We are searching data for your request:
Upon completion, a link will appear to access the found materials.
As of 2020, omeprazole is a widely used OTC medicine for various types of acute heartburn and some other gastrointestinal disorders.
Almost every time I read about it I read that one of the possible side effects is gynecomastia, which Wikipedia defines as "noncancerous increase in the size of male breast tissue".
As a non chemist (let alone biochemist), it is unknown to me why should it at least theoretically cause gynecomastia.
Are omeprazole and other (chemical family) members estrogenic and/or antiandrenergic?
There is not a lot of evidence that the compound itself is estrogenic, but it may affect how estrogen is metabolized in the body, leading to feminizing outcomes.
Pubmed is a good source for information in the biomedical literature- here is a pubmed search that has more information on those terms.
Looking through some of the results of that search, I find that there seems to be a fair amount of evidence that omeprazole has something to do with gynecomastia, but the association is not strong:
- A review of the literature has some conflicting information. One study of general practice in Britain suggested no detectable statistical relationship between taking omeprazole and gynecomastia. However, a smaller study suggested that in people who experienced gynecomastia who were also taking omeprazole, removing omeprazole helped in the majority of cases. I suggest reading the section of that review on omeprazole. The conclusion of the review is that omeprazole probably has a role in gynecomastia.
- There is a literature of studies (mostly in Spain?) ascribing omeprazole a role in gynecomastia. One example.
- There is evidence that omeprazole has a chemical effect on estrogen metabolism. However, it was much less strong than some other drugs examined.
- There is evidence that omeprazole slows the metabolism of estradiol, an active estrogen compound (see Figure 2 in the review linked above).
Overall, people seem to say it (and related compounds) probably has something to do with gynecomastia, but it is not a principal contributor on average. Possibly it shows a synergy with some other drug or some lifestyle variable.
Tamoxifen, a selective estrogen receptor modulator, is widely used in research and clinically in patients. We find that treatment of normal mice with a single ≥3 mg/20 g body weight dose of tamoxifen leads to apoptosis of >90% of all gastric parietal cells (PCs) and metaplasia of zymogenic chief cells within 3 days. Remarkably, gastric histology returns to nearly normal by 3 weeks. Tamoxifen toxicity occurs by oral and intraperitoneal administration, in both sexes, in multiple strains, and does not depend on estrogen, though acid secretion inhibition is partially protective. Thus, substantial gastric toxicity is a heretofore unappreciated tamoxifen side effect.
Conflicts of interest The authors disclose no conflicts.
Funding J.C.M. ( ACS DDC-115769, NIH DK079798-1,2 Funderburg Research Scholar Award Digestive Diseases Research Core Center: NIH 2P30 DK052574-12), W.J.H., S.K., and J.H.G. were supported in part by the Cancer Biology Pathway Program, Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes Jewish Hospital.
Chapter 8 - Osteoclast Function : Biology and Mechanisms
The main function of osteoclasts is to resorb mineralized bone, dentine, and calcified cartilage. There are at least two different routes that the multinucleated osteoclast can take after it has fulfilled its resorption task. It can either undergo fission into mononuclear cells or it can die. Solari et al. in 1995 have provided some in vitro evidence that mononuclear cells can be formed from multinucleated giant cells. Most probably, these postmitotic cells are removed by apoptosis after stopping resorption, and in fact, there is now a lot of evidence that supports this conclusion. At present, little is known about the molecular mechanisms that regulate osteoclast apoptosis in vivo. However, the induction of apoptosis in osteoclasts can be used to inhibit bone resorption and prevent bone loss. It is well established that both aminobisphosphonates and clodronate induce apoptosis in osteoclasts, but their mechanisms of action and kinetics are different. Aminobisphosphonates inhibit protein prenylation, which leads to disturbances in intracellular vesicular trafficking. Apoptosis is most probably secondary to this effect and is observed clearly after the inhibition of bone resorption. However, in case of clodronate, apoptosis in osteoclasts seems to be the primary reason for the inhibition of bone resorption. In addition to bisphosphonates, estrogen and calcitonin have been suggested to regulate osteoclast apoptosis. The importance of the fight extracellular milieu for the osteoclast phenotype and for survival is seen clearly when one compares their sensitivity to extracellular calcium. A moderate concentration of extracellular calcium has been shown to promote apoptosis in osteoclasts cultured on an artificial substrate, whereas if cultured on bone, the cells can tolerate high concentrations of extracellular calcium.
Vaccinations against other bacteria or viruses prevents the death of millions of people yearly order 20 mg omeprazole fast delivery symptoms of gastritis flare up. This is why the development of new vac- cines is a permanent aim of medical research generic omeprazole 40mg otc hemorrhagic gastritis definition. This interest grew because scientists have understood that vaccines can be used not only for prevention of infectious diseases but also for therapy buy discount omeprazole 20mg line gastritis hiv symptom, leading to the concept of therapeutic vaccines. Classical vaccines pioneered by the discoveries of Jenner, Pasteur, and Ramon was based on the principle of inactivation of pathogenicity of a microbe without altering its capacity to induce a protective immune response. Developments during the past decades in biochemistry, molecular biology, and immunology have provided new tools for the development of a new generation of vac- cines. Biochemistry and Immunochemistry contributed to the identification of epitopes endowed with protective capacities. The identification of such antigenic determinants, also called epitopes, on antigens of protein origin allowed for preparation of synthetic peptides or subunit vaccines in the case of antigens of nonprotein origin. Immunology provided the framework for understanding the mechanisms responsible for the activation of lymphocytes fol- lowing vaccination as well as functional analysis of various epitopes that induce a pro- tective immune response. This is particularly important as antibodies mediate the protection against some bacteria cellular immune responses are prevalent against obligatory intracellular microbes. The differences between B- and T-cells are not only func- tional but are also seen in the mechanism of recognition of antigens. The B-cells, via the Ig receptor, recognize both conformational and linear epitopes directly on the surface of native macromolecules. In certain cases the recognition of epitopes leads to activation and differentiation of B-cells directly, i. Whereas Th1 cells polarize the response to IgG2, the collaboration with Th2 leads to IgG1 and IgE (1). Antibodies exert their protective capacity by blocking the microbial receptor through which they bind to the cellular receptor