononuclear phagocytes of innate immunity immediately recognize invading pathogens through the sensing of PAMPs by pathogen-recognition receptors (PRR), including Toll-like receptors (TLRs). Upon PAMP engagement, individual TLRs differentially recruit adaptor molecules such as MyD88, TRIF, TIRAP-dependent NF-kB, MARK, PI3K, and the TRIF/TRAM-dependent IRF3 pathway, and elicits a variety of monocyte and macrophage effectors’ functions.

 

TRIF/TRAM-dependent pathway

Signaling through TRIF activates several transcription factors, including NF-kB, IRF3, and AP-1. This leads to the production of cytokines and type-1 IFN, as well as maturation of myeloid dendric cells. Biological responses from TRIF-dependent signaling depends on both the type of cell responding and the particular TLR that is activated.

In TLR4 signaling, the TLR4 TIR domain use TRAM to recruit TRIF to the signaling complex, either by operating from the plasma membrane or from the endosomes. Localization of TRAM to the endosomes is necessary for IRF3 activation in the TRIF-dependent pathway.

When a lipopolysaccharide binds to TLR4, it leads to rapid zinc influx into the cytoplasm of monocytes and macrophages, which triggers zinc-mediated regulation of major signaling pathways, including TRIF/TRAM pathway.

 

MyD88/TIRAP-dependent NF-kB pathway.

The NF-kB transcription factor is a central regulator of proinflammatory gene induction and functions in a variety of immune responses. It influences the expression of proinflammatory cytokines, Chemokines, acute phase proteins, matrix metalloproteinase, adhesion molecules, growth factors, and other factors involved in inflammatory responses.

Zinc regulates the NF-kB activity by suppressing LPS-induced activation of IKKB. This is through a mechanism that is initiated by the inhibition of cyclic nucleotide phosphodiesterase (PDE), and subsequent elevation of cGMP, cross-activation of protein kinase A (PKA), and inhibitory phosphorylation of protein kinase Raf-1.

Another mechanism which involves direct inhibition of IKK upstream of NF-kB is mediated by ZIP8, which increase intracellular zinc, and involves a direct binding of Zn to IKKB.

 

 

Diabetes Mellitus

Diabetes mellitus (DM) is a hormonal disorder which results in the body not being able to produce enough insulin for glucose metabolism or not being able to respond normally to insulin, thereby causing blood sugar (glucose) levels to be abnormally high.

There are different types of diabetes mellitus, and each have different causes, but they share similar problem of having elevated glucose in the body.

When diabetes mellitus is poorly controlled, it can degenerate to serious damage to a wide range of the body’s tissues and organs, such as the kidneys, eyes, nerves, and the heart.

Types of Diabetes mellitus

Type 1 Diabetes mellitus (T1DM)

Type 1 diabetes is also referred to as insulin-dependent diabetes or juvenile-onset diabetes. In type 1 diabetes, the immune system attacks and destroys the insulin producing cells of the pancreas. When this happens, the pancreas produces little amount of insulin that is not enough for glucose metabolism.

Symptoms of T1DM

Some of the symptoms of type 1 diabetes include:

  • Extreme thirst.
  • Increasing hunger, even after eating food.
  • Dry mouth.
  • Frequent urination.
  • Upset stomach and vomiting.
  • Weight loss regardless of frequent food intake.
  • Blurry vision.

Causes of T1DM

Hormonal destruction of pancreas beta cells remains the cause of type 1 diabetes. Insulin helps in moving glucose into the body tissues, which the cells of the body use in generating energy. When beta cells are impaired, there is little or no insulin available for glucose transport to the cells. This leads to high blood sugar level, which results in diabetes.

Complications associated with T1DM

Dehydration: Increasing concentration of blood sugar level leads to frequent urination and subsequent dehydration o the body due to loss of body fluids.

Weight loss: The body excretes glucose through urine and sweats. The loss of calories and dehydration results in weight loss.