of permissive cells, promoting phagocytosis via opsonins and complement- dependent lysis. In contrast to B-cells, T-cells are unable to recognize the antigens on the surface of native macromolecules. The peptides are derived from endogenous proteins, including proteins of intracellular microbes. Table 1 depicts the major functions of cells involved in host response to vaccines. It should exhibit a constant antigen specificity without being the subject of genetic variation 4. The preparation of inactivated vaccines is based on a golden rule emerging from Pasteur and Ramons studies leading to prepa- ration of anti-rabies and toxoid vaccines, respectively: a vaccine should be devoid of pathogenicity but should preserve intact its immunogenicity. The killing of bacteria can be achieved by physical means (heat) or by chemical agents. For example, currently used influenza and Salk polio vaccines are produced by inactivation with formalin. Similarly, the conversion of toxins to toxoids was obtained by treatment with formalin. Functional antibodies are pro- duced subsequent to recognition by the Ig receptor of B-cells of a protective epitope on the bacterial membrane or secreted toxins. Can be administered as combined vaccines such as trivalent or quatrivalent vaccines, e. Com- bined vaccines induce similar responses, as do monovalent vaccines, indicating that is no antigen competition. Poor antibody response is seen owing to weak generation of memory B-cells several boosts are often required. The antibody-mediated response against the protective epitope can be diluted by production of antibodies against the multitude of bacterial macromolecules bearing nonprotective epitopes. There is an inability to stimulate the cell-mediated immune responses that contribute to recovery from disease or alter the course of disease in the case of therapeutic vaccines. These vaccines can eas- ily be developed when the disease is caused by a single or a few serotypes of infectious agents (e. They cannot be generated when multiple serotypes are involved in path- ogenicity, as in the case of the nosocomial infection caused by Klebsiella pneumoniae. Subunit vaccines are produced by purification from bacteria of antigens bearing pro- tective epitopes or by molecular methods of expression and purification of recombi- nant proteins. With the exception of the hepatitis B subunit vaccine (which is of a protein nature), these are bacterial polysaccharides Immunity Polysaccharide vaccines are generally poor immunogens and induce T-independent responses dominated by IgM. Mutation of this gene, as in Wiscott-Aldrich syndrome, makes such patients unrespon- sive to subunit polysaccharide vaccines. Disadvantages Antibody response is generally weak, requires several boosts, and is dominated by low-affinity IgM antibodies. Generally, the vaccines are inefficient in newborns and infants because of the ontogenic delay of expression of a B-cell subset responding to polysaccharide antigens. Induction of high-affinity IgG antibodies can be obtained by coupling the polysaccharide to a protein bearing strong T-cell epitopes. Live Attenuated Vaccines The possibility of preparation of live attenuated vaccines is based on Enders (5) dis- covery of a method of culturing viruses in vitro in permissive cells. Live attenuated vaccines are produced by culturing the microbe in special conditions, leading to loss of pathogenicity without altering immunogenicity. The infected cells can produce peptides subsequent to fragmentation of endogenous viral or microbial proteins. Live attenuated vaccines elicit a long-lasting immunity comparable to that induced during natural infection. Disadvantages The preparation of live attenuated vaccines requires a tedious procedure to select the microbes that are devoid of pathogenicity, and manufacturing is costly. Internal Image Idiotype Vaccines Idiotypes are phenotypic markers of antigen receptors of lymphocytes. Idiotype are immunogenic and able to induce antiidiotypic antibodies (Ab2s), which in turn express their own idiotypes. As a statistical necessity, Jerne (6) introduced the concept that the idiotypes of antiidiotype antibodies could mimic the antigen recognized by antibody-Ab1.
These include Americans defined as having high blood pressure (tra- sedentary lifestyle purchase omeprazole 20mg amex gastritis diet herbs, obesity buy omeprazole 40mg line gastritis nutrition diet, and diets high in total and ditionally defined as a reading of 140/90 mm Hg as saturated fats omeprazole 20 mg for sale gastritis nursing diagnosis. Initial medical studies of antihypertensive treat- as less than 40 mg/dl for men but a level less than ments clearly demonstrated a benefit of treatment in 50 mg/dl is considered a marginal risk factor for women men as well as elderly women with insignificant effect and frequently is a marker of the metabolic syndrome. This was Dietary modification by reducing fat intake and likely because most trials did not include sufficient increasing fiber content is often the first step in therapy numbers of women to come to a reliable conclusion. In for those with elevated cholesterol levels and should fact, 3 of the 10 major older clinical trials (a type of be used in conjunction with drug therapy when this medical study) excluded women. Highly effective and potent medications, recent studies that clear benefit for women was demon- namely, the statin class of drugs, are now available strated. Western societies contains between 50 and 100 g of fat Most recently, the Heart Protection Study enrolled and 0. Patients treated with sim- lipoproteins lead to elevated levels of cholesterol and vastatin had a 27% reduction in major coronary events. While some individuals have This benefit was similar in both sexes and was, inter- genetic abnormalities that lead to impaired metabolism estingly, irrespective of initial cholesterol level. As is the case in patients with male patients can significantly reduce cardiovascular diabetes, management of those with the metabolic syn- complications. This is largely due to the increasing prevalence Cigarette smoking is the most important pre- of obesity as well as the aging of the population. It remains the major pre- morbidity and mortality of diabetes is mostly due to ventable cause of early death, disability, and health atherosclerosis. Estimates suggest that 11% appears that diabetes confers a higher degree of risk on of deaths in women are attributable to smoking and females than males. The number of ciga- betes have an absolute risk for coronary events similar rettes smoked per day is directly related to cardiovas- to diabetic men. Smoking as few as 14 or 514 cigarettes The metabolic changes in diabetes are complex a day increases the risk of coronary events two- to and a major reason for the increased risk is the alter- threefold. In addition, smoking is a major contribu- diabetes have a more abnormal lipid profile, which may tor to the incidence of stroke and peripheral vascular explain their particular susceptibility to atherosclerosis. Along with aggressive con- The need and benefits of smoking cessation cannot trol of the blood glucose level, other risk factors such be overemphasized. Stopping cigarette smoking is a dif- as hypertension and lipid abnormalities should be opti- ficult task and often requires a multifaceted approach mized. The target blood pressure in a patient with dia- including patient education, pharmacologic agents as betes is no more than 130/80 mm Hg as measured with well as a close partnership between the patient and the a blood pressure cuff. This is particularly important since A syndrome in which multiple cardiac risk factors data suggest that smoking cessation techniques are less are present, so-called syndrome X or insulin resis- effective in women and that women have higher tance syndrome, is marked by truncal obesity (waist of relapse rates. The National that this protein serves simply as a marker of the pres- Institutes of Health Consensus Panel on Physical ence and extent of atherosclerosis instead of playing Activity and Cardiovascular Health recommends that a a causative role. Some of the same medications used person accumulate at least 30 minutes of moderate in the treatment of elevated cholesterol levels also intensity physical activity on a daily basis. Smoking, hypertension, between elevated levels of homocysteine in the blood and diabetes were associated with a 2. This could be one of the major reasons why Hypertension, Nutrition, Smoking people seek plastic surgery. Both men and women feel the pressure to look their best, and more men are seek- Suggested Reading ing plastic surgery because of this very fact. How we feel about our- Expert Panel on Detection, Evaluation, and Treatment of High Blood selves affects how we relate to others. Journal of the American Medical many people who might be considered homely are per- Association, 285, 24862497. Mayo Clinic Proceedings, with ones self-image and allow healthy self-confidence 73, 157165. Risk factors that attenuate a psychological evaluation may be suggested prior to the female coronary disease advantage. The choice of surgeon can be the most important prevention of coronary heart disease in women. If the plastic surgeon is board eligi- Risks and benefits of estrogen plus progestin in healthy post- ble, it means that he/she has completed education, but menopausal women. In addition, a lot of the plastic surgeons have their own webpage, which can educate you about that particular person. Cosmetic Surgery Cosmetic surgery (also called Asking other patients about your surgeon can provide plastic surgery) is used both to correct true deformities very valuable information. In our culture, not cover cosmetic surgery, so checking with your there is a tremendous emphasis placed on our personal insurer is very important as well. No one ever sees a should carefully consider the risks and benefits before 200 Couples Therapy undergoing any procedure. Undergoing cosmetic assess how strong the boundaries are around the couple surgery involves a large commitment on the part of and around each individual. Suggested Resources Intergenerational Therapy as developed by Murray Website: www. Goals of therapy are to help the couple through insight, understand their family of origin issues so they are less Couples Therapy All individuals have a basic likely to repeat them. At the same time, we also have a basic need such theorists as Albert Ellis and Neil Jacobson focuses to be separate and develop our individual potential. The cognitive therapist helps Balancing these conflicting needs is the central issue of the couple pinpoint how they act toward each other to intimate relationships and helping couples establish or try to control each other in order to get their needs met. This is addressed by understanding how the destructive behavior and the beliefs that support that couple manages, respects, and accepts differences. Accepting differences supports individual development Solution-Focused Therapy as developed by Steve and frees partners to be truly intimate by reducing the DeShazer and his colleagues proposes that a couple inevitable power struggles which emerge when chang- does not need to understand a problem to develop a ing a partner takes precedence over acceptance. The focus of the work is identifying Couples therapy can address the needs of married strengths and resources to be adapted to create a solu- couples, same-sex couples, premarital couples, or cou- tion. Goal setting is central to the approach and is ples in a committed relationship who have chosen not accomplished by identifying specific behaviors and to marry. It is indicated when one or both partners feel interactions that the couple would like to increase. Couples ples previous attempts at developing solutions and therapy is not indicated if domestic violence is an issue. Often couples come for counseling at tran- arating from parents, and increasing the opportunity for sition points in their lives such as the birth of child, job developing autonomy.
In the present study, to examine the possibility that omeprazole may aggravate the effect of environmental carcinogens through CYP1A1 induction, we exposed benzo[a]pyrene and omeprazole simultaneously to human and mouse hepatoma cells. Omeprazole-induced CYP1A1 induction has been reported to be species-specific, and it induces CYP1A1 through AhR activation in human cells, but not in mouse cells and tissues [ 12 ]. Therefore, it is expected that it does not affect benzo[a]pyrene cytotoxicity in mouse Hepa-1c1c7 cells, because the expression of CYP1A1 mRNA was barely induced (fig. 2C). Omeprazole induced CYP1A1 mRNA only in human HepG2 cells (fig. 2A). Contrary to expectation, omeprazole reduced benzo[a]pyrene cytotoxicity in both mouse and human cells in a similar fashion (fig. 1). These results suggest that the CYP1A1 induction by omeprazole could be irrelevant to the aggravation of benzo[a]pyrene cytotoxicity.
The cytotoxicity of benzo[a]pyrene requires metabolic activation by specific CYPs, because it is not reactive per se. If benzo[a]pyrene metabolites such as benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide were produced by CYPs, they form DNA adducts and represent cytotoxicity. In addition, reactive oxidant species generated as a by-product of CYP-mediated metabolic processes may be also involved in the toxicity. Several CYP species involved in benzo[a]pyrene metabolism have been reported, but which CYP species mainly mediates benzo[a]pyrene cytotoxicity is still controversial [ 17, 23, 24 ]. CYP1A1/2, 1B1, 3A4, 2C8 and 2C9/10 are considered to be the candidates for benzo[a]pyrene metabolism. A cell strain derived from Hepa-1c1c7 cells lacking AhR expression proved to be benzo[a]pyrene-resistant [ 19 ], which suggests that the manifestation of benzo[a]pyrene cytotoxicity requires the AhR-mediated induction of particular CYPs, CYP1A1, CYP1A2, CYP1B1 and CYP3A4. In HepG2 cells, CYP1A1 was induced by omeprazole alone, but the high level of CYP1A1 induced by benzo[a]pyrene was not affected by the simultaneous omeprazole treatment (figs 2A,B and 3). These results suggest that activation of the AhR pathway by omeprazole could not be involved in the aggravation of benzo[a]pyrene cytotoxicity in HepG2 cells.
The EROD assay clearly showed that omeprazole inhibits the EROD activity (i.e. CYP1A1/1A2 activity) [ 25 ], in intact Hepa-1c1c7 cells (fig. 4C). The experiment using recombinant human CYPs revealed that omeprazole has potent inhibitory activity against CYP1A1 and CYP3A4, but not against CYP1A2 (fig. 6). The CYP1B1 activity was not measured, because this enzyme is not expressed in HepG2 cells [ 8, 26 ]. These results suggest that omeprazole alleviated benzo[a]pyrene cytotoxicity by directly inhibiting the CYP1A1 and/or CYP3A4 enzymatic activity.