Diabetic ketoacidosis(DKA): Due to the body’s inability to utilize the excess glucose for fuel, it breaks down adipose tissues instead. The use of fats for fuel generation creates chemicals called Ketones. The excess glucose, dehydration and increasing ketones are referred to as Ketoacidosis, and can be life threatening if not treated urgently.

Risk factors of T1DM

According some findings, only about 5% of persons with diabetes have type 1. T1DM attacks both gender equally. Some of the risk factors associated T1DM are:

  • Having a parent or sibling with type 1 diabetes.
  • Being Caucasian.
  • Being younger than 20 years.

Diagnosis and Treatment of T1DM

Type 1 diabetes can be diagnosed by checking the blood sugar level of the patient. It can be treated by injecting insulin into the body.

 

 Type 2 DM

Type 2 diabetes mellitus is a condition in which the cells of the body become resistant to insulin. In this case, unlike in type 1 diabetes, the pancreas makes enough insulin that can transport glucose to the body cells but, unfortunately, those glucose molecules cannot get into the cells, because the cells resist insulin. This also leads to a buildup of glucose in the body.

Basically, type 2 diabetes affects mostly middle-aged or older persons, which is why it is called adult-onset diabetes. But type 2 diabetes also affects kids and teens because of childhood obesity.

Symptoms of T2DM

Just like in type 1diabetes, the symptoms of T2DM includes:

  • Excessive urination.
  • Being very thirsty.
  • Blurry vision.
  • Tingling and numbness on hands and feet.
  • Wounds that don’t heal.
  • Weight loss.
  • Vulnerability to infections.

Causes of T2DM

T2DM is basically caused by insulin resistance by the cells of the body. However, some factors such as obesity, and metabolic syndrome can leads to insulin resistance by the body.

Complications associated with T2DM

Potential complications of type 2 diabetes include:

  • Atherosclerosis
  • Gastro paresis
  • Gum disease
  • Hearing loss
  • Kidney disease
  • Sexual dysfunction
  • Stroke
  • Urinary tract infection

 

T2DM treatment

Treatment of T2DM involves a mixture of medication and changes in lifestyle, especially with regards to food intake.

Lifestyle changes

Weight loss: Research has shown that diabetes is associated with obesity. Being able to shed off 5% of body weight is a good way to manage diabetes.

Healthy eating: As there is no specific diet for T2DM, involving the service of a registered dietician would help.

Exercise: A regular exercise, say, for 20 to 30 minutes every day is a good way to go.

Always watch your blood sugar levels.

Medications

Metformin: Metformin lowers the amount of glucose produced by the liver and helps the body respond effectively to type 2 diabetes.

Thiazolidinedione: It makes the body become more sensitive to insulin, and works much like metformin. However, the side effect has to do with heart problems.

DPP-4 inhibitors: They help in lowering blood glucose levels. But they can cause joint pains and inflammation of the pancreas.

 

 

Alzheimer’s disease

Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain; and it is the major cause of dementia, and is characterized by a decline in thinking ability and independence in personal daily activities. It also causes the brain shrinkage and death. Alzheimer’s disease affects people of age 65 years and above with only 10% of cases occurring in people younger than this.

In AD, plaques are formed in the hippocampus, which helps in encoding memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions.

 

Symptoms of Alzheimer’s disease

Alzheimer’s disease develops in a progressive manner, with the symptoms becoming worse over time. The key features of AD are memory loss, and it is also the first symptoms to develop.

Symptoms of Alzheimer’s disease include:

Memory loss: An AD patient usually has difficulty in taking and processing new information as well as in remembering new information. This leads to:

  • Repeating questions and conversations.
  • Forgetting about events or appointments.
  • They wander about and usually get lost.

Cognitive deficit: The patient experiences difficulty in reasoning, complex task and in judgment.

Problem with recognition: The patient may not be able to recognize faces or objects.

Problems with speaking, reading and writing: The patient would develop difficulties remembering common words, or make more speech, writing and spelling errors.