We examined the effects of ellipticine, a CYP1A1 inhibitor [ 27 ], and ketoconazole, a CYP3A4 inhibitor [ 28 ], on benzo[a]pyrene cytotoxicity to confirm which CYP dominantly contributes to the toxicity. Ketoconazole reduced benzo[a]pyrene cytotoxicity in Hepa-1c1c7 cells only at high doses (>10 µM) (fig. 5). However, it has been reported that ketoconazole inhibits CYP3A4 at much lower doses (<1 µM). For example, ketoconazole inhibits testosterone 11β-hydroxylation with IC50 value at 0.03 µM, and erythromycin N-demethylation with Ki value at 0.7 µM [ 29, 30 ]. These results show that CYP3A4 should not contribute dominantly to benzo[a]pyrene cytotoxicity. In contrast, the CYP1A1 inhibitor ellipticine completely blocked benzo[a]pyrene cytotoxicity (fig. 5). The kinetic analysis revealed that omeprazole is a potent inhibitor of CYP1A1, because the affinity of omeprazole to the enzyme is stronger than that to the substrate, that is, the Ki value (3.21 µM) is smaller than the Km value (50.1 µM) (fig. 7). These results ensure that CYP1A1 dominantly contributes to benzo[a]pyrene cytotoxicity. We have determined the inhibition effect of omeprazole on CYP1A1 enzyme by using recombinant human CYP1A1. We expect mouse CYP1A1 also to be inhibited by omeprazole, because similar results of EROD activity inhibition were obtained in Hepa1c1c7 and HepG2 cells in our study (fig. 4).
Taken together, these findings indicate that omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibiting the CYP1A1 activity in Hepa-1c1c7 and HepG2 cells. CYP1A1 is also a member of the CYP enzyme group that can be inhibited by omeprazole. The protection effect of omeprazole on the cytotoxicity of benzo[a]pyrene is more significant in Hepa1c1c7 than in HepG2 cells (fig. 1), although inhibition of EROD activity was comparable in both cell lines (fig. 4). Other causes, such as susceptibility to the reactive oxygen species, expression pattern of CYP species and the presence of omeprazole metabolites, may be involved in the protection effect, and these factors may be different between the two cell lines.
Figures 2 and 3 show that omeprazole concentration higher than 50 µM is required for the AhR-mediated CYP1A1 induction in HepG2 cells. This omeprazole concentration inhibits recombinant human CYP1A1 activity to less than 10% (fig. 6) and EROD activity in benzo[a]pyrene-treated HepG2 cells (fig. 4B). These results suggest that sufficiently high omeprazole concentrations to induce CYP1A1 inhibits CYP1A1 enzymatic activity, which in turn might indicate that omeprazole could not aggravate the effects of benzo[a]pyrene-type precarcinogens, which are chemicals metabolically activated by CYP1A1 through the AhR pathway.
Some phytochemicals, such as flavones and anthraquinone, have activities for both induction and inhibition of CYP1A1 [ 31-34 ]. Berberine, a plant isoquinoline alkaloid, has this ‘biphasic effect’ on CYP1A1 and has been used as a therapeutic agent like omeprazole [ 35 ]. To examine the aggravating effects of these chemicals on precarcinogens, it is necessary to carry out experiments similar to those of our present study.
3. Structure-Function Relationships
The molecular basis of CAC substrate-binding and transport, as well as its regulation by post-translational modifications, have been explored using the site-directed mutagenesis approach complemented with bioinformatics and chemical targeting, together with parallel investigations in intact mitochondria to explore the physiological roles of these modifications. Together with those regarding the oxoglutarate carrier [96,97,98], the structure/function relationship studies concerning CAC are the most advanced within the mitochondrial carrier family members. These studies started with the construction of the homology model of CAC in its cytosolic open conformation based on the ADP/ATP carrier (AAC, SLC25A4) structure . Later, the structural fold and dynamics have been updated with the homology model of the matrix open conformation of CAC obtained by using the recently solved AAC structure in its matrix open conformation as a template . The molecular map of the amino acids involved in the catalytic process of CAC has been defined together with the role of specific residues in the molecular mechanism of transport and the regulation of the carrier function.
3.1. Substrate Binding Site and Translocation Events
The residues responsible for substrate-binding were first hypothesized by bioinformatics in some yeast carriers, including the homolog of the human CAC [100,101]. Then, the identification of the amino acid residues of the mammalian CAC involved in substrate-binding and translocation has been conducted, exploiting site-directed mutagenesis, on the rat and human CACs that are virtually coincident, being 92% identical. The impairment or loss of function observed in conservative or non-conservative mutants, respectively, clearly demonstrated the role of each crucial residue in terms of the importance of the chemical features of the amino acid side-chains. As reported below, the amino acids involved in carnitine binding/translocation have been mapped. Asp-179, Arg-275, and Arg-178 ( Figure 3 a) undergo ionic and/or hydrogen bond interactions with carnitine, being involved in binding the trimethylammonium and the carboxyl groups, respectively. These charged residues that line the central water-filled cavity of the transport protein are conserved along with the CAC orthologs  according to their important role. The electric charges of the residues at positions 179 and 275 are more important than the side-chain length since the Vmax and/or the Km values show the greatest changes upon substituting the charged residues with neutral ones. In line with the crucial role of Arg-275, the point mutation Arg275Gln in the CAC of three patients was associated with severe carnitine deficiency . His-29 is also conserved throughout the CAC sub-family members. The mutation of His-29 with Ala, Asp, Lys, Phe, Asn, or Tyr severely impairs the function. Only if His-29 is substituted by Gln, the activity of the transporter is comparable to that of the wild-type CAC. Indeed, the N amide of Gln structurally corresponds to the τ-N (distal) of the His-29 imidazole, indicating that the main role of His-29 in the formation of an H-bond with the substrate. This bond is established with the β-OH of carnitine or with the β-O- of acyl-carnitines. Therefore, His-29 plays a role in facilitating the correct positioning of the substrate preceding the translocation event towards the opposite side of the membrane ( Figure 3 b) .
Ribbon diagrams of CAC showing the amino acids involved in carnitine binding. (a) Lateral view of the CAC structural model. The residues Arg-178, Asp-179, Arg-275, and His-29 are highlighted with a ball and stick representation. The transmembrane spanning α-helices are numbered. (b) Enlarged view of the residues interacting with carnitine. The dotted line indicates the following step in the translocation process in which carnitine will interact with His-29 before the matrix gate opens (see also Figure 5). Amino acid residues are dispayed with ball and stick rappresentation in which oxygen and nitrogen atoms are depicted in red and blu respectively. CAC model and carnitine position have been obtained as .