Personality and behavior changes: The patient may experience certain changes in personality and behavior that include:

  • A loss of interest of motivation in activities they previously enjoyed engaging in.
  • A loss of empathy.
  • The person may become upset, angry or worried often than before.

 

Stages of Alzheimer’s disease

Alzheimer’s disease occurs in stages; from mild to severe cases.

 

Mild Alzheimer’s disease

Patients with mild AD have memory problems and cognitive difficulties, which may also include:

  • Difficulties in handling money or paying bills.
  • Wandering aimlessly and getting lost often.
  • Experiencing behavioral and personality changes.
  • Not being able to perform daily task in shorter time.

 

Moderate AD

In this stage of the disease, the parts of the brain responsible for language, senses, reasoning and consciousness are damaged. The patient finds it difficult recognizing family and friends, lose the ability to learn new things and finds it difficult coping with new the situation. Hallucinations, delusions and paranoid sets in.

 

Severe AD

In this stage, plaques and tangle, which cause brain tissue to shrink substantially, begin to occur.

 

Risk Factors of Alzheimer’s Disease

Age

The older a person becomes, the greater the person’s chances of developing Alzheimer’s disease. Age remains the greatest risk factor of Alzheimer’s disease.

Family history: An individual, whose parents or sibling has the disease, is at a higher risk of developing the disease.

Down syndrome

Many people with Down syndrome develop Alzheimer’s disease later on. This may be associated with having three copies of chromosome 21 and subsequently three copies of the gene for coding the protein that leads to the formation of beta-amyloid. Patients of Down syndrome expresses signs and symptoms of AD 10 to 20 years earlier than in general population.

Head Trauma

Patients who suffer traumatic brain injury (TBI) are at greater risk of developing AD. The more severe the TBI, the greater the chances of developing AD.

 

Treatments of Alzheimer’s disease

Alzheimer’s disease has no cure, currently. But there are however, some available medicines that can temporarily reduce the symptoms. Some of the medications for AD are:

Acetylcholinesterase (AChE) inhibitors

The medicine works by increasing the cellular levels of acetylcholine. Acetylcholine is a brain neurotransmitter that helps nerve cells communicate with each other.

AChE inhibitors include Donepezil, Galantamine and Rivastigmine. They can be prescribed for people with early-to mild-stage AD.

Some side effects associated with these medications include nausea, vomiting and loss of appetite.

Memantine

Memantine works by inhibiting the effects of excess amount of glutamate. It is best used to treat moderate or severe AD and good for those who cannot use AChE inhibitors.

Side effects associated with memantine medication include headache, constipation and dizziness.

 

 

Alopecia areata

Alopecia areata is an autoimmune disorder that affects the hair follicles and causes the hair to pull out of their follicles. It is also known as spot baldness. The pattern and amount of hair loss is different for different individuals. Some individual loss their hairs in just a little patch while others lose theirs in different sport on the head.

Many people who develop Alopecia are usually healthy. They may lose their hairs and at times, nails changes, however, they remain healthy. When Alopecia affects the nail, one may see ridges, dents or brittle nails, while some develop red colored nails.

Types of Alopecia areata

Although Alopecia areata is common in its form, there are, however rare other types such as:

Alopecia areata totalis which occur when an individual lose all the hairs on the head.

Alopecia areata universalis is the loss of hair over the entire body.

Diffuse Alopecia areata Occurs when the hair becomes thin rather than lost patches.

Ophiasis Alopecia areata Leads to loss of hair in bands around the sides and back of the head.

 

Alopecia symptoms

  • Some of the symptoms of A. areata include:
  • Formation of small patches on scalp or other body parts.
  • The formed patches may enlarge and grow together into a bald spot.
  • Hair loss occurs over a shot time.
  • More hair loss occurs during cold wealther
  • Fingernails become brittle, red and dented.