Besides carnitine, acyl-carnitines are transported by CAC. These carnitine derivatives contain hydrophobic chains, esterified to the hydroxyl group of carnitine, with a length ranging from 2 (acetyl) to 16 (palmitoyl) or more carbon atoms. Val-25, Pro-78, Val-82, Met-84, and Cys-89, all belonging to the first and second transmembrane α-helices of the protein (H1-H2), constitute the “hydrophobic pocket” of CAC that binds the carbon chain of the acyl-carnitines ( Figure 4 ). The ability of this “hydrophobic pocket” to interact with hydrophobic molecules correlates well with the higher average hydrophobicity of transmembrane α-helices H1 and H2 of CAC concerning that of the corresponding α-helices of the other members of the SLC25 family [66,100].
Lateral view of the CAC structural model highlighting the residues involved in binding the acyl moieties of acyl-carnitines. CAC residues are displayed with sphere representation.
Once the carnitine or the acyl-carnitine has interacted with the proper residues in the c-state, a charged gate constituted by the amino acid side chains of Asp-32, Lys-35, Glu-132, Lys-135, Asp-231, and Lys-234 ( Figure 5 a) located below the binding site, needs to be unlocked for the translocation to occur [99,104,105,106,107]. The six residues form three ion pairs resulting from the interactions between the couples: Asp-32 with Lys-135, Glu-132 with Lys-234, and Asp-231 with Lys-35. The role of these residues and their interactions have been validated using the mutagenesis approach . Once the gate is opened by the fast interaction of the substrate with at least one of the charged residues, i.e., Lys-35, the carrier changes its conformation from the cytosolic state opened to the matrix opened state. The protein is stabilized in the matrix opened conformation by a gate, similar to the matrix one that is formed towards the cytosolic face and is composed of four charged residues, namely, Lys-97, Glu-191, Lys-194, and Glu-288 ( Figure 5 b). The other two residues of the cytosolic gate of CAC are uncharged in contrast to the corresponding residues of other carriers [96,106]. The free energy of the cytosolic gate of CAC is, therefore, lower than that of the matrix gate. This probably determines an imperfect coupling of the flux of substrates in the outward and inward directions, conferring to CAC the capacity to mediate a uniport reaction besides the antiport reaction [31,106].
Lateral views of CAC highlighting the residues of the matrix and cytosolic gates. (a) The residues Asp-32, Lys-35, Glu-132, Lys-135, Asp-231, and Lys-234 forming the matrix gate are depicted in red (negatively charged residues) or in blue (positively charged residues) (b) the residues Lys-97, Glu-191, Lys-194, and Glu-288 forming the cytosolic gate are depicted in red (negatively charged residues) or in blue (positively charged residues).
3.2. The Molecular Basis of the Antiport Mode
CAC shares with the other mitochondrial carriers the peculiar structure constituted by six transmembrane segments arranged in three intramembrane domains, which rotate to allow the conformational changes required for the transport reaction . The antiport mode of transport is determined by the coupling of substrate-binding with gate opening on one side and gate closing on the other side. Indeed, given that the substrate considerably decreases the activation free-energy barrier of the carrier transition, the rate of transition of the unbound carrier from an outward open conformation (c-state) to the inward open one (m-state) or vice versa ( Figure 6 ) is much lower than that of the substrate-bound carrier .
Sketch of the transport cycle of CAC. The states of the transporter during the antiport reaction are displayed: (1) c-state in the absence of substrate, (2) c-state with the external substrate entering the carrier, (3) occluded state or transition state with the external substrate bound to the substrate-binding site, (4) m-state in the absence of substrate, (5) m-state with the internal substrate entering the carrier, (6) occluded state or transition state with the internal substrate bound to the substrate-binding site. The role of K35 and W224 during the transport cycle is highlighted with dotted lines.
In the case of CAC, the identification of the residues, which are crucial for the coupling of substrate-binding with gate opening, was achieved by mutations that specifically abolish the antiport function without interfering with the uniport function. One of these residues is Lys-35, whose substitution with an uncharged residue impairs the antiport reaction, suggesting that Lys-35 interacts with the carboxyl group of carnitine favoring the gate opening . The companion amino acid residue involved in binding the ammonium group of carnitine is Trp-224, whose substitution completely abolishes the antiport function and converts the protein into a uniporter with a specific activity and substrate specificity equal to those of the unidirectional transport activity of the wild-type CAC. The distance between Lys-35 and Trp-224 in the cytosolic open conformation ( Figure 7 a) corresponds to the distance between the ammonium and the carboxyl groups of carnitine, in line with the interaction of carnitine with these residues, which triggers the gate opening and closing. The distance between these residues increases in the matrix open conformation preceding the substrate release ( Figure 7 b). In the absence of the interaction of carnitine with Lys-35 and Trp-224, the CAC gate could open as well, but at a much lower rate constant leading to the uniport function. Trp-224 is conserved in all CAC sub-family members. Indeed, the substitution of this residue in the CAC of A. nidulans leads to the same alterations as in the mammalian transporter, indicating that the molecular determinant of the antiport function has been conserved during evolution . Interestingly, a corresponding Trp residue is not present in the other proteins of the SLC25 family except in the ornithine/citrulline carrier, whose substrate, ornithine, harbors a positively charged amino group. In this carrier, the substitution of the Trp unveils a low rate of uniport activity [110,111].
Lateral views of the CAC structural model showing the residues involved in the coupling of substrate-binding with gate opening and gate closing. (a) Ribbon diagram of the carrier in c-state in which the residues Trp 224 and K35 are at a distance of 4 Å and are depicted with a ball and stick (b) ribbon diagram of the carrier in m-state in which the residues Trp 224 and K35 are at a distance of 12 Å and are depicted in ball and stick.
Omeprazole enhances the colonic expression of the Mg2+ transporter TRPM6
Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, used by millions of patients suffering from gastric acid-related complaints. Although PPIs have an excellent safety profile, an increasing number of case reports describe patients with severe hypomagnesemia due to long-term PPI use. As there is no evidence of a renal Mg2+ leak, PPI-induced hypomagnesemia is hypothesized to result from intestinal malabsorption of Mg2+. The aim of this study was to investigate the effect of PPIs on Mg2+ homeostasis in an in vivo mouse model. To this end, C57BL/6J mice were treated with omeprazole, under normal and low dietary Mg2+ availability. Omeprazole did not induce changes in serum Mg2+ levels (1.48&thinsp±&thinsp0.05 and 1.54&thinsp±&thinsp0.05 mmol/L in omeprazole-treated and control mice, respectively), urinary Mg2+ excretion (35&thinsp±&thinsp3 &mumol/24 h and 30&thinsp±&thinsp4 &mumol/24 h in omeprazole-treated and control mice, respectively), or fecal Mg2+ excretion (84&thinsp±&thinsp4 &mumol/24 h and 76&thinsp±&thinsp4 &mumol/24 h in omeprazole-treated and control mice, respectively) under any of the tested experimental conditions. However, omeprazole treatment did increase the mRNA expression level of the transient receptor potential melastatin 6 (TRPM6), the predominant intestinal Mg2+ channel, in the colon (167&thinsp±&thinsp15 and 100&thinsp±&thinsp7 % in omeprazole-treated and control mice, respectively, P&thinsp<&thinsp0.05). In addition, the expression of the colonic H+,K+-ATPase (cHK-&alpha), a homolog of the gastric H+,K+-ATPase that is the primary target of omeprazole, was also significantly increased (354&thinsp±&thinsp43 and 100&thinsp±&thinsp24 % in omeprazole-treated and control mice, respectively, P&thinsp<&thinsp0.05). The expression levels of other magnesiotropic genes remained unchanged. Based on these findings, we hypothesize that omeprazole inhibits cHK-&alpha activity, resulting in reduced extrusion of protons into the large intestine. Since TRPM6-mediated Mg2+ absorption is stimulated by extracellular protons, this would diminish the rate of intestinal Mg2+ absorption. The increase of TRPM6 expression in the colon may compensate for the reduced TRPM6 currents, thereby normalizing intestinal Mg2+ absorption during omeprazole treatment in C57BL/6J mice, explaining unchanged serum, urine, and fecal Mg2+ levels.
Pflügers Archiv European Journal of Physiologyl of Physiology &ndash Springer Journals
Prevention of Osteoporosis
Prevention of osteoporosis is generally more successful than treatment because it is easier to prevent loss of bone density than to restore density once it has been lost. Prevention measures are recommended for anyone who has bone loss or who has risk factors for bone loss, regardless of whether they have had an osteoporosis-related fracture. Osteoporosis prevention involves
Managing risk factors (for example, quitting smoking and avoiding excess alcohol and caffeine use)
Consuming adequate amounts of calcium and vitamin D
Engaging in weight-bearing exercise (such as walking, climbing stairs, or weight training)
Certain measures can help prevent fractures. Many older people are at risk of falls because of poor coordination, poor vision, muscle weakness, confusion, and use of drugs that cause light-headedness when people stand or of drugs that cause confusion. Modifying the home environment for safety and working with a physical therapist to develop an exercise program can help. Strengthening exercises, including core strengthening, may help improve balance.
Quercetin is a very popular flavonoid. The supplement has been linked to reduced blood sugar levels, blood pressure, inflammation, and enhanced exercise performance. Scientists also believe that quercetin has anticancer, anti-allergy, and brain-protective properties.
If you want to supplement your diet with quercetin, you should seek advice from a doctor or a healthcare provider first. Finally, ensure you buy quercetin powder only from reputable suppliers.
Co-founder, the company’s core administration leadership PhD received from Fudan University in organic chemistry. More than nine years of experience in organic synthesis field of medicinal chemistry. Rich experience in combinatorial chemistry, medicinal chemistry and custom synthesis and project management.
- For stress: Ashwagandha root extract 300 mg twice daily after food (KSM66, Ixoreal Biomed) or 240 mg daily (Shoden, Arjuna Natural Ltd.) for 60 days.
Ahumada F, Aspee F, Wikman G, and et al. Withania somnifera extract. Its effect on arterial blood pressure in anaesthetized dogs. Phytotherapy Research 19915:111-114.
Anbalagan K and Sadique J. Withania somnifera (ashwagandha), a rejuvenating herbal drug which controls alpha-2 macroglobulin synthesis during inflammation. Int.J.Crude Drug Res. 198523(4):177-183.
Anbalagan, K. and Sadique, J. Influence of an Indian medicine (Ashwagandha) on acute-phase reactants in inflammation. Indian J Exp Biol. 198119(3):245-249. View abstract.
Begum, V. H. and Sadique, J. Long term effect of herbal drug Withania somnifera on adjuvant induced arthritis in rats. Indian J Exp Biol. 198826(11):877-882. View abstract.
Bhat, J., Damle, A., Vaishnav, P. P., Albers, R., Joshi, M., and Banerjee, G. In vivo enhancement of natural killer cell activity through tea fortified with Ayurvedic herbs. Phytother.Res 201024(1):129-135. View abstract.
Bhattacharya, S. K. and Muruganandam, A. V. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem.Behav 200375(3):547-555. View abstract.
Bhattacharya, S. K., Bhattacharya, A., Sairam, K., and Ghosal, S. Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine 20007(6):463-469. View abstract.
Choudhary, M. I., Nawaz, S. A., ul-Haq, Z., Lodhi, M. A., Ghayur, M. N., Jalil, S., Riaz, N., Yousuf, S., Malik, A., Gilani, A. H., and ur-Rahman, A. Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. Biochem.Biophys.Res Commun. 8-19-2005334(1):276-287. View abstract.
Davis, L. and Kuttan, G. Effect of Withania somnifera on DMBA induced carcinogenesis. J Ethnopharmacol. 200175(2-3):165-168. View abstract.
Deocaris, C. C., Widodo, N., Wadhwa, R., and Kaul, S. C. Merger of ayurveda and tissue culture-based functional genomics: inspirations from systems biology. J.Transl.Med. 20086:14. View abstract.
Devi, P. U., Sharada, A. C., and Solomon, F. E. Antitumor and radiosensitizing effects of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma-180. Indian J Exp Biol. 199331(7):607-611. View abstract.
Devi, P. U., Sharada, A. C., and Solomon, F. E. In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma. Cancer Lett. 8-16-199595(1-2):189-193. View abstract.
Devi, P. U., Sharada, A. C., Solomon, F. E., and Kamath, M. S. In vivo growth inhibitory effect of Withania somnifera (Ashwagandha) on a transplantable mouse tumor, Sarcoma 180. Indian J Exp Biol. 199230(3):169-172. View abstract.