 

Causes of Alopecia areata and risk factors

Alopecia is caused by autoimmune attacks on the body. Most times, it is the hair follicles that are attacked. Some risk factors associated with the condition include:

  • Asthma
  • Down syndrome
  • Pernicious anaemia
  • Thyroid disease
  • Seasonal allergies

 

Treatment

Alopecia has no cure. It can only be managed. Some of the drugs used in managing the it are:

Corticosteroids The anti-inflammatory drugs are administered by injection into the scalp area, given as a pill or rubbed on the skin as an ointment, cream, or foam. This method however, may take longer time to work.

Topical immunotherapy Used when the hair loss is severe and occurs more than once.

Minoxidil also known by a brand name, Rogaine. Minoxidil can help keep the hair growth stimulated by another treatment. It can be applied 2 to 3 times a day.

 

 

LUPUS

Systemic Lupus erythematosus (SLE) or simply, Lupus is a chronic inflammatory and autoimmune disease with a wide range of clinical presentations resulting from its effect on multiple organs and systems. Patients with SLE experience a loss of self tolerance. This is because of abnormal immunological function and the production of auto-antibodies; thus, leading to the formation of immune complexes that may have adverse effects on healthy tissues. Most patients also experience periodic flares of varying severity or instances in which no observable signs or symptoms are present.

Abnormal innate immune responses play significant role in the pathogenesis of SLE. They lead to tissue injury through the release of inflammatory cytokines and also to abnormal activation of auto-reactive T and B cells, with the later leading to pathogenic autoantibody production and resultant organ injury.

Due to its complex nature, SLE is sometimes known as the “disease of a thousand faces.”

 

TYPES OF LUPUS

Continue reading “LUPUS”

What is the Mechanism of Action of Corticosteroid?

 

Corticosteroid is synthetic drug that mimic the adrenal hormone, cortisol, used in the management of many inflammatory and autoimmune health conditions. They modify the functions of epidermal and dermal cells and of leukocytes involved in proliferative and inflammatory diseases of the skin.

Corticosteroids can be used in treating several health conditions, such as:

  • Asthma
  • Allergies
  • Eczema
  • Hives
  • Psoriasis
  • Chronic obstructive pulmonary disease
  • Gout
  • Lupus
  • Multiple sclerosis
  • Autoimmune diseases

Types of corticosteroids

Corticosteroids come in different forms. Some of the corticosteroids used in treating inflammations include cortisone, prednisone and methylprednisolone. Prednisone is the most commonly used type of steroids used in treating certain rheumatoid diseases like rheumatoid arthritis or lupus.

 

How to administer corticosteroid

Corticosteroid comes in different forms based on their ease of administration. They can be localized of systemic.

Localized steroids target a specific part of the body and can be applied through:

  • Eye drops
  • Ear drops
  • Skin cream and ointments
  • Inhalers

Systemic steroids circulate through the blood. They can be applied by oral, intravenous or subcutaneous injection.

 

Mechanism of action of Corticosteroids

In its mechanism of action, corticosteroid react with receptor proteins in the cytoplasm to form a steroid-receptor complex. The complex thus formed moves into the nucleus, where it binds to DNA. By binding to the DNA and changing the transcription of mRNA, corticosteroid stimulates the production of glycoprotein called Lipocortin. Lipocortin inhibits the activity of phospholipase A2, which releases arachidonic acid, the precusor of prostanoid and leukoctrienes, from phospholipids. Corticosteroid also inhibits the transcription of mRNA responsible for interleukine-1 formation. Thus, by inhibiting arachidonic acid metabolism and interleukin-1 formation, steroids produce anti-inflammatory, immunosuppressive and anti-mytogenic effects.

Adverse effects of corticosteroids

Corticosteroid in its mechanism of action, especially glucocorticosteroid, has been shown to stimulate osteoclastic activity in the first 6-12 months of therapy, followed by a decrease in bone formation and life span. It promotes the apoptosis of osteolasts and osteocytes. It can also cause adrenal suppression in patients that are been treated with it.  Other side effects of steroids include cushingoid appearance and weight gain, hyperglycemia and diabetes, cataracts and glaucoma.