Dhuley, J. N. Effect of ashwagandha on lipid peroxidation in stress-induced animals. J Ethnopharmacol. 199860(2):173-178. View abstract.
Dhuley, J. N. Therapeutic efficacy of Ashwagandha against experimental aspergillosis in mice. Immunopharmacol.Immunotoxicol. 199820(1):191-198. View abstract.
Ghosal S, Lal J, Srivastava R, and et al. Immunomodulatory and CNS effects of sitoindosides 9 and 10, two new glycowithanolides from Withania somnifera. Phytotherapy Research 19893(5):201-206.
Gupta, S. K., Dua, A., and Vohra, B. P. Withania somnifera (Ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications. Drug Metabol.Drug Interact. 200319(3):211-222. View abstract.
Kaur, K., Rani, G., Widodo, N., Nagpal, A., Taira, K., Kaul, S. C., and Wadhwa, R. Evaluation of the anti-proliferative and anti-oxidative activities of leaf extract from in vivo and in vitro raised Ashwagandha. Food Chem.Toxicol. 200442(12):2015-2020. View abstract.
Khattak, S., Saeed, Ur Rehman, Shah, H. U., Khan, T., and Ahmad, M. In vitro enzyme inhibition activities of crude ethanolic extracts derived from medicinal plants of Pakistan. Nat.Prod.Res 200519(6):567-571. View abstract.
Kulkarni, S. K. and Dhir, A. Withania somnifera: an Indian ginseng. Prog.Neuropsychopharmacol.Biol.Psychiatry 7-1-200832(5):1093-1105. View abstract.
Kuppurajan K, Rajagopalan SS, Sitoraman R, and et al. Effect of Ashwagandha (Withania somnifera Dunal) on the process of ageing on human volunteers. Journal of Research in Ayurveda and Siddha 19801(2):247-258.
Lu, L., Liu, Y., Zhu, W., Shi, J., Liu, Y., Ling, W., and Kosten, T. R. Traditional medicine in the treatment of drug addiction. Am J Drug Alcohol Abuse 200935(1):1-11. View abstract.
Malhotra, C. L., Mehta, V. L., Das, P. K., and Dhalla, N. S. Studies on Withania-ashwagandha, Kaul. V. The effect of total alkaloids (ashwagandholine) on the central nervous system. Indian J Physiol Pharmacol. 19659(3):127-136. View abstract.
Malhotra, C. L., Mehta, V. L., Prasad, K., and Das, P. K. Studies on Withania ashwagandha, Kaul. IV. The effect of total alkaloids on the smooth muscles. Indian J Physiol Pharmacol. 19659(1):9-15. View abstract.
Malviya, N., Jain, S., Gupta, V. B., and Vyas, S. Recent studies on aphrodisiac herbs for the management of male sexual dysfunction--a review. Acta Pol.Pharm. 201168(1):3-8. View abstract.
Mikolai, J., Erlandsen, A., Murison, A., Brown, K. A., Gregory, W. L., Raman-Caplan, P., and Zwickey, H. L. In vivo effects of Ashwagandha (Withania somnifera) extract on the activation of lymphocytes. J.Altern.Complement Med. 200915(4):423-430. View abstract.
Praveenkumar, V., Kuttan, R., and Kuttan, G. Chemoprotective action of Rasayanas against cyclosphamide toxicity. Tumori 8-31-199480(4):306-308. View abstract.
Sehgal, V. N., Verma, P., and Bhattacharya, S. N. Fixed-drug eruption caused by ashwagandha (Withania somnifera): a widely used Ayurvedic drug. Skinmed. 201210(1):48-49. View abstract.
Sharada, A. C., Solomon, F. E., Devi, P. U., Udupa, N., and Srinivasan, K. K. Antitumor and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma in vivo. Acta Oncol. 199635(1):95-100. View abstract.
Singh, R. H., Narsimhamurthy, K., and Singh, G. Neuronutrient impact of Ayurvedic Rasayana therapy in brain aging. Biogerontology. 20089(6):369-374. View abstract.
Tohda, C. [Overcoming several neurodegenerative diseases by traditional medicines: the development of therapeutic medicines and unraveling pathophysiological mechanisms]. Yakugaku Zasshi 2008128(8):1159-1167. View abstract.
Upadhaya L and et al. Role of an indigenous drug Geriforte on blood levels of biogenic amines and its significance in the treatment of anxiety neurosis. Acta Nerv Super 199032(1):1-5.
Vaishnavi, K., Saxena, N., Shah, N., Singh, R., Manjunath, K., Uthayakumar, M., Kanaujia, S. P., Kaul, S. C., Sekar, K., and Wadhwa, R. Differential activities of the two closely related withanolides, Withaferin A and Withanone: bioinformatics and experimental evidences. PLoS.One. 20127(9):e44419. View abstract.
Ven Murthy, M. R., Ranjekar, P. K., Ramassamy, C., and Deshpande, M. Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha. Cent.Nerv.Syst.Agents Med.Chem. 9-1-201010(3):238-246. View abstract.
Venkataraghavan S, Seshadri C, Sundaresan TP, and et al. The comparative effect of milk fortified with Aswagandha, Aswagandha and Punarnava in children - a double-blind study. J Res Ayur Sid 19801:370-385.
Agarwal R, Diwanay S, Patki P, Patwardhan B. Studies on immunomodulatory activity of Withania somnifera (Ashwagandha) extracts in experimental immune inflammation. J Ethnopharmacol 199967:27-35. View abstract.
Agnihotri AP, Sontakke SD, Thawani VR, Saoji A, Goswami VS. Effects of Withania somnifera in patients of schizophrenia: a randomized, double blind, placebo controlled pilot trial study. Indian J Pharmacol. 201345(4):417-8. View abstract.
Ahmad MK, Mahdi AA, Shukla KK, et al. Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril 201094:989-96. View abstract.
Ahumada F, Aspee F, Wikman G, Hancke J. Withania somnifera exract. Its effects on arterial blood pressure in anaesthetized dogs. Phytother Res 19915:111-14.
Ambiye VR, Langade D, Dongre S, Aptikar P, Kulkarni M, Dongre A. Clinical Evaluation of the Spermatogenic Activity of the Root Extract of Ashwagandha (Withania somnifera) in Oligospermic Males: A Pilot Study. Evid Based Complement Alternat Med. 20132013:571420. View abstract.
Andallu B, Radhika B. Hypoglycemic, diuretic and hypocholesterolemic effect of winter cherry (Withania somnifera, Dunal) root. Indian J Exp Biol 200038:607-9. View abstract.
Archana R, Namasivayam A. Antistressor effect of Withania somnifera. J Ethnopharmacol 199964:91-3. View abstract.
Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol 199735:236-9. View abstract.
Biswal BM, Sulaiman SA, Ismail HC, Zakaria H, Musa KI. Effect of Withania somnifera (Ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther. 201312(4):312-22. View abstract.
Björnsson HK, Björnsson ES, Avula B, et al. Ashwagandha-induced liver injury: A case series from Iceland and the US Drug-Induced Liver Injury Network. Liver Int. 202040(4):825-829. View abstract.
Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 201234(3):255-62. View abstract.
Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 201374(11):1076-83. View abstract.
Choudhary D, Bhattacharyya S, Joshi K. Body weight management in adults under chronic stress through treatment with ashwagandha root extract: a double-blind, randomized, placebo-controlled trial. J Evid Based Complementary Altern Med. 2017 Jan22(1):96-106 View abstract.
Cooley K, Szczurko O, Perri D, et al. Naturopathic care for anxiety: a randomized controlled trial ISRC TN78958974. PLoS One 20094:e6628. View abstract.
Dasgupta A, Peterson A, Wells A, Actor JK. Effect of Indian Ayurvedic medicine Ashwagandha on measurement of serum digoxin and 11 commonly monitored drugs using immunoassays: study of protein binding and interaction with Digibind. Arch Pathol Lab Med 2007131:1298-303. View abstract.
Dasgupta A, Tso G, Wells A. Effect of Asian ginseng, Siberian ginseng, and Indian ayurvedic medicine Ashwagandha on serum digoxin measurement by Digoxin III, a new digoxin immunoassay. J Clin Lab Anal 200822:295-301. View abstract.
Davis L, Kuttan G. Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice. J Ethnopharmacol 199862:209-14. View abstract.
Davis L, Kuttan G. Effect of Withania somnifera on cyclophosphamide-induced urotoxicity. Cancer Lett 2000148:9-17. View abstract.
Deshpande A, Irani N, Balkrishnan R, Benny IR. A randomized, double blind, placebo controlled study to evaluate the effects of ashwagandha (Withania somnifera) extract on sleep quality in healthy adults. Sleep Med. 202072:28-36. View abstract.
Dongre S, Langade D, Bhattacharyya S. Efficacy and safety of ashwagandha (withania somnifera) root extract in improving sexual function in women: a pilot study. Biomed Res Int 20152015:284154.View abstract.
Durg S, Bavage S, Shivaram SB. Withania somnifera (Indian ginseng) in diabetes mellitus: A systematic review and meta-analysis of scientific evidence from experimental research to clinical application. Phytother Res. 202034(5):1041-1059. View abstract.
Fuladi S, Emami SA, Mohammadpour AH, Karimani A, Manteghi AA, Sahebkar A. Assessment of Withania somnifera root extract efficacy in patients with generalized anxiety disorder: A randomized double-blind placebo-controlled trial. Curr Clin Pharmacol. 2020. View abstract.
Jahanbakhsh SP, Manteghi AA, Emami SA, Mahyari S, et al. Evaluation of the efficacy of withania somnifera (ashwagandha) root extract in patients with obsessive-compulsive disorder: a randomized double-blind placebo-controlled trial. Complement Ther Med 2016 Aug27:25-9.View abstract.
Katz M, Levine AA, Kol-Degani H, Kav-Venaki L. A compound herbal preparation (CHP) in the treatment of children with ADHD: a randomized controlled trial. J Atten Disord 201014:281-91. View abstract.
Kelgane SB, Salve J, Sampara P, Debnath K. Efficacy and tolerability of ashwagandha root extract in the elderly for improvement of general well-being and sleep: A prospective, randomized, double-blind, placebo-controlled study. Cureus. 202012(2):e7083. View abstract.
Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol 199133:91-5. View abstract.
Kumar G, Srivastava A, Sharma SK, Rao TD, Gupta YK. Efficacy and safety evaluation of ayurvedic treatment (ashwagandha powder and sidh makardhwaj) in rheumatoid arthritis patients: a pilot perspective study. Indian J Med Res 2015 Jan141(1):100-6. View abstract.
Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine (Baltimore). 201998(37):e17186. View abstract.
Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 20005:334-46. View abstract.
Nagashayana N, Sankarankutty P, Nampoothiri MRV, et al. Association of l-DOPA with recovery following Ayurveda medication in Parkinson's Disease. J Neurol Sci 2000176:124-7. View abstract.
Panda S, Kar A. Changes in thyroid hormone concentrations after administration of ashwagandha root extract to adult male mice. J Pharm Pharmacol 199850:1065-68. View abstract.
Panda S, Kar A. Withania somnifera and Bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice. J Ethnopharmacol 199967:233-39. View abstract.
Pérez-Gómez J, Villafaina S, Adsuar JC, Merellano-Navarro E, Collado-Mateo D. Effects of ashwagandha (Withania somnifera) on VO2max: A systematic review and meta-analysis. Nutrients. 202012(4):1119. View abstract.
Salve J, Pate S, Debnath K, Langade D. Adaptogenic and anxiolytic effects of ashwagandha root extract in healthy adults: A double-blind, randomized, placebo-controlled clinical study. Cureus. 201911(12):e6466. View abstract.
Sharma AK, Basu I, Singh S. Efficacy and safety of Ashwagandha root extract in subclinical hypothyroid patients: a double-blind, randomized placebo-controlled trial. J Altern Complement Med. 2018 Mar24(3):243-248. View abstract.
Sriranjini SJ, Pal PK, Devidas KV, Ganpathy S. Improvement of balance in progressive degenerative cerebellar ataxias after Ayurvedic therapy: a preliminary report. Neurol India 200957:166-71. View abstract.
Sud Khyati S, Thaker B. A randomized double blind placebo controlled study of ashwagandha on generalized anxiety disorder. Int Ayurvedic Med J 20131(5):1-7.
Upton R, ed. Ashwagandha Root (Withania somnifera): Analytical, quality control, and therapuetic monograph. Santa Cruz, CA: American Herbal Pharmacopoeia 2000:1-25.